title: In vivo structure and dynamics of the RNA genome of SARS-Cov-2

abstract: The SARS-CoV-2 coronavirus, which causes the COVID-19 pandemic, is one of the largest positive strand RNA viruses. Here we developed a simplified SPLASH assay and comprehensively mapped the in vivo RNA-RNA interactome of SARS-CoV-2 RNA during the viral life cycle. We observed canonical and alternative structures including 3-UTR and 5-UTR, frameshifting element (FSE) pseudoknot and genome cyclization in cells and in virions. We provide direct evidence of interactions between Transcription Regulating Sequences (TRS-L and TRS-Bs), which facilitate discontinuous transcription. In addition, we reveal alternative short and long distance arches around FSE, forming a "high-order pseudoknot" embedding FSE, which might help ribosome stalling at frameshift sites. More importantly, we found that within virions, while SARS-CoV-2 genome RNA undergoes intensive compaction, genome cyclization is weakened and genome domains remain stable. Our data provides a structural basis for the regulation of replication, discontinuous transcription and translational frameshifting, describes dynamics of RNA structures during life cycle of SARS-CoV-2, and will help to develop antiviral strategies.


title: Structural characterization of cocktail-like targeting polysaccharides from Ecklonia kurome Okam and their anti-SARS-CoV-2 activities in vitro

abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent responsible for the worldwide coronavirus disease 2019 (COVID-19) outbreak. Investigation has confirmed that polysaccharide heparan sulfate can bind to the spike protein and block SARS-CoV-2 infection. Theoretically, similar structure of nature polysaccharides may also have the impact on the virus. Indeed, some marine polysaccharide has been reported to inhibit SARS-Cov-2 infection in vitro, however the convinced targets and mechanism are still vague. By high throughput screening to target 3CLpro enzyme, a key enzyme that plays a pivotal role in the viral replication and transcription using nature polysaccharides library, we discover the mixture polysaccharide 375 from seaweed Ecklonia kurome Okam completely block 3Clpro enzymatic activity (IC50, 0.48 {micro}M). Further, the homogeneous polysaccharide 37502 from the 375 may bind to 3CLpro molecule well (kD value : 4.23 x 10-6). Very interestingly, 37502 also can potently disturb spike protein binding to ACE2 receptor (EC50, 2.01 {micro}M). Importantly, polysaccharide 375 shows good anti-SARS-CoV-2 infection activity in cell culture with EC50 values of 27 nM (99.9% inhibiting rate at the concentration of 20 {micro}g/mL), low toxicity (LD50: 136 mg/Kg on mice). By DEAE ion-exchange chromatography, 37501, 37502 and 37503 polysaccharides are purified from native 375. Bioactivity test show that 37501 and 37503 may impede SARS-Cov-2 infection and virus replication, however their individual impact on the virus is significantly less that of 375. Surprisingly, polysaccharide 37502 has no inhibition effect on SARS-Cov-2. The structure study based on monosaccharide composition, methylation, NMR spectrum analysis suggest that 375 contains guluronic acid, mannuronic acid, mannose, rhamnose, glucouronic acid, galacturonic acid, glucose, galactose, xylose and fucose with ratio of 1.86 : 9.56 : 6.81 : 1.69 : 1.00 : 1.75 : 1.19 : 11.06 : 4.31 : 23.06. However, polysaccharide 37502 is an aginate which composed of mannuronic acid (89.3 %) and guluronic acid (10.7 %), with the molecular weight (Mw) of 27.9 kDa. These results imply that mixture polysaccharides 375 works better than the individual polysaccharide on SARS-Cov-2 may be the cocktail-like polysaccharide synergistic function through targeting multiple key molecules implicated in the virus infection and replication. The results also suggest that 375 may be a potential drug candidate against SARS-CoV-2.

category: biochemistry


title: Enhanced Cholesterol-dependent Hemifusion by Internal Fusion Peptide 1 of SARS Coronavirus-2 Compared to its N-terminal Counterpart

abstract: Membrane fusion is an important step for the entry of the lipid-sheathed viruses into the host cells. The fusion process is being carried out by fusion proteins present in the viral envelope. The class I viruses contains a 20-25 amino acid sequence at its N-terminal of the fusion domain, which is instrumental in fusion, and is termed as  fusion peptide. However, Severe Acute Respiratory Syndrome Coronavirus (SARS) coronaviruses contain more than one fusion peptide sequences. We have shown that the internal fusion peptide 1 (IFP1) of SARS-CoV is far more efficient than its N-terminal counterpart (FP) to induce hemifusion between small unilamellar vesicles. Moreover, the ability of IFP1 to induce hemifusion formation increases dramatically with growing cholesterol content in the membrane. Interestingly, IFP1 is capable of inducing hemifusion, but fails to open pore.

category: biophysics


title: Comprehensive mapping of local and diaspora scientists: a database and analysis of 63951 Greek scientists

abstract: Research policy and planning for a given country may benefit from reliable data on both its scientific workforce as well as the diaspora of scientists for countries with substantial brain drain. Here we use a systematic approach using Scopus to generate a comprehensive country-level database of all scientists in Greece. Moreover, we expand that database to include also Greek diaspora scientists. The database that we have compiled includes 63951 scientists who have published at least 5 papers indexed in Scopus. Of those, 35116 have an affiliation in Greece. We validate the sensitivity and specificity of the database against different control sets of scientists. We also analyze the scientific disciplines of these scientists according to the Science Metrix classification (174 subfield disciplines) and provide detailed data on each of the 63951 scientists using multiple citation indicators and a composite thereof. These analyses demonstrate differential concentrations in specific subfields for the local versus the diaspora cohorts, as well as an advantage of the diaspora cohort in terms of citation indicators especially among top-impact researchers. The approach that we have taken can be applied to map also the scientific workforce of other countries and nations for evaluation, planning and policy purposes.

category: scientific communication and education


title: A single-cell based precision medicine approach using glioblastoma patient-specific models

abstract:
Glioblastoma (GBM) is a heterogeneous tumor made up of cell states that evolve over time. Here, we modeled tumor evolutionary trajectories during standard-of-care treatment using multimodal single-cell analysis of a primary tumor sample, corresponding mouse xenografts subjected to standard of care therapy, and recurrent tumor at autopsy. We mined the multimodal data with single cell SYstems Genetics Network AnaLysis (scSYGNAL) to identify a network of 52 regulators that mediate treatment-induced shifts in xenograft tumor-cell states that were also reflected in recurrence. By integrating scSYGNAL-derived regulatory network information with transcription factor accessibility deviations derived from single-cell ATAC-seq data, we developed consensus networks that regulate subpopulations of primary and recurrent tumor cells. Finally, by matching targeted therapies to active regulatory networks underlying tumor evolutionary trajectories, we provide a framework for applying single-cell-based precision medicine approaches in a concurrent, neo-adjuvant, or recurrent setting.

SummaryInference of mechanistic drivers of therapy-induced evolution of glioblastoma at single cell resolution using RNA-seq and ATAC-seq from patient samples and model systems undergoing standard-of-care treatment informs strategy for identification of tumor evolutionary trajectories and possible cell state-directed therapeutics.

category: systems biology


title: ATRIOVENTRICULAR NODAL FUNCTION, ATRIAL FIBRILLATION AND VENTRICULAR TACHYCARDIA IN GIRAFFES

abstract: Unique cardiovascular adaptations in giraffes (Giraffa Camelopardalis reticulata) have been the focus of numerous investigations for almost a century. The vertical distance between the heart and brain impose high pressure on the giraffe left ventricle leading to thickening that exceeds heart in other mammals. Yet, cardiovascular function appears to be unimpacted by these morphologic differences. Physiologically adapted atrioventricular conduction may contribute to these unique cardiovascular characteristics. Atrioventricular (AV) function was assessed to determine whether physiologically adapted AV intervals might optimize the delay between atrial and ventricular contractions. Using ambulatory and intracardiac recordings, we report a longer PR interval in giraffes than predicted by allometric scaling. Slow ventricular response during atrial fibrillation further supports species-specific atrioventricular adaptations.

category: zoology


title: The impact of C-Tactile Low threshold mechanoreceptors on affective touch and social interactions in mice.

abstract: Affective touch is necessary for proper neurodevelopment and sociability. However, it is still unclear how the neurons innervating the skin detect affective and social behaviours. To clarify this matter, we targeted a specific population of somatosensory neurons in mice, named C-low threshold mechanoreceptors (C-LTMRs), that appears particularly well suited physiologically and anatomically to perceive affective and social touch but whose contribution to these processes has not yet been resolved. Our observations revealed that C-LTMRs functional deficiency from birth induced social isolation and reduced tactile interactions in adults. Conversely, transient increase in C-LTMRs excitability in adults using chemogenetics was rewarding, temporally promoted touch seeking behaviours and thus had pro-social effects on group dynamics. This work provides the first empirical evidence that specific peripheral inputs alone can drive complex social behaviour, demonstrating the existence of a specialised neuronal circuit originating from the skin wired to promote interaction with other individuals.

category: neuroscience


title: Controlling one's world: identification of sub-regions of primate PFC underlying goal-directed behavior

abstract: Impaired detection of causal relationships between actions and their outcomes can lead to maladaptive behavior. However, causal roles of specific prefrontal cortex (PFC) sub-regions and the caudate nucleus in mediating such relationships in primates are unclear. We inactivated and over-activated five PFC sub-regions, reversibly and pharmacologically: areas 24 (perigenual anterior cingulate cortex), 32 (medial PFC), 11 (anterior orbitofrontal cortex, OFC), 14 (rostral ventromedial PFC/medial OFC) and 14-25 (caudal ventromedial PFC), and the anteromedial caudate, to examine their role in expressing learned action-outcome contingencies using a contingency degradation paradigm in marmosets. Area 24 or caudate inactivation impaired the response to contingency change, while area 11 inactivation enhanced it, and inactivation of areas 14, 32 or 14-25 had no effect. Over-activation of areas 11 and 24 impaired this response. These findings demonstrate distinct roles of PFC sub-regions in goal-directed behavior and illuminate the candidate neurobehavioral substrates of psychiatric disorders including obsessive-compulsive disorder.


title: Fatigue, Alertness and Risk Prediction for Shift Workers

abstract:
Executive summaryO_LIThis report describes the principal outcomes of an Impact Acceleration Account project (grant number EP/I000992/1) between the University of Surrey and Transport for London carried out between Oct. 2019 and Mar. 2020.
C_LIO_LIThe aim of the project was to compare the Health and Safety Executive (HSE) Fatigue Risk tool with SAFTE and other more recent models of fatigue, where fatigue here primarily means a reduced ability to function effectively and efficiently as a result of inadequate sleep.
C_LIO_LIWe have not sought to discuss the useability of the HSE Fatigue Risk tool or SAFTE since this has been discussed comprehensively elsewhere (e.g. [1, 2]). We have instead focussed on the fundamental principles underlying the models.
C_LIO_LIAll current biomathematical models have limitations and make asumptions that are not always evident from the accompanying documentation. Since full details of the HSE Fatigue Risk tool and the SAFTE model are not publicly available, Sections 1 and 2 give a mathematical description of the equations that we believe underlie each of these models.
C_LIO_LIA comparison of predictions made by our versions of the HSE and SAFTE equations for one particular shift schedule of relevance to the UK and global tunnelling and construction industries is shown in Section 3. In this comparison, we use data collected durings TfLs Crossrail project by Dragados1. Essentially, both models give broadly the same message for the schedule we looked at, but the ability to display fatigue as it develops within a shift is a strength of SAFTE.
C_LIO_LIA summary of the strengths and limitations of the use of these kind of scheduling tools is given in the final Section 4. Limitations include:
O_LIModels do not describe fatigue during times when people are not in shift (e.g. driving home). However, they could readily be extended to do so.
C_LIO_LIModels assume people start well-rested. This is not always a good assumption and can lead to an under-estimate of fatigue.
C_LIO_LIMost models are currently based on population averages, but there are large individual different. It would be possible to further develop models to include uncertainty in fatigue predictions associated with individual differences.
C_LIO_LIFew mdels include the light environment, which is important both to promote short-term alertness and facilitate circadian alignment.
C_LIO_LIModels are not transparent, which makes them hard to independently validate.
C_LIO_LIIt is hard to relate the outputs of current models to measureable outcomes in the field.
C_LI
C_LIO_LIWe also discuss briefly recent developments in mathematical modelling of fatigue and possible future directions. These include
O_LIGuidance on scheduling and education on sleep and fatigue should be considered at least as important as current biomathematical models.
C_LIO_LIOnly by analysing and integrating high quality individual data on sleep, fatigue, performance, near misses, accidents, actual shift patterns with models can we develop better models and management systems to reduce fatigue and associated risks. Wearables combined with apps present a great opportunity to collect data at scale but need to be used appropriately.
C_LIO_LIThe importance of making time for sleep is not always recognised. Education, early diagnosis of sleep disorders such as sleep apnea, and self-monitoring all have a role to play in reducing fatigue-related risk in the work-place.
C_LI
C_LIO_LISection 3 and Section 4 may be understood without reading the intermediate more mathematical sections.
C_LI


title: Friction is preferred over grasp configuration in precision grip grasping

abstract:
How humans visually select where to grasp an object depends on many factors, including grasp stability and preferred grasp configuration. We examined how endpoints are selected when these two factors are brought into conflict: Do people favor stable grasps or do they prefer their natural grasp configurations? Participants reached to grasp one of three cuboids oriented so that its two corners were either aligned with, or rotated away from, each individuals natural grasp axis (NGA). All objects were made of brass (mass: 420 g) but the surfaces of their sides were manipulated to alter friction: 1) all-brass, 2) two opposing sides covered with wood, while the other two remained of brass, or 3) two opposing sides covered with sandpaper, and the two remaining brass sides smeared with vaseline. Grasps were evaluated as either clockwise (thumb to the left of finger in frontal plane) or counterclockwise of the NGA. Grasp endpoints depended on both object orientation and surface material. For the all-brass object, grasps were bimodally distributed in the NGA-aligned condition but predominantly clockwise in the NGA-unaligned condition. These data reflected participants natural grasp configuration independently of surface material. When grasping objects with different surface materials, endpoint selection changed: Participants sacrificed their usual grasp configuration to choose the more stable object sides. A model in which surface material shifts participants preferred grip angle proportionally to the perceived friction of the surfaces accounts for our results. Our findings demonstrate that a stable grasp is more important than a biomechanically comfortable grasp configuration.

NEW & NOTEWORTHYWhen grasping an object, humans can place their fingers at several positions on its surface. The selection of these endpoints depends on many factors, with two of the most important being grasp stability and grasp configuration. We put these two factors in conflict and examine which is considered more important. Our results highlight that humans are not reluctant to adopt unusual grasp configurations in order to satisfy grasp stability.


title: A large-scale neural network training framework for generalized estimation of single-trial population dynamics

abstract: Large-scale recordings of neural activity are providing new opportunities to study network-level dynamics. However, the sheer volume of data and its dynamical complexity are critical barriers to uncovering and interpreting these dynamics. Deep learning methods are a promising approach due to their ability to uncover meaningful relationships from large, complex, and noisy datasets. When applied to high-D spiking data from motor cortex (M1) during stereotyped behaviors, they offer improvements in the ability to uncover dynamics and their relation to subjects behaviors on a millisecond timescale. However, applying such methods to less-structured behaviors, or in brain areas that are not well-modeled by autonomous dynamics, is far more challenging, because deep learning methods often require careful hand-tuning of complex model hyperparameters (HPs). Here we demonstrate AutoLFADS, a large-scale, automated model-tuning framework that can characterize dynamics in diverse brain areas without regard to behavior. AutoLFADS uses distributed computing to train dozens of models simultaneously while using evolutionary algorithms to tune HPs in a completely unsupervised way. This enables accurate inference of dynamics out-of-the-box on a variety of datasets, including data from M1 during stereotyped and free-paced reaching, somatosensory cortex during reaching with perturbations, and frontal cortex during cognitive timing tasks. We present a cloud software package and comprehensive tutorials that enable new users to apply the method without needing dedicated computing resources.


title: Lower neural value signaling in the prefrontal cortex is related to childhood family income and depressive symptomatology during adolescence

abstract: Lower family income during childhood is related to increased rates of adolescent depression, though the specific mechanisms are poorly understood. Evidence suggests that individuals with depression demonstrate hypoactivation in brain regions involved in reward learning and decision-making processes (e.g., portions of the prefrontal cortex). Separately, lower family income has been associated with neural alterations in similar regions. We examined associations between family income, depression, and brain activity during a reward learning and decision-making fMRI task in a sample of adolescents (full n=94; usable n=78; mean age=15.4 years). We identified neural regions representing 1) expected value (EV), the learned subjective value of an object, and 2) prediction error, the difference between EV and the actual outcome received. Regions of interest related to reward learning were examined in connection to childhood family income and parent-reported adolescent depressive symptoms. As hypothesized, lower activity in the subgenual anterior cingulate (sACC) for EV in response to approach stimuli was associated with lower childhood family income, as well as greater symptoms of depression measured one-year after the neuroimaging session. These results are consistent with the hypothesis that lower early family income leads to disruptions in reward and decision-making brain circuitry, which leads to adolescent depression.


title: Clostridium difficile exploits a host metabolite produced during toxin-mediated infection

abstract: Several enteric pathogens can gain specific metabolic advantages over other members of the microbiota by inducing host pathology and inflammation. The pathogen Clostridium difficile (Cd) is responsible for a toxin-mediated colitis that causes 15,000 deaths in the U.S. yearly1, yet the molecular mechanisms by which Cd benefits from toxin-induced colitis remain understudied. Up to 21% of healthy adults are asymptomatic carriers of toxigenic Cd2, indicating that Cd can persist as part of a healthy microbiota; antibiotic-induced perturbation of the gut ecosystem is associated with transition to toxin-mediated disease. To understand how Cd metabolism adapts from a healthy gut to the inflamed conditions its toxins induce, we used RNA-seq to define the metabolic state of wild-type Cd versus an isogenic mutant lacking toxins in a mouse model. Combining bacterial and mouse genetics, we demonstrate that Cd utilizes sorbitol derived from both diet and host. Host-derived sorbitol is produced by the enzyme aldose reductase, which is expressed by diverse immune cells and is upregulated during inflammation, including during Cd toxin-mediated disease. This work highlights a mechanism by which Cd can utilize a host-derived nutrient generated during toxin-induced disease by an enzyme not previously associated with infection.

category: microbiology


title: Human urine alters methicillin-resistant Staphylococcus aureus virulence and transcriptome

abstract:
Gram-positive methicillin-resistant Staphylococcus aureus (MRSA) is an emerging cause of hospital-associated urinary tract infections, especially in catheterized individuals. Despite being rare, MRSA-UTI are prone to potentially life-threatening exacerbations such as bacteremia that can be refractory to routine antibiotic therapy. Hence, MRSA-UTI is an important of research topic. To delineate molecular mechanisms governing MRSA urinary pathogenesis, we exposed three S. aureus strains, of which two were MRSA, to human urine and analyzed virulence characteristics and gene expression. We also analyzed MRSA-1369 transcriptome following cultivation in human urine for 2h. Our results reveal that human urine induces global changes in MRSA transcriptome, marked by changes in genes encoding proteins involved in metabolic pathways, virulence, and transcriptional regulators. In addition, in vitro assays also showed that human urine alters, in a strain-specific manner, adherence to human bladder epithelial cells and fibronectin, hemolysis of sheep RBCs, and surface hydrophobicity. In summary, our results provide first important insights into how the urine may specifically alter MRSA physiology in turn facilitating MRSA survival in the nutrient-limiting and hostile urinary microenvironment.

ImportanceMethicillin-resistant Staphylococcus aureus (MRSA) is an uncommon cause of urinary tract infections (UTI) in the general population. However, it is important to understand MRSA pathophysiology in the urinary tract because isolation of MRSA in urine samples is often secondary to potentially life-threatening MRSA bacteremia. In this report, we describe that cultivation in human urine alters MRSA global gene expression and virulence. We hypothesize that these alterations may aid MRSA adapt to the nutrient-limiting, immunologically hostile conditions within the urinary tract.


title: Strong selective pressure by parasitoids mitigates the costs of consuming chemically defended plants

abstract:
O_LIPlant-herbivore co-evolutionary interactions have led to a range of plant defenses that minimize insect damage and a suite of counter-adaptations that allow herbivores to feed on defended plants. Consuming plant secondary compounds results in herbivore growth and developmental costs but can have beneficial effects such as deterrence or harm of parasitoid enemies. Therefore, the role of secondary compounds on herbivore fitness must be considered in the context of the abundance and level of harm from natural enemies and the costs herbivores incur feeding on plant secondary compounds.
C_LIO_LIIn this study, I combined field measurements of Cotesia congregata wasp parasitism pressure with detailed measurements of the costs of plant secondary compounds across developmental stages in the herbivore host, Manduca sexta.
C_LIO_LII show that C. congregata parasitoids exert large negative selective pressures, killing 31-57% of M. sexta larvae in the field. Manduca sexta developed fastest during instars most at risk for parasitoid oviposition but growth was slowed by consumption of plant secondary compounds. The negative effects of consuming plant secondary compounds as larvae influenced adult size traits but there were no immune, survival, or fecundity costs.
C_LIO_LIThese results suggest that developmental costs experienced by M. sexta herbivores consuming defensive compounds are minor in comparison to the strong negative survival pressures from abundant parasitoid enemies.
C_LI

category: ecology


title: Manduca sexta experience high parasitoid pressures in the field but minor fitness costs of consuming plant secondary compounds


title: Large-scale genetic association and single cell accessible chromatin mapping defines cell type-specific mechanisms of type 1 diabetes risk

abstract: Translating genome-wide association studies (GWAS) of complex disease into mechanistic insight requires a comprehensive understanding of risk variant effects on disease-relevant cell types. To uncover cell type-specific mechanisms of type 1 diabetes (T1D) risk, we combined genetic association mapping and single cell epigenomics. We performed the largest to-date GWAS of T1D in 489,679 samples imputed into 59.2M variants, which identified 74 novel association signals including several large-effect rare variants. Fine-mapping of 141 total signals substantially improved resolution of causal variant credible sets, which primarily mapped to non-coding sequence. To annotate cell type-specific regulatory mechanisms of T1D risk variants, we mapped 448,142 candidate cis-regulatory elements (cCREs) in pancreas and peripheral blood mononuclear cell types using snATAC-seq of 131,554 nuclei. T1D risk variants were enriched in cCREs active in CD4+ T cells as well as several additional cell types including pancreatic exocrine acinar and ductal cells. High-probability T1D risk variants at multiple signals mapped to exocrine-specific cCREs including novel loci near CEL, GP2 and CFTR. At the CFTR locus, the likely causal variant rs7795896 mapped in a ductal-specific distal cCRE which regulated CFTR and the risk allele reduced transcription factor binding, enhancer activity and CFTR expression in ductal cells. These findings support a role for the exocrine pancreas in T1D pathogenesis and highlight the power of combining large-scale GWAS and single cell epigenomics to provide insight into the cellular origins of complex disease.

category: genetics


title: Adaptive optics enhanced all-optical photoacoustic tomography

abstract: All-optical ultrasound detection bears a number of unique advantages for photoacoustic tomography, including the ability for high resolution sampling of the acoustic field and its compatibility with a wide variety of other optical modalities. However, optical schemes based on miniaturized cavities are sensitive to optical aberrations as well as manufacturing-induced cavity imperfections which degrade sensor sensitivity and deteriorate photoacoustic image quality. Here we present an experimental method based on adaptive optics that is capable of enhancing the overall sensitivity of Fabry-Perot based photoacoustic sensors. We experimentally observe clear improvements in photoacoustic signal detection as well as overall image quality after photoacoustic tomography reconstructions when applied to mammalian tissues in vivo.

category: bioengineering


title: Robust T1 MRI cortical surface pipeline for neonatal brain and systematic evaluation using multi-site MRI datasets

abstract: The human brain grows the most dramatically during the perinatal and early postnatal periods, during which preterm birth or perinatal injury that may alter brain structure and lead to developmental anomalies. Thus, characterizing cortical thickness of developing brains remains an important goal. However, this task is often complicated by inaccurate cortical surface extraction due to small-size brains. Here, we propose a novel complex framework for the reconstruction of neonatal WM and pial surfaces, accounting for large partial volumes due to small-size brains. The proposed approach relies only on T1-weighted images unlike previous T2-weighted image-based approaches while only T1-weighted images are sometimes available under the different clinical/research setting. Deep neural networks are first introduced to the neonatal MRI pipeline to address the mis-segmentation of brain tissues. Furthermore, this pipeline enhances cortical boundary delineation using combined models of the CSF/GM boundary detection with edge gradient information and a new skeletonization of sulcal folding where no CSF voxels are seen due to the limited resolution. We also proposed a systematic evaluation using three independent datasets comprising 736 preterm and 97 term neonates. Qualitative assessment for reconstructed cortical surfaces shows that 86.9% are rated as accurate across the three site datasets. In addition, our landmark-based evaluation shows that the mean displacement of the cortical surfaces from the true boundaries was less than a voxel size (0.532{+/-}0.035mm). Evaluating the proposed pipeline (namely NEOCIVET 2.0) shows the robustness and reproducibility across different sites and different age-groups. The mean cortical thickness measured positively correlated with postmenstrual age (PMA) at scan (p<0.0001); Cingulate cortical areas grew the most rapidly whereas the inferior temporal cortex grew the least rapidly. The range of the cortical thickness measured was biologically congruent (1.3mm at 28 weeks of PMA to 1.8mm at term equivalent). Cortical thickness measured on T1 MRI using NEOCIVET 2.0 was compared with that on T2 using the established dHCP pipeline. It was difficult to conclude that either T1 or T2 imaging is more ideal to construct cortical surfaces. NEOCIVET 2.0 has been open to the public through CBRAIN (https://mcin-cnim.ca/technology/cbrain/), a web-based platform for processing brain imaging data.

category: bioinformatics


title: New Gene Embedding Learned from Biomedical Literature and Its Application in Identifying Cancer Drivers

abstract: To investigate molecular mechanism of diseases, we need to understand how genes are functionally associated. Computational researchers have tried to capture functional relationships among genes by constructing an embedding space of genes from multiple sources of high-throughput data. However, correlations in high-throughput data does not necessarily imply functional relations. In this study, we generated gene embedding from literature by constructing semantic representation for each gene. This approach enabled us to cover genes less mentioned in literature and revealed novel functional relationships among genes. Evaluation showed that the learned gene embedding was consistent with pathway knowledge and enhanced the search for cancer driver genes. We further applied our gene embedding to identify protein complexes and functional modules from gene networks. Performance in both scenarios was significantly improved with gene embedding.


title: Characterisation of the R2R3 Myb subgroup 9 family of transcription factors in tomato

abstract:
Tomato (Solanum lycopersicum) has many epidermal cell outgrowths including conical cells and multiple types of trichomes. These include the anther-specific trichome mesh which holds the anthers connate. The R2R3 Myb Subgroup 9 family of transcription factors is involved in development of epidermal cell outgrowths throughout the angiosperms. No previous study has examined all members of this transcription factor family in a single species. All 7 R2R3 Myb Subgroup 9 genes were isolated from tomato. They were ectopically expressed in tobacco to assess their ability to induce epidermal cell outgrowth. Endogenous expression patterns were examined by semi-quantitative RT-PCR at different stages of floral development relative to the development of anther trichomes. We report variation in the degree of epidermal cell outgrowth produced in transgenic tobacco for each ectopically expressed gene. Based on expression profile and ectopic activity, SlMIXTA-2 is likely involved in the production of leaf trichomes while SlMYB17-2 is the best candidate for the regulation of the anther trichome mesh. Analysis of the phenotypes of transgenic plants ectopically expressing all 7 genes has revealed the different extent to which members of the same transcription factor subfamily can induce cellular outgrowth.

HighlightCharacterisation of all members of an important family of transcription factors within tomato showing that all are able to induce epidermal cell outgrowths to varying degrees.

category: plant biology


title: The cost of correcting for error during sensorimotor adaptation

abstract: Learning from error is often a slow process. To accelerate learning, previous motor adaptation studies have focused on explicit factors such as reward or punishment, but the results have been inconsistent. Here, we considered the idea that a movement error carries an implicit cost for the organism because the act of correcting for error consumes time and energy. If this implicit cost could be modulated, it may robustly alter how the brain learns from error. To vary the cost of error, we considered a simple saccade adaptation task but combined it with motion discrimination: movement errors resulted in corrective saccades, but those corrections took time away from acquiring information in the discrimination task. We then modulated error cost using coherence of the discrimination task and found that when error cost was large, pupil diameter increased, and the brain learned more from error. However, when error cost was small, the pupil constricted, and the brain learned less from the same error. Thus, during sensorimotor adaptation, the act of correcting for error carried an implicit cost for the brain. Modulating this cost affects how the brain learns from error.


title: Accurate bulk quantitation of droplet digital PCR

abstract: Droplet digital PCR provides superior accuracy in nucleic acid quantitation. The requirement of microfluidics to generate and analyze the emulsions, however, is a barrier to its adoption, particularly in low resource or clinical settings. Here, we report a novel method to prepare ddPCR droplets by vortexing and readout the results by bulk analysis of recovered amplicons. We demonstrate the approach by accurately quantitating SARS-CoV-2 sequences using entirely bulk processing and no microfluidics. Our approach for quantitating reactions should extend to all digital assays that generate amplicons, including digital PCR and LAMP conducted in droplets, microchambers, or nanoliter wells. More broadly, our approach combines important attributes of ddPCR, including enhanced accuracy and robustness to inhibition, with the high-volume sample processing ability of quantitative PCR.

category: molecular biology


title: CRISPR/Cas-9 mediated knock-in by homology dependent repair in the West Nile Virus vector Culex quinquefasciatus Say

abstract: Culex quinquefasciatus Say is a brown, medium sized mosquito distributed widely in both tropical and subtropical regions of the world. It is a night-active, opportunistic blood-feeder and is responsible for vectoring many animal and human diseases, including West Nile Virus and avian malaria. Current vector control methods (e.g. physical / chemical) are increasingly ineffective; use of insecticides also imposes some hazards to both human and ecosystem health. Recent advances in genome editing have allowed the development of genetic methods of insect control, which is species-specific and, theoretically, highly effective. CRISPR/Cas9 is a bacteria-derived programmable gene editing tool that has been shown to be functional in a range of species. We demonstrate here, the first successful germline gene knock-in by homology dependent repair in C. quinquefasciatus. Using CRISPR/Cas9, we integrated exogenous sequence comprising a sgRNA expression cassette and marker gene encoding a fluorescent protein fluorophore (Hr5/IE1-DsRed, Cq7SK-sgRNA) into the kynurenine 3-monooxygenase (kmo) gene. We achieved a minimum transformation rate of 2.8% similar to rates achieved in other mosquito species. Precise knock-in at the intended locus was confirmed by sequencing. Insertion homozygotes displayed a white eye phenotype in early-mid stage larvae and a recessive lethal phenotype by pupation. This work shows an alternative and efficient method for genetic engineering of C. quinquefasciatus, providing a new tool for researchers interested in developing genetic control tools for this vector.


title: MoTSE: an interpretable task similarity estimator for small molecular property prediction tasks

abstract: Understanding the molecular properties (e.g., physical, chemical or physiological characteristics and biological activities) of small molecules plays essential roles in biomedical researches. The accumulating amount of datasets has enabled the development of data-driven computational methods, especially the machine learning based methods, to address the molecular property prediction tasks. Due to the high cost of obtaining experimental labels, the datasets of individual tasks generally contain limited amount of data, which inspired the application of transfer learning to boost the performance of the molecular property prediction tasks. Our analyses revealed that simultaneously considering similar tasks, rather than randomly chosen ones, can significantly improve the performance of transfer learning in this field. To provide accurate estimation of task similarity, we proposed an effective and interpretable computational tool, named Molecular Tasks Similarity Estimator (MoTSE). By extracting task-related local and global knowledge from pretrained graph neural networks (GNNs), MoTSE projects individual tasks into a latent space and measures the distance between the embedded vectors to derive the task similarity estimation and thus enhance the molecular prediction results. We have validated that the task similarity estimated by MoTSE can serve as a useful guidance to design a more accurate transfer learning strategy for molecular property prediction. Experimental results showed that such a strategy greatly outperformed baseline methods including training from scratch and multitask learning. Moreover, MoTSE can provide interpretability for the estimated task similarity, through visualizing the important loci in the molecules attributed by the attribution method employed in MoTSE. In summary, MoTSE can provide an accurate method for estimating the molecular property task similarity for effective transfer learning, with good interpretability for the learned chemical or biological insights underlying the intrinsic principles of the task similarity.


title: Anterior insula-associated social novelty recognition: orchestrated regulation by a local retinoic acid cascade and oxytocin signaling

abstract:
BackgroundDeficits in social cognition consistently underlie functional disabilities in a wide range of psychiatric disorders. Neuroimaging studies have suggested that the anterior insula is a  common core brain region that is impaired across neurological and psychiatric disorders, which include social cognition deficits. Nevertheless, neurobiological mechanisms of the anterior insula for social cognition remain elusive.

MethodsTo determine the role of anterior insula in social cognition, we manipulated expression of Cyp26B1, an anterior insula-enriched molecule that is crucial for retinoic acid degradation and involved in the pathology of neuropsychiatric conditions. Social cognition was mainly assayed using the three-chamber social interaction test. We conducted multimodal analyses at the molecular, cellular, circuitry, and behavioral levels.

ResultsAt the molecular/cellular level, anterior insula-mediated social novelty recognition is maintained by proper activity of the layer 5 pyramidal neurons, for which retinoic acid-mediated gene transcription can play a role. We also demonstrate that oxytocin influences the anterior insula-mediated social novelty recognition, not by direct projection of oxytocin neurons, nor by direct diffusion of oxytocin to the anterior insula, which contrasts the modes of oxytocin regulation onto the posterior insula. Instead, oxytocin affects oxytocin receptor-expressing neurons in the dorsal raphe nucleus where serotonergic neurons are projected to the anterior insula. Furthermore, we show that serotonin 5HT2C receptor expressed in the anterior insula influences social novelty recognition.

ConclusionsAnterior insula plays a pivotal role in social novelty recognition that is partly regulated by a local retinoic acid cascade, but also remotely regulated by oxytocin via a non-classic mechanism.

category: animal behavior and cognition


title: Correlation of Computerized Tomography (CT) Severity Score for COVID-19 pneumonia with Clinical Outcomes

abstract:
IntroductionVarious CT severity scores have already been described in literature since the start of this pandemic. One pertinent issue with all of the previously described severity scores is their relative challenging calculation and variance in inter-observer agreement. The severity score proposed in our study is relatively simpler, easier to calculate and apart from a trained radiologist, can easily be calculated even by physicians with good inter-observer agreement. Therefore, a rapid CT severity score calculation can give a clue to physician about possible clinical outcome without being dependent on radiologist who may not be readily available especially in third world countries.

ObjectiveThe objective of this study is to develop a simple CT severity score (CT-SS) with good inter-observer agreement and access its correlation with clinical outcome.

MethodsThis retrospective study was conducted by the Department of Radiology and Internal Medicine, at the Aga Khan University Hospital Karachi, from April 2020 to August 2020. Non-probability consecutive sampling was used to include all patients who were positive for COVID-19 on PCR, and underwent CT chest examination at AKUH. Severity of disease was calculated in each lobe on the basis of following proposed CT severity scoring system (CT-SS). For each lobe the percentage of involvement by disease was scored - 0% involvement was scored 0, <50% involvement was scored 1 and >50% involvement was scored 2. Maximum score for one lobe was 2 and hence total maximum overall score for all lobes was 10. Continuous data was represented using mean and standard deviation, and compared using independent sample t-tests. Categorical data was represented using frequencies and percentages, and compared using Chi-squared tests. Inter-observer reliability between radiologist and COVID intensivist for the 10 point CT-SS rated on 0-10 was assessed using the Kappa statistic. A p-value < 0.05 was considered significant for all analyses.

ResultsA total of 73 patients were included, the majority male (58.9%) with mean age 55.8 {+/-} 13.93 years. The CT-SS rated on 0-10 showed substantial inter-observer reliability between radiologist and intensivist with a Kappa statistic of 0.78. Patients with CT-SS 8-10 had a significantly higher ICU admission & intubation rate (53.8% vs. 23.5%) and mortality rate (35.9% vs. 11.8%; p = 0.017), as compared to those with CT-SS 0-7.

ConclusionWe conclude that the described CT severity score (CT-SS) is a quick, effective and easily reproducible tool for prediction of adverse clinical outcome in patients with COVID 19 pneumonia. The tool shows good inter-observer agreement when calculated by radiologist and physician independently.

category: pathology


title: The human cerebellum is essential for modulating perceptual sensitivity based on temporal expectations

abstract: A functional benefit of attention is to proactively enhance perceptual sensitivity in space and time. Although attentional orienting has traditionally been associated with cortico-thalamic networks, recent evidence has shown that individuals with cerebellar degeneration (CD) show a reduced reaction time benefit from cues that enable temporal anticipation. While this deficit may reflect impairment in anticipatory motor preparation, it could also arise from cerebellar contribution to attentional modulation in time of perceptual sensitivity. To examine this, we tested CD participants on a non-speeded, challenging perceptual discrimination task, asking if they benefit from temporal cues. Strikingly, the CD group showed no duration-specific perceptual sensitivity benefit when cued by repeated but aperiodic presentation of the target interval. In contrast, they performed similar to controls when cued by a rhythmic stream. This dissociation further specifies the functional domain of the cerebellum and establishes its role in the attentional adjustment of perceptual sensitivity in time.


title: Serotonin modulates learning content-specific neuroplasticity of functional brain networks

abstract: Learning-induced neuroplastic changes, further modulated by content and setting, are mirrored in brain functional connectivity (FC). In animal models, serotonergic agents were shown to facilitate neuroplasticity. This is especially prominent during emotional relearning, such as fear extinction, which may translate to clinical improvements in human patients. To investigate this assumption, 99 healthy subjects underwent six weeks of emotional or non-emotional learning and subsequent relearning. Resting-state functional magnetic resonance imaging was performed before and after the learning phases to investigate changes in FC. During relearning, subjects received either a daily dose of the selective serotonin reuptake inhibitor (SSRI) escitalopram or placebo. Escitalopram intake modulated FC changes in a network comprising Brocas area, the medial prefrontal cortex, the right inferior temporal and left lingual gyrus. More specifically, escitalopram increased the bidirectional connectivity between medial prefrontal cortex and lingual gyrus for non-emotional and additionally the connectivity from medial prefrontal cortex to Brocas area for emotional relearning. The context-dependence of these effects supports the assumption that SSRIs in clinical practice might improve neuroplasticity rather than psychiatric symptoms per se. Correlations with learning behavior further point towards a relationship with extinction processes in relearning. These results demonstrate that escitalopram intake during relearning results in content-dependent network adaptations and support the conclusion that enhanced neuroplasticity might be the major underlying mechanism also in humans. Beyond expanding the complexities of learning, these findings emphasize the influence of external factors on serotonin-facilitated neuroplasticity of the human brain.


title: Sleep problems in preschoolers with autism spectrum disorders are associated with sensory sensitivities and thalamocortical overconnectivity

abstract: Projections between the thalamus and sensory cortices are established early in development and play an important role in sleep regulation as well as in relaying sensory information to cortex. Atypical thalamocortical functional connectivity frequently observed in children with autism spectrum disorders (ASD) might therefore be linked to sensory and sleep problems common in ASD. Here we investigated the relationship between auditory-thalamic functional connectivity measured during natural sleep fMRI, sleep problems, and sound sensitivities in 70 toddlers and preschoolers (1.5 to 5-year-olds) with ASD compared to a matched group of 46 typically developing (TD) children. In children with ASD, sleep problems and sensory sensitivities were positively correlated, and increased sleep latency was associated with overconnectivity between the thalamus and auditory cortex in a subsample with high quality MRI data (n=29). Additionally, auditory cortex BOLD signal amplitude was elevated in children with ASD, potentially reflecting reduced sensory gating or a lack of auditory habituation during natural sleep. These findings indicate that atypical thalamocortical functional connectivity can be detected early in development and may play a crucial role in sleep problems and sensory sensitivities in ASD.


title: First evidence of nocardiosis in farmed red drum (Sciaenops ocellatus, Linnaeus) caused by Nocardia seriolae in the Gulf of Mexico

abstract: Between August and December 2013, the offshore cages of a commercial marine farm culturing red drum Sciaenops ocellatus in Campeche Bay were affected by an outbreak of an ulcerative granulomatous disease, reaching 70% cumulative mortality. Thirty-one adults displaying open ulcers on the skin were submitted to our laboratory for diagnosis. Multiple white-yellowish nodules (0.1-0.5 cm in diameter) were present in all internal organs, where the kidney and the spleen were the most severely affected. Histopathological observations of these organs evinced typical granulomatous formations. Gram and Ziehl-Neelsen stains on tissue imprints, bacterial swabs and tissue sections revealed Gram-positive, acid-fast, branching beaded long rod filamentous bacteria. Tissue samples resulted positive for nocardiosis when a Nocardia genus specific nested PCR was used. Definite identification at the species level and taxonomic positioning of the fastidious pathogen was achieved through a specific Nocardia seriolae PCR and by sequencing the gyrB gene of pure isolates. After application of antibiotics during fry production, a posterior follow-up monitoring (from 2014 to 2017) detected mild but recurrent outbreaks of the bacteria with no seasonality pattern. To the extent of our current knowledge, this is the first report of piscine nocardiosis (in a new host -red drum) in Mexico.


title: Compound FC-10696 Inhibits Egress and Spread of Marburg Virus

abstract: Marburg virus (MARV) VP40 protein (mVP40) directs egress and spread of MARV, in part, by recruiting specific host WW-domain containing proteins via its conserved PPxY Late (L) domain motif to facilitate efficient virus-cell separation. We reported previously that small molecule compounds targeting the viral PPxY/host WW-domain interaction inhibited VP40-mediated egress and spread. Here, we report on the antiviral potency of novel compound FC-10696, which emerged from extensive structure activity relationship (SAR) of a previously described series of PPxY inhibitors. We show that FC-10696 inhibits egress of both mVP40 VLPs and egress and spread of authentic MARV from HeLa cells and primary human macrophages. Moreover, FC-10696 treated mice displayed delayed onset of weight loss, clinical signs, and significantly lower viral loads compared to controls, with 14% of animals surviving 21 days following a lethal MARV challenge. Thus, FC-10696 represents a first-in-class, host-oriented inhibitor effectively targeting late stages of the MARV lifecycle.


title: Mechanisms Driving Genome Reduction of a Novel Roseobacter Lineage Showing Vitamin B12 Auxotrophy

abstract: Members of the marine Roseobacter group are key players in the global carbon and sulfur cycles. While over 300 species have been described, only 2% possess reduced genomes (mostly 3-3.5 Mbp) compared to an average roseobacter (>4 Mbp). These taxonomic minorities are phylogenetically diverse but form a Pelagic Roseobacter Cluster (PRC) at the genome content level. Here, we cultivated eight isolates constituting a novel Roseobacter lineage which we named  CHUG. Metagenomic and metatranscriptomic read recruitment analyses showed that CHUG members were globally distributed and active in marine environments. CHUG members possess some of the smallest genomes (~2.52 Mb) among all known roseobacters, but they do not exhibit canonical features of genome streamlining like higher coding density or fewer paralogues and pseudogenes compared to their sister lineages. While CHUG members are clustered with traditional PRC members at the genome content level, they show important differences. Unlike other PRC members, neither the relative abundances of CHUG members nor their gene expression levels are correlated with chlorophyll a concentration across the global samples. Moreover, CHUG members cannot synthesize vitamin B12, a key metabolite made by most roseobacters but not by many phytoplankton species and thus thought to mediate the roseobacter-phytoplankton interactions. This combination of features is evidence for the hypothesis that CHUG members may have evolved a free-living lifestyle decoupled from phytoplankton. This ecological transition was accompanied by the loss of signature genes involved in roseobacter-phytoplankton symbiosis, suggesting that relaxation of purifying selection is likely an important driver of genome reduction in CHUG.


title: Genetic Control of Pluripotency Epigenome Determines Differentiation Bias in Mouse Embryonic Stem Cells

abstract: Genetically diverse pluripotent stem cells (PSCs) display varied, heritable responses to differentiation cues in the culture environment. By harnessing these disparities through derivation of embryonic stem cells (ESCs) from the BXD mouse genetic reference panel, along with C57BL/6J (B6) and DBA/2J (D2) parental strains, we demonstrate genetically determined biases in lineage commitment and identify major regulators of the pluripotency epigenome. Upon transition to formative pluripotency using epiblast-like cells (EpiLCs), B6 quickly dissolves naive networks adopting gene expression modules indicative of neuroectoderm lineages; whereas D2 retains aspects of naive pluripotency with little bias in differentiation. Genetic mapping identifies 6 major trans-acting loci co-regulating chromatin accessibility and gene expression in ESCs and EpiLCs, indicating a common regulatory system impacting cell state transition. These loci distally modulate occupancy of pluripotency factors, including TRIM28, P300, and POU5F1, at hundreds of regulatory elements. One trans-acting locus on Chr 12 primarily impacts chromatin accessibility in ESCs; while in EpiLCs the same locus subsequently influences gene expression, suggesting early chromatin priming. Consequently, the distal gene targets of this locus are enriched for neurogenesis genes and were more highly expressed when cells carried B6 haplotypes at this Chr 12 locus, supporting genetic regulation of biases in cell fate. Spontaneous formation of embryoid bodies validated this with B6 showing a propensity towards neuroectoderm differentiation and D2 towards definitive endoderm, confirming the fundamental importance of genetic variation influencing cell fate decisions.

category: genomics


title: A Novel in vitro Model for Mature Toxoplasma gondii Bradyzoites Reveals their Metabolome and a Diminished Role of the Mitochondrial Tricarboxylic Acid Cycle

abstract: The apicomplexan parasite Toxoplasma gondii forms bradyzoite-containing tissue cysts that cause chronic and drug-tolerant infections. However, current in vitro models do not allow long-term culture of these cysts to maturity. Here, we developed a human myotube-based in vitro culture model of functionally mature tissue cysts that are orally infectious to mice and tolerate exposure to a range of antibiotics and temperature stresses. Metabolomic characterization of purified cysts reveals global changes that comprise increased levels of amino acids and decreased abundance of nucleobase- and tricarboxylic acid cycle-associated metabolites. In contrast to fast replicating tachyzoite forms of T. gondii these tissue cysts tolerate exposure to the aconitase inhibitor sodium fluoroacetate. Direct access to persistent stages of T. gondii under defined cell culture conditions will be essential for the dissection of functionally important host-parasite interactions and drug evasion mechanisms. It will also facilitate the identification of new strategies for therapeutic intervention.


title: In vitro maturation of Toxoplasma gondii bradyzoites in human myotubes and their metabolomic characterization


title: Identifying Plasmodium falciparum transmission patterns through parasite prevalence and entomological inoculation rate

abstract: Monitoring malaria transmission is a critical component of efforts to achieve targets for elimination and eradication. Two commonly monitored metrics of transmission intensity are parasite prevalence (PR) and the entomological inoculation rate (EIR). Using geostatistical methods, we investigate the relationship between Plasmodium falciparum PR and EIR using data collected over 38 months in a rural area of Malawi. Our results indicate that hotspots identified through the EIR and PR partly overlapped during high transmission seasons but not during low transmission seasons. The estimated relationship showed a one-month delayed effect of EIR on PR such that at low transmission levels increases in EIR are associated with rapid rise in PR, but at high transmission levels, decreases in EIR do not translate into notable reductions in PR. Our study emphasises the need for integrated malaria control strategies that combines vector and human host managements monitored by both entomological and parasitaemia indices.

category: physiology


title: Overburdening of peer reviewers. A multi-disciplinary and multi-stakeholder perspective on causes, effects and potential policy implications

abstract: Peer review of manuscripts is labour-intensive and time-consuming. Individual reviewers often feel themselves overburdened with the amount of reviewing they are requested to do. Aiming to explore how stakeholder groups perceive reviewing burden and what they believe to be the causes of a potential overburdening of reviewers, we conducted focus groups with early-, mid-, and senior career scholars, editors, and publishers. By means of a thematic analysis, we aimed to identify the causes of overburdening of reviewers. First, we show that, across disciplines and roles, stakeholders believed that the reviewing workload has become so enormous that the academic community is no longer able to supply the reviewing resources necessary to address its demand for peer review. Second, the reviewing workload is distributed unequally across the academic community, thereby overwhelming small groups of scholars. Third, stakeholders believed the overburdening of reviewers to be caused by (i) an increase in manuscript submissions; (ii) insufficient editorial triage; (iii) a lack of reviewing instructions; (iv) difficulties in recruiting reviewers; (v) inefficiencies in manuscript handling and (vi) a lack of institutionalisation of peer review. These themes were assumed to mutually reinforce each other and to relate to an inadequate incentive structure in academia that favours publications over peer review. In order to alleviate reviewing burden, a holistic approach is required that addresses both the increased demand for and the insufficient supply of reviewing resources.


title: A processing pipeline for image reconstructed fNIRS analysis using both MRI templates and individual anatomy

abstract:
AimWe demonstrate a pipeline with accompanying code to allow users to clean and prepare optode location information, prepare and standardize individual anatomical images, create the light model, run the 3D image reconstruction, and analyze data in group space.

ApproachWe synthesize a combination of new and existing software packages to create a complete pipeline, from raw data to analysis.

ResultsThis pipeline has been tested using both templates and individual anatomy, and on data from different fNIRS data collection systems. We show high temporal correlations between channel-based and image-based fNIRS data. In addition, we demonstrate the reliability of this pipeline with a sample dataset that included 74 children as part of a longitudinal study taking place in Scotland. We demonstrate good correspondence between data in channel space and image reconstructed data.

ConclusionsThe pipeline presented here makes a unique contribution by integrating multiple tools to assemble a complete pipeline for image reconstruction in fNIRS. We highlight further issues that may be of interest to future software developers in the field.

SignificanceImage reconstruction of fNIRS data is a useful technique for transforming channel-based fNIRS into a volumetric representation and managing spatial variance based on optode location. We present a novel integrated pipeline for image reconstruction of fNIRS data using either MRI templates or individual anatomy.


title: Dissociable mechanisms of reward learning co-mature during human adolescence as predicted by macaque lesion models

abstract: Reward-guided learning and decision-making is a fundamental adaptive ability and depends on a number of component processes. We investigate how such component processes mature during human adolescence. Our approach was guided by analyses of the effects of lateral orbitofrontal lesions in macaque monkeys, as this part of the brain shows clear developmental maturation in humans during adolescence. Using matched tasks and analyses in humans (n=388, 11-35yrs), we observe developmental changes in two key learning mechanisms as predicted from the monkey data. First, choice-reward credit assignment - the ability to link a specific outcome to a specific choice - is reduced in adolescents. Second, the effects of the global reward state - how good the environment is overall recently - exerts a distinctive pattern of influence on learning in humans compared to other primates and across adolescence this pattern becomes more pronounced. Both mechanisms were correlated across participants suggesting that associative learning of correct reward assignments and GRS based learning constitute two complementary mechanisms of reward-learning that co-mature during adolescence.


title: Opioid withdrawal produces sex-specific effects on fentanyl-vs.-food choice and mesolimbic transcription

abstract:
BackgroundOpioid withdrawal is a key driver of opioid addiction and an obstacle to recovery. However, withdrawal effects on opioid reinforcement and mesolimbic neuroadaptation are understudied and the role of sex is largely unknown.

MethodsMale (n=10) and female (n=9) rats responded under a fentanyl-vs.-food "choice" procedure during daily 2h sessions. In addition to the daily choice sessions, rats were provided extended access to fentanyl during 12h sessions. After two weeks of this self-administration regimen, the nucleus accumbens (NAc) and ventral tegmental area (VTA) of a subset of rats were subjected to RNA sequencing. In the remaining rats, a third week of this self-administration regimen was conducted, during which methadone effects on fentanyl-vs.-food choice were determined.

ResultsPrior to opioid dependence, male and female rats similarly allocated responding between fentanyl and food. Abstinence from extended fentanyl access elicited a similar increase in somatic withdrawal signs in both sexes. Despite similar withdrawal signs and extended access fentanyl intake, opioid withdrawal was accompanied by a maladaptive increase in fentanyl choice in males, but not females. Behavioral sex differences corresponded with transcriptional hyperfunction in the NAc and VTA of opioid-withdrawn females relative to males. Methadone blocked withdrawal-associated increases in fentanyl choice in males, but failed to further decrease fentanyl choice in females.

ConclusionsThese results provide foundational evidence of sex-specific neuroadaptations to opioid withdrawal, which may be relevant to the female-specific resilience to withdrawal-associated increases in opioid choice and aid in the identification of novel therapeutic targets.


title: Mitochondrial function is essential for humoral immunity by controlling flux of the TCA cycle, phosphatidic acid and mTOR activity in B cells

abstract: The function of mitochondrial respiration during B cell fate decisions and differentiation remains equivocal. This study reveals that selection for mitochondrial fitness occurs during B cell activation and is essential for subsequent plasma cell differentiation. By expressing a mutated mitochondrial helicase in transitional B cells, we depleted mitochondrial DNA during B cell maturation, resulting in reduced oxidative phosphorylation. Although no changes in follicular B cell development were evident, germinal centers, class switch recombination to IgG, plasma cell generation and humoral immunity were diminished. Defective oxidative phosphorylation led to aberrant flux of the tricarboxylic acid cycle and lowered the amount of saturated phosphatidic acid. Consequently, MTOR activity and BLIMP-1 induction were curtailed whereas HIF1, glycolysis and AMPK activity were amplified. Exogenous phosphatidic acid increased mTOR activity in activated B cells. Hence, mitochondrial function is required and selected for in activated B cells for the successful generation of functional plasma cells.

category: immunology


title: The total mRNA concentration buffering system in yeast is global rather than gene-specific

abstract: Gene expression in eukaryotes does not follow a linear process from transcription to translation and mRNA degradation. Instead it follows a circular process in which cytoplasmic mRNA decay crosstalks with nuclear transcription. In many instances this crosstalk contributes to buffer mRNA at a roughly constant concentration. Whether the mRNA buffering concept operates on the total mRNA concentration or at the gene-specific level, and if the mechanism to do so is a global or a specific one, remain unknown. Here we assessed changes in mRNA concentrations and their synthesis rates along the transcriptome of aneuploid strains of the yeast Saccharomyces cerevisiae. We also assessed mRNA concentrations and their synthesis rates in non sense-mediated decay (NMD) targets in euploid strains. We found that the altered synthesis rates in the genes from the aneuploid chromosome and the changes in their mRNA stabilities were not counterbalanced. In addition, the stability of NMD targets was not specifically compensated by the changes in synthesis rate. We conclude that there is no genetic compensation of NMD mRNA targets in yeast, and total mRNA buffering uses mostly a global system rather than a gene-specific one.


title: Systemic antisense therapeutics inhibiting DUX4 expression improves muscle function in an FSHD mouse model

abstract: Aberrant expression of the double homeobox 4 (DUX4) gene in skeletal muscle causes muscle deterioration and weakness in Facioscapulohumeral Muscular Dystrophy (FSHD). Since the presence of a permissive pLAM1 polyadenylation signal is essential for stabilization of DUX4 mRNA and translation of DUX4 protein, disrupting the function of this structure can prevent expression of DUX4. We and others have shown promising results using antisense approaches to reduce DUX4 expression in vitro and in vivo following local intramuscular administration. Our group has developed further the antisense chemistries, and demonstrate here enhanced in vitro antisense efficacy. The optimal chemistry was conjugated to a cell-penetrating moiety, and for the first time in FSHD research has been systemically administered into a double-transgenic mouse model of FSHD. After four weekly treatments, mRNA quantities of DUX4 and target genes were reduced by 50% that led to a 5% increase in muscle mass, a 52% improvement in in situ muscle strength, and reduction of muscle fibrosis by 17%. Systemic DUX4 inhibition also improved the locomotor activity significantly and reduced the fatigue level by 22%. Our data overall demonstrate that the optimized antisense approach can contribute to future development of a therapeutic strategy for FSHD.


title: Microclimates can be accurately predicted across ecologically important remote ecosystems

abstract: Microclimate information is often crucial for understanding ecological patterns and processes, including under climate change, but is typically absent from ecological and biogeographic studies owing to difficulties in obtaining microclimate data. Recent advances in microclimate modelling, however, suggest that microclimate conditions can now be predicted anywhere at any time using hybrid physically- and empirically-based models. Here, for the first time, we test the utility of this approach across a remote, inaccessible, and climate change threatened polar island ecosystem at ecologically relevant scales. Microclimate predictions were generated at a 100 x 100 m grain (at a height of 4 cm) across the island, with models parameterised using either meteorological observations from the islands weather station (AWS) or climate reanalysis data (CRA). AWS models had low error rates and were highly correlated with observed seasonal and daily temperatures (root mean squared error of predicted seasonal average Tmean [≤] 0.6 {degrees}C; Pearsons correlation coefficient (r) for the daily Tmean [≥] 0.86). By comparison, CRA models had a slight warm bias in all seasons and a smaller diurnal range in the late summer period than in situ observations. Despite these differences, the modelled relationship between the percentage cover of the threatened endemic cushion plant Azorella macquariensis and microclimate varied little with the source of microclimate data (r = 0.97), suggesting that both model parameterisations capture similar patterns of spatial variation in microclimate conditions across the island ecosystem. Here, we have shown that the accurate prediction of microclimate conditions at ecologically relevant spatial and temporal scales is now possible using hybrid physically- and empirically-based models across even the most remote and climatically extreme environments. These advances will help add the microclimate dimension to ecological and biogeographic studies, which could be critical for delivering climate change-resilient conservation planning in climate-change exposed ecosystems.


title: Data proliferation, reconciliation, and synthesis in viral ecology

abstract: The fields of viral ecology and evolution have rapidly expanded in the last two decades, driven by technological improvements, and motivated by efforts to discover potentially zoonotic wildlife viruses under the rubric of pandemic prevention. One consequence has been a massive proliferation of host-virus association data, which comprise the backbone of research in viral macroecology and zoonotic risk prediction. These data remain fragmented across numerous data portals and projects, each with their own scope, structure, and reporting standards. Here, we propose that synthesis of host-virus association data is a central challenge to improve our understanding of the global virome and develop foundational theory in viral ecology. To illustrate this, we build an open reconciled mammal-virus database from four key published datasets, applying a standardized taxonomy and metadata. We show that reconciling these datasets provides a substantially richer view of the mammal virome than that offered by any one individual database. We argue for a shift in best practice towards the incremental development and use of synthetic datasets in viral ecology research, both to improve comparability and replicability across studies, and to facilitate future efforts to use machine learning to predict the structure and dynamics of the global virome.


title: Geographical variability of bacterial communities of cryoconite holes of Andean glaciers

abstract: Cryoconite holes, ponds full of melting water with a sediment on the bottom, are hotspot of biodiversity of glacier surface. They host a metabolically active bacterial community that is involved in different dynamics concerning glacier ecosystems. Indeed, they are responsible of organic matter production and with other microorganisms establish a real microecosystem. Cryoconite holes have been described in different areas of the world (e.g., Arctic, Antarctic, Alps, Himalaya), and with this study we will provide the first description of bacterial communities of cryoconite holes of the Andes in South America. We collected samples on three high elevation glaciers of the Andes (Iver, Iver East and Morado glaciers) and two Patagonian glaciers located at sea level (Exploradores glacier and Perito Moreno). Results show that the most abundant orders are Burkholderiales, Cytophagales, Sphingobacteriales, Actinomycetales, Pseudomonadales, Rhodospiarillales, Rhizobiales, Sphingomonadales and Bacteroidales, which have been reported on glaciers of other areas of the world, Bacterial communities change from one glacier to another and both water pH and O2 concentration affect bacterial communities composition.


title: Myoglobin primary structure reveals multiple convergent transitions to semi-aquatic life in the world smallest mammalian divers

abstract: Identifying the phylogenomic underpinnings of specialized phenotypes that fueled transitions into new adaptive zones is central to evolutionary biology but is often confounded by a fragmentary fossil record, morphological convergence, and unresolved phylogenetic relationships. The speciose mammalian order Eulipotyphla (e.g., moles, shrews, hedgehogs, solenodons) combines an unusual diversity of semi-aquatic, semi-fossorial, and fossorial forms that arose from terrestrial forbearers, yet the ecomorphological pathways leading to these lifestyles have been disputed for a century and more, calling for novel approaches. Here we resolve previously intractable eulipotyphlan intra-family relationships and establish the net surface charge of the oxygen-storing muscle protein myoglobin-readily determined from its primary structure-as a molecular signature to trace ancient lifestyle transitions based on protein sequence alone. Our analyses confidently resolve fossorial habits having evolved twice in talpid moles and reveal five independent origins of a semi-aquatic lifestyle in the order housing the worlds smallest endothermic divers.

category: evolutionary biology


title: Global analysis of expression, maturation and subcellular localization of mouse liver transcriptome identifies novel sex-biased and TCPOBOP-responsive long non-coding RNAs

abstract: While nuclear transcription and RNA processing and localization are well established for protein coding genes (PCGs), these processes are poorly understood for lncRNAs. Here, we characterize global patterns of transcript expression, maturation and localization for mouse liver RNA, including more than 15,000 lncRNAs. PolyA-selected liver RNA was isolated and sequenced from four subcellular fractions (chromatin, nucleoplasm, total nucleus, and cytoplasm), and from the chromatin-bound fraction without polyA selection. Transcript processing, determined from normalized intronic to exonic sequence read density ratios, progressively increased for PCG transcripts in going from the chromatin-bound fraction to the nucleoplasm and then on to the cytoplasm. Transcript maturation was similar for lncRNAs in the chromatin fraction, but was significantly lower in the nucleoplasm and cytoplasm. LncRNAs were 11-fold more likely to be significantly enriched in the nucleus than cytoplasm, and 100-fold more likely to be significantly chromatin-bound than nucleoplasmic. Sequencing chromatin-bound RNA greatly increased the sensitivity for detecting lowly expressed lncRNAs and enabled us to discover and localize hundreds of novel regulated liver lncRNAs, including lncRNAs showing sex-biased expression or responsiveness to a xenobiotic agonist ligand of constitutive androstane receptor (Nr1i3). Integration of our findings with prior studies and lncRNA annotations identified candidate regulatory lncRNAs for a variety of hepatic functions based on gene co-localization within topologically associating domains or transcription divergent or antisense to PCGs associated with pathways linked to hepatic physiology and diseases.


title: Using Bayesian Optimization to Identify Optimal Exoskeleton Parameters Targeting Propulsion Mechanics: A Simulation Study

abstract:
In this study, we determined the feasibility of modeling the relationship between robot control parameters and propulsion mechanics as a Gaussian process. Specifically, we used data obtained in a previous experiment that used pulses of torque applied at the hip and knee joint, at early and late stance, to establish the relationship a 3D control parameter space and the resulting changes in hip extension and propulsive impulse. We estimated Gaussian models both at the group level and for each subject. Moreover, we used the estimated subject-specific models to simulate virtual human-in-the-loop optimization (HIL) experiments based on Bayesian optimization to establish their convergence under multiple combinations of acquisition functions and seed point selection methods.

Results of the group-level model are in agreement with those obtained with linear mixed effect model, thus establishing the feasibility of Gaussian process modeling. The estimated subject-specific optimal conditions have large between-subject variability in the metric of propulsive impulse, with only 31% of subjects featuring a subject-specific optimal point in the surrounding of the group-level optimal point. Virtual HIL experiments indicate that expected improvement is the most effective acquisition method, while no significant effect of seed point selection method was observed. Our study may have practical effects on the adoption of HIL robot-assisted training methods focused on propulsion.


title: A sequence-based method for predicting extant fold switchers that undergo α-helix <-> β-strand transitions

abstract: Extant fold-switching proteins remodel their secondary structures and change their functions in response to cellular stimuli, regulating biological processes and affecting human health. In spite of their biological importance, these proteins remain understudied. Few representative examples of fold switchers are available in the Protein Data Bank, and they are difficult to predict. In fact, all 96 experimentally validated examples of extant fold switchers were stumbled upon by chance. Thus, predictive methods are needed to expedite the process of discovering and characterizing more of these shapeshifting proteins. Previous approaches require a solved structure or all-atom simulations, greatly constraining their use. Here, we propose a high-throughput sequence-based method for predicting extant fold switchers that transition from -helix in one conformation to {beta}-strand in the other. This method leverages two previous observations: (1) -helix <-> {beta}-strand prediction discrepancies from JPred4 are a robust predictor of fold switching, and (2) the fold-switching regions (FSRs) of some extant fold switchers have different secondary structure propensities when expressed in isolation (isolated FSRs) than when expressed within the context of their parent protein (contextualized FSRs). Combining these two observations, we ran JPred4 on the sequences of isolated and contextualized FSRs from 14 known extant fold switchers and found -helix <->{beta}-strand prediction discrepancies in every case. To test the overall robustness of this finding, we randomly selected regions of proteins not expected to switch folds (single-fold proteins) and found significantly fewer -helix <-> {beta}-strand prediction discrepancies (p < 4.2*10-20, Kolmogorov-Smirnov test). Combining these discrepancies with the overall percentage of predicted secondary structure, we developed a classifier that often robustly identifies extant fold switchers (Matthews Correlation Coefficient of 0.70). Although this classifier had a high false negative rate (6/14), its false positive rate was very low (1/211), suggesting that it can be used to predict a subset of extant fold switchers from billions of available genomic sequences.


title: satuRn: Scalable Analysis of differential Transcript Usage for bulk and single-cell RNA-sequencing applications

abstract: Alternative splicing produces multiple functional transcripts from a single gene. Dysregulation of splicing is known to be associated with disease and as a hallmark of cancer. Existing tools for differential transcript usage (DTU) analysis either lack in performance, cannot account for complex experimental designs or do not scale to massive scRNA-seq data. We introduce satuRn, a fast and flexible quasi-binomial generalized linear modelling framework that is on par with the best performing DTU methods from the bulk RNA-seq realm, while providing good false discovery rate control, addressing complex experimental designs and scaling to scRNA-seq applications.


title: MolRep: A Deep Representation Learning Library for Molecular Property Prediction

abstract:
SummaryRecently, novel representation learning algorithms have shown potential for predicting molecular properties. However, unified frameworks have not yet emerged for fairly measuring algorithmic progress, and experimental procedures of different representation models often lack rigorousness and are hardly reproducible. Herein, we have developed MolRep by unifying 16 state-of-the-art models across 4 popular molecular representations for application and comparison. Furthermore, we ran more than 12.5 million experiments to optimize hyperparameters for each method on 12 common benchmark data sets. As a result, CMPNN achieves the best results ranked the 1st in 5 out of 12 tasks with an average rank of 1.75. Relatively, ECC has good performance in classification tasks and MAT good for regression (both ranked 1st for 3 tasks) with an average rank of 2.71 and 2.6, respectively.

AvailabilityThe source code is available at: https://github.com/biomed-AI/MolRep

Supplementary informationSupplementary data are available online.


title: Multiplatform Integrative Analyses of Immunosuppressive Signatures in Cortisol-secreting Adrenocortical Carcinoma

abstract: Adrenocortical carcinoma (ACC) is a rare but highly aggressive malignancy and nearly half of ACC tumors have been shown to overproduce and secrete adrenal steroids. Excess cortisol secretion, in particular, has been associated with poor prognosis among ACC patients. Furthermore, recent immunotherapy clinical trials demonstrated significant immunoresistance among cortisol-secreting ACC (CS-ACC) patients when compared to their non-Cortisol-secreting (nonCS-ACC) counterparts. The immunosuppressive role of excess glucocorticoid therapies and secretion is well established, however, the impact of the cortisol hypersecretion on ACC tumor microenvironment (TME), immune expression profiles, and immune cell responses remain largely undefined. In this study, we characterized the TME of ACC patients and compared the immunogenomic profiles of nonCS-ACC and CS-ACC tumors to assess the impact of differentially expressed genes (DEGs) related to immune processes on patient prognosis. Comprehensive multiplatform immunogenomic computational analyses of ACC tumors deciphered an immunosuppressive expression profile with a direct impact on patient survival. We identified several primary immunogenomic prognostic indicators and potential targets within the tumor immune landscape of CS-ACC that define a distinct TME and provide additional insight into the understanding of potential contributory mechanisms underlying failure of initial immunotherapeutic trials and poor prognosis of patients with CS-ACC.

category: cancer biology


title: A triple-negative matrix-producing breast carcinoma is arrested by tumor-targeting Salmonella typhimurium A1-R in a PDOX model

abstract:
Background/AimMatrix-producing breast carcinoma (MPBC), is a rare, recalcitrant and highly aggressive. The present study aimed to determine the efficacy of tumor-targeting Salmonella typhimurium (S. typhimurium) A1-R on a triple-negative MPBC in a patient-derived orthotopic xenograft (PDOX) model.

MethodsThe PDOX model was established in the left second mammary gland of a nude mouse by surgical orthotopic implantation (SOI) of the patient triple-negative MPBC PDOX models were randomized into two groups: G1, control group (n=6); G2, tumor-targeting S. typhimurium A1-R group (n=7, intravenous (i.v.) injection via tail vein, weekly, for two weeks). All mice were sacrificed on day 15. Tumor volume and body weight were measured one time per week.

ResultsS. typhimurium A1-R arrested tumor growth compared to the control group (P = 0.016).

ConclusionThe results of the present study suggest that S. typhimurium A1-R has future clinical potential in triple-negative MPBC patients.


title: Environment-Dependent Switch between Two Immune Systems against Ralstonia solanacearum Infections in Pepper

abstract:
O_LIAlthough plant diseases generally cause more severe symptoms under conditions of high temperature and high humidity(HTHH), how plant respond to pathogen attack under this condition remains elusive.
C_LIO_LIAs an example, we herein comparatively studied pepper(Capsicum annuum) immunity against Ralstonia solanacearum under HTHH and ambient temperature by approaches of reverse genetics. We found that pepper respond to R.solanacearum infection by activating salicylic-acid- and jasmonic-acid-mediated immunity at ambient temperature. Under HTHH, However, it no longer activates JA-mediated immunity and activates only transient SA signaling at the early stage of R.solanacearum infection, but instead induces cytokinin mediated immunity.
C_LIO_LIThese two immune systems are positively regulated by CaWRKY40 via binding the WT-box and a novel W-box like (WL) box, respectively, in an environment-dependent manner: CaWRKY40 is activated upon R. solanacearum infection under HTHH, thereby upregulating ISOPENTENYLTRANSFERASE5(IPT5). The resulting cytokinin then works synergistically with CaWRKY40 in activating a subset of glutathione S-transferase genes via chromatin activation and WL-box binding, but prevent CaWRKY40 from activating ISOCHORISMATE SYNTHASE1 (ICS1) or SA-/JA-dependent pathogenesis-related genes by chromatin inactivation or by blocking WT-box binding.
C_LIO_LIThese results highlight the specific pepper immune response to R. solanacearum infection under HTHH and its synergistic activation by CaWRKY40 and cytokinins.
C_LI


title: An open-source tool to assess the carbon footprint of research

abstract:
The scrutiny over the carbon footprint of academics has increased rapidly in the last few years. This has resulted in a series of publications providing various estimates of the carbon footprint of one or several research activities, principally at the scale of a university or a research center or, more recently, a field of research. The variety of tools or methodologies - on which these estimates rely - unfortunately prevents from any direct comparison because of the sensitivity of carbon footprint assessments to variations in the scope and to key parameters such as emission factors. In an effort to enabling a robust comparison of research carbon footprints across institutions, contexts or disciplines, we present an open-source web application, GES 1point5 designed to estimate the carbon footprint of a department, research lab or team in any country of the world with a transparent and common methodology. The current version of GES 1point5, open-source and freely available, takes into account the most common and often predominant emission sources in research labs: buildings, digital devices, commuting, and professional travel. GES 1point5 is developed by an interdisciplinary team of scientists from several public research institutions in France as part of the Labos 1point5 project. GES 1point5 is therefore presently tailored for the French context but can be adjusted to any national contexts by adjusting the values of emission factors. The versatility and usability of the software have been empirically validated by its adoption by several hundred research labs in France over the last 18 months. In addition to enabling the estimation and monitoring of greenhouse gas (GHG) emissions at the scale of a research lab, GES 1point5 is designed to aggregate the data entered by the labs and the corresponding GHG emissions estimates into a comprehensive database. GES 1point5 can therefore allow to (i) identify robust determinants of the carbon footprint of research activities across a network of research labs (ii) estimate the carbon footprint of research at the national scale. A preliminary analysis of the carbon footprint of more than one hundred laboratories is presented to illustrate the potential of the approach. While assessments of carbon footprints are often externalized onto extension services and proprietary softwares, GES 1point5 is designed as a hands-on, pedagogic and transparent tool for research labs to monitor and reduce their own carbon footprint. This internalization has strong positive co-benefits for academics in terms of awareness and empowerment. We further expect that international dissemination of GES 1point5 will contribute to establishing a global understanding of the drivers of the research carbon footprint worldwide and an identification of the levers to decrease it.

Availability and implementationGES 1point5 is available online at http://labos1point5.org/ges-1point5 and its source code can be downloaded from the GitLab platform at https://framagit.org/labos1point5/l1p5-vuejs.

category: scientific communication and education


title: Integrating protein networks and machine learning for disease stratification in the Hereditary Spastic Paraplegias

abstract: The Hereditary Spastic Paraplegias are a group of neurodegenerative diseases characterized by spasticity and weakness in the lower body. Despite the identification of causative mutations in over 70 genes, the molecular aetiology remains unclear. Due to the combination of genetic diversity and variable clinical presentation, the Hereditary Spastic Paraplegias are a strong candidate for protein-protein interaction network analysis as a tool to understand disease mechanism(s) and to aid functional stratification of phenotypes. In this study, experimentally validated human protein-protein interactions were used to create a protein-protein interaction network based on the causative Hereditary Spastic Paraplegia genes. Network evaluation as a combination of both topological analysis and functional annotation led to the identification of core proteins in putative shared biological processes such as intracellular transport and vesicle trafficking. The application of machine learning techniques suggested a functional dichotomy linked with distinct sets of clinical presentations, suggesting there is scope to further classify conditions currently described under the same umbrella term of Hereditary Spastic Paraplegias based on specific molecular mechanisms of disease.

category: systems biology


title: Atopic Biomarker Changes after Exposure to Porphyromonas gingivalis Lipopolysaccharide: A Small Experimental Study in Wistar Rat

abstract:
BackgroundIgE and IgG4 are implicated in atopic development and clinically utilized as major biomarkers. Atopic responses following certain pathogens such as Porphyromonas gingivalis is currently an area of interest for further research.

PurposeThe aim of this study is to measure the level of IgE, IgG4, and IgG4/IgE ratio periodically after exposure of periodontal pathogen Porphyromonas gingivalis (Pg) lipopolysaccharide (LPS).

MethodsWe used 16 wistar rats (Rattus norvegicus) randomly subdivided into 4 groups, group 1 were injected by placebo, group 2 by LPS Pg 0.3 g/mL,group 3 by LPS Pg 1 g/mL, and group 4 by LPS Pg 3 g/mL. Sera from both groups were taken from retro-orbital plexus before and after exposure.

ResultsLevel of IgE and IgG4 increased significantly following exposure of LPS Pg at day-4 and day-11. Greater increase of IgE rather than IgG4 contributes to rapid decline of IgG4/IgE ratio, detected in the peripheral blood at day-4 and day-11.

ConclusionModulation of atopic responses following exposure to LPS Pg is reflected by decrease in IgG4/IgE ratio that accompanies an increase of IgE.

Clinical significancePorphyromonas gingivalis, a keystone pathogen during periodontal disease, may have a tendency to disrupt atopic biomarkers.


title: Ecological correlates of reproductive status in a guild of Afrotropical understory trees

abstract: The relative abundance patterns of tropical trees have been of interest since the expeditions of Alfred Russel Wallace, but little is known about how differences in relative abundance relate to reproductive patterns. Flowering is resource-dependent and fitness differences as well as differences in the quality of the abiotic and biotic neighborhood may contribute to the variation in reproductive status responsible for population-level flowering patterns. This variation determines the density and distance between flowering conspecifics and may alter relative abundance extremes among species during reproduction, factors known to influence pollination success. We collected flowering status data for a guild of twenty-three co-occurring tree species that flower in the understory of the Korup Forest Dynamics Plot in Cameroon. We examined how the occurrence and location of reproductive events were related to spatial patterns of adult abundance, focal tree size, neighborhood crowding, and habitat, while accounting for the influence of shared ancestry. Across species, the probability of flowering was higher for individuals of rarer species and for larger individuals but was unrelated to neighborhood crowding or habitat differences. Relative abundance extremes were reduced when only flowering individuals were considered, leading to a negative relationship between plot abundance and flowering probability at the species level that was not structured by shared ancestry. Spatially, flowering conspecifics tended to be overdispersed relative to all adult conspecifics. Rare species are predicted to suffer Allee effects or reduced fitness due to the difficulty of finding mates at low densities and frequencies. Here, however, rare species appear to maximize the size of their mate pool, compared to abundant species. If this partial  leveling of the playing field during reproduction is typical, it has consequences for our understanding of biodiversity maintenance and species coexistence in tropical forests.


title: Impact of K-Pg Mass Extinction Event on Crocodylomorpha Inferred from Phylogeny of Extinct and Extant Taxa

abstract: Crocodilians and their allies have survived several mass extinction events. However, the impact of the K-Pg mass extinction event on crocodylomorphs is considered as minor or non-existent although other clades of archosaurs, e.g., non-avian dinosaurs and pterosaurs, went extinct completely. Previous approaches using fossil occurrence data alone have proven inconclusive. In this paper, we take a phylogenetic approach using extant and extinct species. The time-calibrated phylogeny of extant crocodilians provides insights into the pattern of recent biodiversity changes whereas fossil occurrence data provide insights about the more ancient past. The two data sources combined into a single phylogeny with extinct and extant taxa provide a holistic view of the historical biodiversity. To utilize this combined data and to infer the impact of the K-Pg mass extinction event, we derive the likelihood function for a time-varying (episodic) serially sampled birth-death model that additionally incorporates mass extinctions and bursts of births. We implemented the likelihood function in a Bayesian framework with recently developed smoothing priors to accommodate for both abrupt and gradual changes in speciation, extinction and fossilization rates. Contrary to previous research, we find strong evidence for the K-Pg extinction event in crocodiles and their allies. This signal is robust to uncertainty in the phylogeny and the prior on the mass extinctions. Through simulated data analyses, we show that there is high power to detect this mass extinction and little risk of false positives.


title: A novel Wnt/beta-catenin signaling driven adipocyte population that is required for beiging

abstract: Wnt/{beta}-catenin signaling has been well established as a potent inhibitor of adipogenesis. Here, we identified a population of adipocytes that exhibit persistent activity of Wnt/{beta}-catenin signaling, as revealed by the Tcf/Lef-Gfp reporter allele, in embryonic and adult mouse fat depots, named as Wnt+ adipocytes. We showed that the {beta}-catenin-mediated signaling activation in these cells is Wnt ligand- and receptor-independent but relies on AKT/mTOR pathway and is essential for cell survival. Such adipocytes are distinct from classical ones in transcriptomic and genomic signatures and can be induced from various sources of mesenchymal stromal cells including human cells. Genetic lineage-tracing and targeted cell ablation studies revealed that these adipocytes convert into beige adipocytes directly and are also required for beige fat recruitment under thermal challenge, demonstrating both cell autonomous and non-cell autonomous roles in adaptive thermogenesis. Furthermore, mice bearing targeted ablation of these adipocytes exhibited glucose intolerance, while mice receiving exogenously supplied such cells manifested enhanced glucose utilization. Our studies uncover a unique adipocyte population in regulating beiging in adipose tissues and systemic glucose homeostasis.


title: A Wnt/β-catenin signaling driven adipocyte population required for beiging and glucose homeostasis


title: Discovery and functional assessment of a novel adipocyte population driven by intracellular Wnt/β-catenin signaling in mammals