title: Hierarchical Clustering on RNA Dependent RNA Polymerase using Machine Learning.

abstract:
RNA Dependent RNA Polymerase (RdRP) catalyzes the replication of RNA from an RNA template and is mostly found in Viruses. We have collected over 161 viral RdRP FASTA Sequences from the NCBI protein database using python script. Each of these sequences was transformed with TfidfVectorizer using sklearn module, with the "one Letter" word, because each Letter belongs to one Amino acid. These transformed data were sent to Hierarchical clustering using scipy library and visualized data using Dendrogram. These Machine Learning technique is able to classify or segment similar RdRp into one cluster. Each of these clusters was tested for their multiple sequence alignment with COBALT of NCBI. We observed that these clusters predicted similar RdRP among various viruses. These techniques can be further improved to segment or classify various proteins. These Machine Learning or Artificial Intelligence techniques need more improvement in their algorithms to solve genomics and proteomics.

RepositoryPrograms and Datasets : https://github.com/DSPavan/RdRP


title: Assessing the use of ellipsoidal microparticles for determining lipid membrane viscosity

abstract:
The viscosity of lipid membranes sets the timescales of membrane-associated flows and therefore influences the dynamics of a wide range of cellular processes. Techniques to measure membrane viscosity remain sparse, however, and reported measurements to date, even of similar systems, give viscosity values that span orders of magnitude. To address this, we improve a method based on measuring both the rotational and translational diffusion of membrane-anchored microparticles and apply this approach and one based on tracking the motion of phase-separated lipid domains to the same system of phase-separated giant vesicles. We find good agreement between the two methods, with inferred viscosities within a factor of two of each other. Our technique uses ellipsoidal microparticles, and we show that the extraction of physically meaningful viscosity values from their motion requires consideration of their anisotropic shape. The validation of our method on phase-separated membranes makes possible its application to other systems, which we demonstrate by measuring the viscosity of bilayers composed of lipids with different chain lengths ranging from 14 to 20 carbon atoms, revealing a very weak dependence of two-dimensional viscosity on lipid size. The experimental and analysis methods described here should be generally applicable to a variety of membrane systems, both reconstituted and cellular.

Statement of SignificanceThe lipid bilayers that underlie cellular membranes are two-dimensional fluids whose viscosity sets timescales of flow. Lipid membrane viscosity remains poorly quantified, with a paucity of methods and considerable disagreement between values reported using different techniques. We describe a method based on measuring the Brownian diffusion of ellipsoidal microparticles which we apply to phase-separated membranes alongside a previously established method for determining membrane viscosity, finding good agreement between the two techniques. We further examine homogenous membranes composed of lipids with different chain lengths, not amenable to phase-separationbased methods, revealing a very weak dependence of viscosity on lipid size. Our approach should be applicable to a wide range of membrane systems, both in vitro and in living cells.

category: biophysics


title: Integrative Genome Modeling Platform reveals essentialityof rare contact events in 3D genome organizations

abstract:
A multitude of sequencing-based and microscopy technologies provide the means to unravel the relationship between the three-dimensional (3D) organization of genomes and key regulatory processes of genome function. However, it remains a major challenge to systematically integrate all available data sources to characterize the nuclear organization of genomes across different spatial scales. Here, we develop a multi-modal data integration approach to produce genome structures that are highly predictive for nuclear locations of genes and nuclear bodies, local chromatin compaction, and spatial segregation of functionally related chromatin.

By performing a quantitative assessment of the predictive power of genome structures generated from different data combinations, we demonstrate that multimodal data integration can compensate for systematic errors and missing values in some of the data and thus, greatly increases accuracy and coverage of genome structure models. We also show that alternative combinations of different orthogonal data sources can converge to models with similar predictive power. Moreover, our study reveals the key contributions of low-frequency inter-chromosomal contacts (e.g., "rare" contact events) to accurately predicting the global nuclear architecture, including the positioning of genes and chromosomes. Overall, our results highlight the benefits of multi-modal data integration for genome structure analysis, available through the Integrative Genome structure Modeling (IGM) software package that we introduce here.


title: Induction of soluble platelet activation markers and FXIII deficiency promote COVID-19 severity

abstract:
IntroductionCoagulation dysfunction and thromboembolism emerge as strong comorbidity factors in severe COVID-19. However, it is unclear when particularly platelet activation markers and coagulation factors dysregulated during the pathogenesis of COVID-19. Here, we sought to assess the levels of coagulation and platelet activation markers at moderate and severe stages of COVID-19 to understand the pathogenesis.

MethodsTo understand this, hospitalized COVID-19 patients with (severe cases that required intensive care) or without pneumonia (moderate cases) were recruited. Phenotypic and molecular characterizations were performed employing basic coagulation tests including PT, APTT, D-Dimer and TFPI. The flow cytometry-based multiplex assays were performed to assess FXI, anti-thrombin, prothrombin, fibrinogen, FXIII, P-selectin, sCD40L, plasminogen, tissue-plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1) and D-Dimer.

ResultsThe investigations revealed induction of plasma P-selectin and CD40 ligand (sCD40L) in moderate COVID-19 cases which were significantly abolished with the progression of COVID-19 severity. Moreover, a profound reduction in plasma tissue factor pathway inhibitor (TFPI) and FXIII were identified particularly in the severe COVID-19. Further analysis revealed fibrinogen induction in both moderate and severe patients. Interestingly, an elevated PAI-1 more prominently in moderate, and tPA particularly in severe COVID-19 cases were observed. Particularly, the levels of fibrinogen and tPA directly correlated with the severity of the disease.

ConclusionsIn summary, induction of soluble P-selectin, sCD40L, fibrinogen and PAI-1 in moderate COVID-19 cases suggests the activation of platelets and coagulation system before patients require intensive care. These findings would help in designing better thromboprophylaxis to limit the COVID-19 severity.

category: pathology


title: SARS-CoV-2 infection induces soluble platelet activation markers and PAI-1 in the early moderate stage of COVID-19


title: An NLR Integrated Decoy toolkit to identify plant pathogen effector targets

abstract:
Plant resistance genes (or NLR "Nod-like Receptors") are known to contain atypical domains procuring them with a decoy capacity. Some of these integrated domains (or ID) allow the plant to lure the virulence determinants ("effectors") of pathogens and triggering a specific NLR immune reaction.

In this work, our goal was to generate a library of known IDs that could be screened with plant pathogen effectors in order to identify putative new effector virulence targets and NLR-effector pairs.

We curated the IDs contained in NLRs from seven model and crop plant species. We cloned 52 IDs representing 31 distinct Pfam domains. This library was screened for interaction by yeast-two-hybrid with a set of 31 conserved Ralstonia solanacearum type III effectors. This screening and the further in planta interaction assay allowed us to identify three interactions, involving different IDs (kinase, DUF3542, WRKY) and two type III effectors (RipAE and PopP2).

PopP2 was found to physically interact with ID#85, an atypical WRKY domain integrated in the GmNLR-ID85 NLR protein from Soybean. Using a imaging method in living plant cells, we showed that PopP2 associates with ID#85 in the nucleus. But unlike the known WRKY-containing Arabidopsis RRS1-R NLR receptor, this newly identified soybean WRKY domain could not be acetylated by PopP2 and its atypical sequence (WRKYGKR) also probably renders it inefficient in plant immunity triggering.

This ID toolkit is available for screening with other plant pathogen effectors and should prove useful to discover new effectors targets and potentially engineer new plant resistance genes.

category: plant biology


title: An NLR Integrated Domain toolkit to identify plant pathogen effector targets


title: speedingCARs: accelerating the engineering of CAR T cells by signaling domain shuffling and single-cell sequencing

abstract: Chimeric antigen receptors (CARs) consist of an extracellular antigen-binding region fused to intracellular signaling domains, thus enabling customized T cell responses against target cells. Due to the low-throughput process of systematically designing and functionally testing CARs, only a small set of immune signaling domains have been thoroughly explored, despite their major role in T cell activation, effector function and persistence. Here, we present speedingCARs, an integrated method for engineering CAR T cells by signaling domain shuffling and functional screening by single-cell sequencing. Leveraging the inherent modularity of natural signaling domains, we generated a diverse library of 180 unique CAR variants, which were genomically integrated into primary human T cells by CRISPR-Cas9. Functional and pooled screening of the CAR T cell library was performed by co-culture with tumor cells, followed by single-cell RNA sequencing (scRNA-seq) and single-cell CAR sequencing (scCAR-seq), thus enabling high-throughput profiling of multi-dimensional cellular responses. This led to the discovery of several CAR variants that retained the ability to kill tumor cells, while also displaying diverse transcriptional signatures and T cell phenotypes. In summary, speedingCARs substantially expands and characterizes the signaling domain combinations suited for CAR design and supports the engineering of next-generation T cell therapies.

category: synthetic biology


title: Single Nucleotide Polymorphisms in the Bovine TLR2 Extracellular Domain Contribute to Breed and Species-Specific Innate Immune Functionality

abstract: Recent evidence suggests that several cattle breeds may be more resistant to infection with the zoonotic pathogen Mycobacterium bovis than others. Our data presented here suggests that the response to mycobacterial antigens varies in macrophages generated from Brown Swiss (BS) and Holstein Frisian (HF) cattle, two breeds belonging to the Bos taurus family. Whole genome sequencing of the Brown Swiss genome identified several potential candidate genes, in particular Toll-like Receptor-2 (TLR2) a pattern recognition receptor (PRR) that has previously been described to be involved in mycobacterial recognition. Further investigation revealed single nucleotide polymorphisms (SNP) in TLR2 that were identified between DNA isolated from cells of BS and HF cows. Interestingly, one specific SNP, H326Q, showed a different genotype frequency in two cattle subspecies, Bos taurus and Bos indicus. Cloning of the TLR2 gene and subsequent gene-reporter and chemokine assays revealed that this SNP, present in BS and Bos indicus breeds, resulted in a significantly higher response to mycobacterial antigens as well as tri-acylated lipopeptide ligands in general. Comparing wild-type and H326Q containing TLR2 responses, wild-type bovine TLR2 response showed clear, diminished mycobacterial antigen responses compared to human TLR2, however bovine TLR2 responses containing H326Q were found to be partially recovered compared to human TLR2. The creation of human:bovine TLR2 chimeras increased the response to mycobacterial antigens compared to the full-length bovine TLR2, but significantly reduced the response compared to the full-length human TLR2. Thus, our data, not only present evidence that TLR2 is a major PRR in the mammalian species-specific response to mycobacterial antigens, but furthermore, that there are clear differences between the response seen in different cattle breeds, which may contribute to their enhanced or reduced susceptibility to mycobacterial infection.

category: immunology


title: Spatial, temporal and molecular dynamics of swine influenza virus-specific CD8 tissue resident memory T cells.

abstract:
We defined naive, central memory, effector memory and terminally differentiated porcine CD8 T cells and analyzed their phenotype in lymphoid and respiratory tissues after influenza infection or immunization using peptide-MHC tetramers of three influenza nucleoprotein (NP) epitopes. The hierarchy of response to the three epitopes changes during the response in different tissues. Most NP-specific CD8 T cells in broncho-alveolar lavage (BAL) and lung are tissue resident memory cells (TRM), that express CD69 and have an effector memory or terminally differentiated phenotype. NP-specific cells isolated from BAL express genes characteristic of TRM, but gene expression differs at 7, 21 and 63 days post infection. The frequency of NP-specific cells declines over 63 days in all tissues but is best maintained in BAL. The pig is a powerful model for understanding how best to induce and harness local immunity to respiratory viruses.

One sentence summaryInfluenza NP-specific porcine tissue resident memory CD8 T cells persist in the lung with major changes in gene expression.


title: Coupled small molecules target RNA interference and JAK/STAT signaling to reduce Zika virus infection in Aedes aegypti

abstract: The recent global Zika epidemics have revealed the significant threat that mosquito-borne viruses pose. There are currently no effective vaccines or prophylactics to prevent Zika virus (ZIKV) infection. Limiting exposure to infected mosquitoes is best way to reduce disease incidence. Recent studies have focused on targeting mosquito reproduction and immune responses to reduce transmission. In particular, previous work evaluated the effect of insulin signaling on antiviral JAK/STAT and RNAi in vector mosquitoes. In this work, we demonstrate that targeting insulin signaling through the repurposing of small molecule drugs results in the activation of both of these antiviral pathways. Activation of this coordinated response additively reduced ZIKV levels in Aedes aegypti mosquitoes. This effect included a quantitatively greater reduction in salivary gland ZIKV levels relative to single pathway activation, indicating the potential for field delivery of these small molecules to substantially reduce virus transmission.

category: microbiology


title: A robust ex vivo system to study cellular dynamics underlying mouse peri-implantation development

abstract: Upon implantation, mammalian embryos undergo major morphogenesis and key developmental processes such as body axis specification and gastrulation. However, limited accessibility obscures study of these crucial processes. Here, we develop an ex vivo Matrigel-collagen-based culture to recapitulate mouse development from E4.5 to 6.0. Our system not only recapitulates embryonic growth, axis initiation, and overall 3D architecture in 49% of cases, its compatibility with light-sheet microscopy enables study of cellular dynamics through automatic cell segmentation. We find that upon implantation, release of the increasing tension in the polar trophectoderm is necessary for its constriction and invagination. The resulting extra-embryonic ectoderm plays a key role in growth, morphogenesis and patterning of the neighboring epiblast, which subsequently gives rise to all embryonic tissues. This 3D-ex vivo system thus offers an unprecedented access to peri-implantation development for in toto monitoring, measurement and spatio-temporally controlled perturbation, revealing a mechano-chemical interplay between extra-embryonic and embryonic tissues.

category: developmental biology


title: SmcHD1 underlies the formation of H3K9me3 blocks on the inactive X chromosome in mice

abstract: Stable silencing of the inactive X chromosome (Xi) in female mammals is critical for the development of embryos and their postnatal health. SmcHD1 is essential for stable silencing of the Xi, and its functional deficiency results in derepression of many X-inactivated genes. Although SmcHD1 has been suggested to play an important role in the formation of higher order chromatin structure of the Xi, the underlying mechanism is largely obscure. Here we explore the epigenetic state of the Xi in SmcHD1-deficient epiblast stem cells (EpiSCs) and mouse embryonic fibroblasts (MEFs) in comparison with their wild-type counterparts. The results suggest that SmcHD1 underlies the formation of H3K9me3-enriched blocks on the Xi, which, although the importance of H3K9me3 has been largely overlooked in mice, play a critical role in the establishment of the stably silenced state. We propose that the H3K9me3 blocks formed on the Xi facilitate robust heterochromatin formation in combination with H3K27me3, and the substantial loss of H3K9me3 caused by SmcHD1 deficiency leads to aberrant distribution of H3K27me3 on the Xi and derepression of X-inactivated genes.

category: genetics


title: Tracheal tube fusion in Drosophila involves release of luminal exosomes from multivesicular bodies

abstract: Extracellular vesicles (EVs) comprise diverse types of cell-released membranous structures that are thought to play important roles in intercellular communication. Despite extensive work on the formation and functions of EVs in cultured cells, studies of EVs in vivo have remained scarce. We report here that EVs are present in the developing lumen of tracheal tubes in Drosophila embryos. We defined two distinct EV subpopulations, one of which contains the Munc13-4 homologue Staccato (Stac) and is spatially and temporally associated with tracheal tube fusion events. The formation of Stac-positive luminal EVs depends on the tip-cell-specific GTPase Arl3, which is also required for the formation of Stac-positive multivesicular bodies, suggesting that Stac-EVs derive from fusion of Stac-MVBs with the luminal membrane in tip cells during anastomosis formation. The GTPases Rab27 and Rab35 cooperate downstream of Arl3 to promote Stac-MVB formation and tube fusion. We propose that Stac-MVBs act as membrane reservoirs that facilitate tracheal lumen fusion in a process regulated by Arl3, Rab27, Rab35, and Stac/Munc13-4.


title: Tracheal tube fusion in Drosophila involves release of exosomes from multivesicular bodies


title: Tracheal tube fusion in Drosophila involves release of extracellular vesicles from multivesicular bodies


title: Forest growth responds more to air pollution than soil acidification

abstract: The forests of central Europe have undergone remarkable transitions in the past 40 years as air quality has improved dramatically. Retrospective analysis of Norway spruce (Picea abies) tree rings in the Czech Republic shows that air pollution (e.g. SO2 concentrations, high acidic deposition to the forest canopy) plays a dominant role in driving forest health. Extensive soil acidification occurred in the highly polluted "Black Triangle" in Central Europe, and upper mineral soils are still acidified. In contrast, acidic atmospheric deposition declined by 80% and atmospheric SO2 concentration by 90% between the late 1980s and 2010s. Annual tree ring width (TRW) declined in the 1970s and subsequently recovered in the 1990s, tracking SO2 concentrations closely. Furthermore, recovery of TRW was similar in unlimed and limed stands. Despite large increases in soil base saturation, as well as soil pH, as a result of repeated liming starting in 1981, TRW growth was similar in limed and unlimed plots. TRW recovery was interrupted in 1996 when highly acidic rim (originating from more pronounced decline of alkaline dust than SO2 from local power plants) injured the spruce canopy, but recovered soon to the pre-episode growth. Across the long-term site history, changes in soil chemistry (pH, base saturation, Bc/Al soil solution ratio) cannot explain observed changes in TRW at the two study sites at which we tracked soil chemistry. Instead, statistically significant recovery in TRW is linked to the trajectory of annual SO2 concentrations or sulfur deposition at all three stands.

category: ecology


title: Differential gene expression reveals host factors for viral shedding variation in mallards (Anas platyrhynchos) infected with low-pathogenic avian influenza virus

abstract: Intraspecific variation in pathogen shedding impacts disease transmission dynamics; therefore, understanding the host factors associated with individual variation in pathogen shedding is key to controlling and preventing outbreaks. In this study, ileum and bursa of Fabricius tissues of mallards (Anas platyrhynchos) infected with low-pathogenic avian influenza (LPAIV) were evaluated at various post-infection time points to determine genetic host factors associated with intraspecific variation in viral shedding. By analyzing transcriptome sequencing data (RNA-seq), we found that LPAIV-infected mallards do not exhibit differential gene expression compared to uninfected birds, but that gene expression was associated with viral shedding quantity early in the infection. In both tissues, immune genes were mostly up-regulated in higher shedding birds and had significant positive relationships with viral shedding. In the ileum, host genes involved in viral cell entry were down-regulated in low shedders one day post-infection (DPI), and host genes promoting viral replication were up-regulated in high shedders on two DPI. Our findings indicate that viral shedding is a key factor for gene expression differences in LPAIV-infected mallards, and the genes identified in this study could be important for understanding the molecular mechanisms driving intraspecific variation in pathogen shedding.

category: genomics


title: Monodopsis and Vischeria genomes elucidate the biology of eustigmatophyte algae

abstract: Members of eustigmatophyte algae, especially Nannochloropsis, have been tapped for biofuel production owing to their exceptionally high lipid content. While extensive genomic, transcriptomic, and synthetic biology toolkits have been made available for Nannochloropsis, very little is known about other eustigmatophytes. Here we present three near-chromosomal and gapless genome assemblies of Monodopsis (60 Mb) and Vischeria (106 Mb), which are the sister groups to Nannochloropsis. These genomes contain unusually high percentages of simple repeats, ranging from 12% to 21% of the total assembly size. Unlike Nannochloropsis, LINE repeats are abundant in Monodopsis and Vischeria and might constitute the centromeric regions. We found that both mevalonate and non-mevalonate pathways for terpenoid biosynthesis are present in Monodopsis and Vischeria, which is different from Nannochloropsis that has only the latter. Our analysis further revealed extensive spliced leader trans-splicing in Monodopsis and Vischeria at 36-61% of genes. Altogether, the high-quality genomes of Monodopsis and Vischeria not only serve as the much-needed outgroups to advance Nannochloropsis research, but also shed new light on the biology and evolution of eustigmatophyte algae.


title: Deciphering the major metabolic pathways associated with aluminum tolerance in popcorn roots using label-free quantitative proteomics

abstract: Aluminum toxicity is one of the most important abiotic stresses that affect crop production worldwide. The soluble form (Al3+) inhibits root growth by altering water and nutrients uptake, which also reduces plant growth and development. Under a long term Al3+ exposure, plants can activate several tolerance mechanisms, and to date, there are no reports of large-scale proteomic data of maize in response to this ion. To investigate the post-transcriptional regulation in response to Al toxicity, we performed a label-free quantitative proteomics for comparative analysis of two Al-contrasting popcorn inbred lines and an Al-tolerant commercial hybrid during 72 h under Al-stress. A total of 489 differentially accumulated proteins (DAPs) were identified in the Al-sensitive inbred line, 491 in the Al-tolerant inbred line, and 277 in the commercial hybrid. Among them, 120 DAPs were co-expressed in both Al tolerant genotypes. Bioinformatics analysis indicated that starch and sucrose metabolism, glycolysis/gluconeogenesis, and carbohydrate metabolism were significant biochemical processes regulated in response to Al toxicity. The up accumulation of sucrose synthase and the increase of sucrose content and starch degradation suggest that these components may enhance popcorn tolerance to Al stress. The up-accumulation of citrate synthase suggests a key role of this enzyme in the detoxification process in the Al-tolerant inbred line. The integration of transcriptomic and proteomic data indicated that the Al tolerance response presents a complex regulatory network into the transcription and translation dynamics of popcorn roots development.


title: Time Evolution of the Stroke Symptom-Herb Networks Based on TCM Prescriptions

abstract:
Traditional Chinese Medicine (TCM) has its origins in distant antiquity and has piled up over a long time with much knowledge about diseases, especially stroke. Different combinations of symptom variables yield different combinations of herbs to form a myriad of prescriptions, and they have undergone repeated confirmation and are worthy objects of excavation and analysis. Herbal studies on stroke have developed from genomics to transcriptomics, proteomics and metabolomics, yet more thought is needed on putting time in a wider perspective of the symptoms and herbs for stroke in Chinese medicine.

Due to this, we studied the dynamic structure of TCM prescriptions on stroke, using over 270 TCM prescription books containing 2231 prescriptions related to stroke recorded from 341 to 2000 CE. We labeled the functions of the prescriptions with the symptoms based on subject terms in MESH Neurologic Manifestations, then standardized the herbs in the prescriptions, and finally connected the co-occurring symptoms and herbs in the prescriptions to build an undirected complex network. The Stroke Symptom-Herb Networks (SSHNs) can be seen from its network characteristics that it is not a random network and has small-world characteristics. It has experienced two peaks in its nearly 1700-year history, during the Song dynasty, the Ming and Qing dynasties. From 600 years onwards, the core herb cluster has been initially formed. The comparison of sub-network similarities allowed us to identify several symptoms with similar herb clusters.

We divided the community based on modularity, and by analyzing the community evolution, we found a more fixed historical evolutionary trend with Hemiplegia and Sialorrhea nodes and their associated symptom and herb nodes. In the time series analysis, we found many symptom-herb combinations that were consistently closely related to historic time depends on assessing the similarity between the symptoms and the herbs. The complex network provides a distinctive perspective for understanding the symptom-herb relationships embedded in TCM prescriptions in remote antiquity.

category: scientific communication and education


title: Basolateral Amygdala Represents and Remembers Ethological Events

abstract: The basolateral amygdala plays a crucial role in memory consolidation yet the general neural mechanism remains elusive. Basolateral amygdala neurons were recorded from freely-moving rats as they interacted with different ethological stimuli: male or female rats, a moving toy and food. Over 20% of neurons showed highly tuned event-specific responses to a single class of stimuli. Firing persisted in 30% of these responsive cells for minutes after the removal of the eliciting stimulus. Neural information flowed directionally from event-specific neurons to less specific neurons with changes in connection strength after removal of the stimulus. We propose that the basolateral amygdala identifies specific ethological events, with circuit-wide activity driven by the event-specific neurons during and after the termination of those events likely facilitating active short-term memory consolidation.

category: neuroscience


title: Presence and Stability of SARS-CoV-2 on Environmental Currency and Money Cards

abstract: The highly contagious nature of SARS-CoV-2 has led to several studies on the transmission of the virus. A little studied potential fomite of great concern in the community is currency, which has been shown to harbor microbial pathogens in several studies. Since the onset of the COVID-19 pandemic, many businesses in the United States have limited the use of banknotes in favor of credit cards. However, SARS-CoV-2 has shown greater stability on plastic in several studies. Herein, the stability of SARS-CoV-2 at room temperature on banknotes, money cards and coins was investigated. In vitro studies with live virus suggested SARS-CoV-2 was highly unstable on banknotes, showing an initial rapid reduction in viable virus and no viral detection by 24 hours. In contrast, SARS-CoV-2 was far more stable on money cards with live virus detected after 48 hours. Environmental swabbing of currency and money cards on and near the campus of Brigham Young University supported these results, with no detection of SARS-CoV-2 RNA on banknotes, and a low level on money cards. No viable virus was detected on either. These preliminary results suggest that the use of money cards over banknotes in order to slow the spread of this virus may be ill-advised. These findings should be investigated further through larger environmental studies involving more locations.


title: Directed Differentiation of Human Pluripotent Stem Cells into Radial Glia and Astrocytes Bypasses Neurogenesis

abstract: Derivation of astrocytes from human pluripotent stem cells (hPSCs) is inefficient and cumbersome, impeding their use in biomedical research. Here, we developed a highly efficient chemically defined astrocyte differentiation strategy that overcomes current limitations. This approach largely bypasses neurogenesis, which otherwise precedes astrogliogenesis during brain development and in vitro experiments. hPSCs were first differentiated into radial glial cells (RGCs) exhibiting in vivo-like radial glia signatures. Activation of NOTCH and JAK/STAT pathways in bona fide RGCs resulted in direct astrogliogenesis confirmed by expression of various glial markers (NFIA, NFIB, SOX9, CD44, S100B, GFAP). Transcriptomic and genome-wide epigenetic analyses confirmed RGC-to-astrocyte differentiation and absence of neurogenesis. The morphological and functional identity of hPSC-derived astrocytes was confirmed by using an array of methods (e.g. electron microscopy, calcium imaging, co-culture with neurons, grafting into mouse brains). Lastly, the scalable protocol was adapted to a robotic platform and used to model Alexander disease. In conclusion, our findings uncover remarkable plasticity in neural lineage progression that can be exploited to manufacture large numbers of human hPSC-derived astrocytes for drug development and regenerative medicine.


title: Water Pollution and Administrative Division Adjustments: A Quasi-natural Experiment in Chaohu Lake of China

abstract: The adjustment of administrative divisions introduces a series of uncertain impacts on the social and economic development in the administrative region. Previous studies focused more on the economic effects of the adjustment of administrative divisions, while, in this paper, we also take environmental effects into consideration. The administrative division adjustment for Chaohu Lake is used as a quasi-natural experiment to explore the influence of the adjustment on pollution control. The synthetic control method is used in this study to access the effect of administrative division adjustment on the water quality indicators of Chaohu Lake and its internal mechanism. Some conclusions are as follows. First, after the administrative division adjustment, some water quality indicators, such as ammonia nitrogen, have indeed been alleviated; however, other major pollution indicators, such as chemical oxygen demand and dissolved oxygen, have deteriorated to varying degrees. Second, the results also reveal that improper development ideas, industrial excessive expansion, and the swing of economic growth and environmental goals are problems after the adjustment. Returning to the original intention of adjustment, rationalizing the Chaohu Lake management system and designing a sound and feasible accountability mechanism are fundamental measures to reduce pollution.


title: Extreme purifying selection against point mutations in the human genome

abstract: Genome sequencing of tens of thousands of humans has enabled the measurement of large selective effects for mutations to protein-coding genes. Here we describe a new method, called ExtRaINSIGHT, for measuring similar selective effects in noncoding as well as in coding regions of the human genome. ExtRaINSIGHT estimates the prevalance of strong purifying selection, or "ultraselection" ({lambda}s), as the fractional depletion of rare single-nucleotide variants in target genomic sites relative to matched sites that are putatively free from selection, after controlling for local variation and neighbor-dependence in mutation rate. We show using simulations that{lambda} s is closely related to the average site-specific selection coefficient against heterozygous point mutations, as predicted at mutation-selection balance. Applying ExtRaINSIGHT to 71,702 whole genome sequences from gnomAD v3, we find strong evidence of ultraselection in evolutionarily ancient miRNAs and neuronal protein-coding genes, as well as at splice sites. By contrast, we find weak evidence in other noncoding RNAs and transcription factor binding sites, and only modest evidence in ultraconserved elements and human accelerated regions. We estimate that ~0.3-0.5% of the human genome is ultraselected, implying ~0.3-0.4 lethal or nearly lethal de novo mutations per potential human zygote. Overall, our study sheds new light on the genome-wide distribution of fitness effects for new point mutations by combining deep new sequencing data sets and classical theory from population genetics.

category: evolutionary biology


title: Pseudoautosomal gene SHOX exhibits sex-biased random monoallelic expression and contributes to sex difference in height

abstract: Adult men are, on average, [~]13 cm taller than adult women. Although previous studies have suggested a significant contribution of sex chromosomal genes to sexual dimorphism in height, all attempts to identify a male-specific growth gene have failed. In the present study, we analyzed transcripts from cartilage tissues, and found that the expression of SHOX, a growth-promoting gene in the pseudoautosomal region on the X and Y chromosomes, was lower in females than in males. DNA methylation analyses showed that SHOX has some characteristics of genes subjected to X chromosome inactivation (XCI). These findings indicate that sex difference in human height is mainly ascribed to incomplete spreading of XCI on a pseudoautosomal gene. More importantly, RT-PCR of fibroblast clones revealed XCI-independent random clonal monoallelic expression of SHOX. We presume that during eutherian evolution, SHOX translocated from an autosome to the proto-sex chromosome without losing the epigenetic memory of random clonal monoallelic expression and subsequently underwent partial XCI. This study provides a novel model of epigenetic gene regulation leading to phenotypic diversity in humans.


title: A multiscale spatiotemporal model explains succession in the early infant gut microbiota as a switch from aerobic to anaerobic metabolism

abstract: The human intestinal microbiome starts to form immediately after birth, and can greatly influence the health of the infant. During the first days facultative anaerobic species generally dominate, followed by a dominance of strictly anaerobic species, particularly Bifidobacterium species. An early transition to Bifidobacterium is associated with health benefits. To study the mechanisms of this transition and its hypothesised relation to oxygen, we introduce a multiscale mathematical model that considers metabolism, spatial bacterial population dynamics and resource sharing. Based on publicly available metabolic network data, the model predicts that differences in oxygen availability explain some of the observed individual variation in succession to anaerobic species. The model also predicts that anaerobic Bifidobacterium species become dominant through metabolizing lactose with a suboptimal yield, but a higher anaerobic growth rate than its competitors. The current work is the first step towards a more comprehensive understanding of the formation of a steady state adult colonic microbiota.

category: systems biology


title: mRNA Vaccination Induces Durable Immune Memory to SARS-CoV-2 with Continued Evolution to Variants of Concern

abstract:
SARS-CoV-2 mRNA vaccines have shown remarkable efficacy, especially in preventing severe illness and hospitalization. However, the emergence of several variants of concern and reports of declining antibody levels have raised uncertainty about the durability of immune memory following vaccination. In this study, we longitudinally profiled both antibody and cellular immune responses in SARS-CoV-2 naive and recovered individuals from pre-vaccine baseline to 6 months post-mRNA vaccination. Antibody and neutralizing titers decayed from peak levels but remained detectable in all subjects at 6 months post-vaccination. Functional memory B cell responses, including those specific for the receptor binding domain (RBD) of the Alpha (B.1.1.7), Beta (B.1.351), and Delta (B.1.617.2) variants, were also efficiently generated by mRNA vaccination and continued to increase in frequency between 3 and 6 months post-vaccination. Notably, most memory B cells induced by mRNA vaccines were capable of cross-binding variants of concern, and B cell receptor sequencing revealed significantly more hypermutation in these RBD variant-binding clones compared to clones that exclusively bound wild-type RBD. Moreover, the percent of variant cross-binding memory B cells was higher in vaccinees than individuals who recovered from mild COVID-19. mRNA vaccination also generated antigen-specific CD8+ T cells and durable memory CD4+ T cells in most individuals, with early CD4+ T cell responses correlating with humoral immunity at later timepoints. These findings demonstrate robust, multi-component humoral and cellular immune memory to SARS-CoV-2 and current variants of concern for at least 6 months after mRNA vaccination. Finally, we observed that boosting of pre-existing immunity with mRNA vaccination in SARS-CoV-2 recovered individuals primarily increased antibody responses in the short-term without significantly altering antibody decay rates or long-term B and T cell memory. Together, this study provides insights into the generation and evolution of vaccine-induced immunity to SARS-CoV-2, including variants of concern, and has implications for future booster strategies.

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title: Intra-host SARS-CoV-2 evolution in the gut of mucosally-infected Chlorocebus aethiops (African green monkeys)

abstract: In recent months, several SARS-CoV-2 variants have emerged that enhance transmissibility and escape host humoral immunity. Hence, the tracking of viral evolutionary trajectories is clearly of great importance. Little is known about SARS-CoV-2 evolution in nonhuman primate models used to test vaccines and therapies and to model human disease. Viral RNA was sequenced from rectal swabs from Chlorocebus aethiops (African green monkeys) after experimental respiratory SARS-CoV-2 infection. Two distinct patterns of viral evolution were identified that were shared between all collected samples. First, mutations in the furin cleavage site that were initially present in the virus as a consequence of VeroE6 cell culture adaptation were subsequently lost in virus recovered in rectal swabs, confirming the necessity of this motif for viral infection in vivo. Three amino acid changes were also identified; ORF 1a S2103F, and spike D215G and H655Y, that were detected in rectal swabs from all sampled animals. These findings are demonstrative of intra-host SARS-CoV-2 evolution unique to this nonhuman primate species and may identify a host-adapted variant of SARS-CoV-2 that would be useful in future development of primate disease models.


title: Deep immune profiling of the maternal-fetal interface with mild SARS-CoV-2 infection

abstract: Pregnant women are an at-risk group for severe COVID-19, though the majority experience mild/asymptomatic disease. Although severe COVID-19 has been shown to be associated with immune activation at the maternal-fetal interface even in the absence of active viral replication, the immune response to asymptomatic/mild COVID-19 remains unknown. Here, we assessed immunological adaptations in both blood and term decidua from 9 SARS-exposed pregnant women with asymptomatic/mild disease and 15 pregnant SARS-naive women. In addition to selective loss of tissue-resident decidual macrophages, we report attenuation of antigen presentation and type I IFN signaling but upregulation of inflammatory cytokines and chemokines in blood monocyte derived decidual macrophages. On the other hand, infection was associated with remodeling of the T cell compartment with increased frequencies of activated CD69+ tissue-resident T cells and decreased abundance of Tregs. Interestingly, frequencies of cytotoxic CD4 and CD8 T cells increased only in the blood, while CD8 effector memory T cells were expanded in the decidua. In contrast to decidual macrophages, signatures of type I IFN signaling were increased in decidual T cells. Finally, T cell receptor diversity was significantly reduced with infection in both compartments, albeit to a much greater extent in the blood. The resulting aberrant immune activation in the placenta, even with asymptomatic disease may alter the exquisitely sensitive developing fetal immune system, leading to long-term adverse outcomes for offspring.


title: Reconstructing hunter-gatherer planet Earthusing machine-learning

abstract:
Estimating the total human population size (i.e., abundance) of the preagricultural planet is important for setting the baseline expectations for human-environment interactions if all energy and material requirements to support growth, maintenance, and well-being were foraged from local environments. However, demographic parameters and biogeographic distributions do not preserve directly in the archaeological record. Rather than attempting to estimate human abundance at some specific time in the past, a principled approach to making inferences at this scale is to ask what the human demography and biogeography of a hypothetical planet Earth would look like if populated by ethnographic hunter-gatherer societies. Given ethnographic hunter-gatherer societies likely include the largest, densest, and most complex foraging societies to have existed, we suggest population inferences drawn from this sample provide an upper bound to demographic estimates in prehistory. Our goal in this paper is to produce principled estimates of hunter-gatherer abundance, diversity, and biogeography. To do this we trained an extreme gradient boosting algorithm (XGBoost) to learn ethnographic hunter-gatherer population densities from a large matrix of climatic, environmental, and geographic data. We used the predictions generated by this model to reconstruct the hunter-gatherer biogeography of the rest of the planet. We find the human abundance of this world to be 6.1{+/-}2 million with an ethnolinguistic diversity of 8,330{+/-}2,770 populations, most of whom would have lived near coasts and in the tropics.

Significance StatementUnderstanding the abundance of humans on planet Earth prior to the development of agriculture and the industrialized world is essential to understanding human population growth. However, the problem is that these features of human populations in the past are unknown and so must be estimated from data. We developed a machine learning approach that uses ethnographic and environmental data to reconstruct the demography and biogeography of planet Earth if populated by hunter-gatherers. Such a world would house about 6 million people divided into about 8,330 populations with a particular concentration in the tropics and along coasts.


title: Direct capture and sequencing reveal ultra-short single-stranded DNA in biofluids

abstract: Direct capture and sequencing revealed a new DNA population in biofluids, named ultra-short single-stranded DNA (ussDNA), which was neglected by conventional DNA extraction and sequencing approaches. Evaluation of the size distribution and abundance of ussDNA in biofluids manifested generality of its presence in human, animal, and plants. Red blood cells were found to contain abundant ussDNA with enriched functional elements, and thus possesses great potential as a novel DNA biomarker.


title: Plasma Contains Ultra-short Single-stranded DNA in Addition to Nucleosomal cfDNA

abstract: Plasma cell-free DNA is a widely used biomarker for diagnostic screening. We introduce uscfDNA-seq, a single-stranded cell-free DNA NGS pipeline, which bypasses previous limitations to reveal a novel population of ultrashort single-stranded cell-free DNA in plasma with a modal size of 50nt. This species of cfDNA aligns predominantly to the nuclear genome and could potentially be used for novel biomarker discovery.


title: BRANEart: identify stability strength and weakness regions in membrane proteins

abstract: Understanding the role of stability strengths and weaknesses in proteins is a key objective for rationalizing their dynamical and functional properties such as conformational changes, catalytic activity, and protein-protein and protein-ligand interactions. We present BRANEart, a new, fast and accurate method to evaluate the per-residue contributions to the overall stability of membrane proteins. It is based on an extended set of recently introduced statistical potentials derived from membrane protein structures, which better describe the stability properties of this class of proteins than standard potentials derived from globular proteins. We defined a per-residue membrane propensity index from combinations of these potentials, which can be used to identify residues which strongly contribute to the stability of the transmembrane region or which would, on the contrary, be more stable in extramembrane regions, or vice versa. Large-scale application to membrane and globular proteins sets and application to tests cases show excellent agreement with experimental data. BRANEart thus appears as a useful instrument to analyze in detail the overall stability properties of a target membrane protein, to position it relative to the lipid bilayer, and to rationally modify its biophysical characteristics and function. BRANEart can be freely accessed from http://babylone.3bio.ulb.ac.be/BRANEart.

category: bioinformatics


title: From complete cross-docking to partners identification and binding sites predictions

abstract: Proteins ensure their biological functions by interacting with each other. Hence, characterising protein interactions is fundamental for our understanding of the cellular machinery, and for improving medicine and bioengineering. Over the past years, a large body of experimental data has been accumulated on who interacts with whom and in what manner. However, these data are highly heterogeneous and sometimes contradictory, noisy, and biased. Ab initio methods provide a means to a "blind" protein-protein interaction network reconstruction. Here, we report on a molecular cross-docking-based approach for the identification of protein partners. We applied it to a few hundred of proteins, and we systematically investigated the influence of several key ingredients, such as the size and quality of the interfaces and the scoring function. We achieved some significant improvement compared to previous works, and a very high discriminative power on some specific functional classes. In addition, we assessed the ability of the approach to account for protein surface multiple usages, and we compared it with a sequence-based deep learning method. This work may contribute to guiding the exploitation of the large amounts of protein structural models now available toward the discovery of unexpected partners and their complex structure characterisation.


title: Vapor cannabis exposure generationally affects male reproductive functions in mice

abstract:
This study was performed to examine whether vapor exposure to cannabis plant matter negatively impacts male reproductive functions and testis development in mice. Adult CD-1 male mice (F0) were exposed to air (control) or 200 mg of vaporized cannabis plant matter 3x/day over a 10 day period. Subsequently, F0 males were bred with drug naive CD-1 females to generate F1 males, and F1 offspring were used to generate F2 males. Cannabis vapor exposure decreased sperm count and/or motility in F0 and F1 males and disrupted the progression of germ cell development, as morphometric analyses exhibited an abnormal distribution of the stages of spermatogenesis in F0 males. Although plasma levels of testosterone were not affected by cannabis exposure in any ages or generations of males, dysregulated steroidogenic enzymes, Cyp11a1 and Cyp19a1, were observed in F0 testis. In the neonatal testis from F1 males, while apoptosis was not altered, DNA damage and DNMT1, but not DNMT3A and DNMT3B, were increased in germ cells following cannabis exposure. In contrast, the alterations of DNA damage and DNMT1 expression were not observed in F2 neonatal males. These results suggest that cannabis vapor exposure generationally affects male reproductive functions, probably due to disruption of spermatogenesis in the developing testis.

GRAPHICAL ABSTRACT

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C_LIO_LICannabis vapor exposure to F0 males causes reduced sperm counts in F1, but not in F2 males.
C_LIO_LIPlasma testosterone levels are not affected in F0, F1 and F2 males by cannabis exposure.
C_LIO_LICannabis increases DNA damage and the expression of DNA methyltransferase (DNMT) 1 in the F1 neonatal testis.
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category: pharmacology and toxicology


title: The loss of enzymatic activity of the PHARC associated lipase ABHD12 results in increased phagocytosis that causes neuroinflammation

abstract: Phagocytosis is an important evolutionary conserved process, essential for clearing pathogens and cellular debris in higher organisms, including humans. This well-orchestrated innate immunological response is intricately regulated by numerous cellular factors, important amongst which, are the immunomodulatory lysophosphatidylserines (lyso-PSs) and the pro-apoptotic oxidized phosphatidylserines (PSs) signaling lipids. Interestingly, in mammals, both these signaling lipids are physiologically regulated by the lipase ABHD12, mutations of which, cause the human neurological disorder PHARC. Despite the biomedical significance of this lipase, detailed mechanistic studies and the specific contribution of ABHD12 to innate processes like phagocytosis remain poorly understood. Here, by immunohistochemical and immunofluorescence approaches, using the murine model of PHARC, we show, that upon an inflammatory stimulus, activated microglial cells in the cerebellum of mice deficient in ABHD12 have an amoeboid morphology, increased soma size, and display heightened phagocytosis activity. We also report that upon an inflammatory stimulus, cerebellar levels of ABHD12 increase to possibly metabolize the heightened oxidized PS levels, temper phagocytosis and in turn control neuroinflammation during oxidative stress. Next, to complement these findings, using biochemical approaches in cultured microglial cells, we show that the pharmacological inhibition and/or genetic deletion of ABHD12 results in increased phagocytic uptake in a fluorescent bead uptake assay. Together, our studies provide compelling evidence that ABHD12 plays an important role in regulating phagocytosis in cerebellar microglial cells, and provides a possible explanation, as to why human PHARC subjects display neuroinflammation and atrophy in the cerebellum.


title: Getting the gist faster: Blurry images enhance the early temporal similarity between neural signals and convolutional neural networks

abstract: Humans are able to recognize objects under a variety of noisy conditions, so models of the human visual system must account for how this feat is accomplished. In this study, we investigated how image perturbations, specifically reducing images to their low spatial frequency (LSF) components, affected correspondence between convolutional neural networks (CNNs) and brain signals recorded using magnetoencephalography (MEG). Using the high temporal resolution of MEG, we found that CNN-Brain correspondence for deeper and more complex layers across CNN architectures emerged earlier for LSF images than for their unfiltered broadband counterparts. The early emergence of LSF components is consistent with the coarse-to-fine theoretical framework for visual image processing, but surprisingly shows that LSF signals from images are more prominent when high spatial frequencies are removed. In addition, we decomposed MEG signals into oscillatory components and found correspondence varied based on frequency bands, painting a full picture of how CNN-Brain correspondence varies with time, frequency, and MEG sensor locations. Finally, we varied image properties of CNN training sets, and found marked changes in CNN processing dynamics and correspondence to brain activity. In sum, we show that image perturbations affect CNN-Brain correspondence in unexpected ways, as well as provide a rich methodological framework for assessing CNN-Brain correspondence across space, time, and frequency.


title: Dominant role of adult neurogenesis-induced structural heterogeneities in driving plasticity heterogeneity in dentate gyrus granule cells

abstract: Neurons and synapses manifest pronounced variability in the amount of plasticity induced by identical activity patterns. The mechanisms underlying such plasticity heterogeneity, implicated in context-specific resource allocation during encoding, have remained unexplored. Here, we employed a systematic, unbiased, and physiologically constrained search to identify the mechanisms behind plasticity heterogeneity in dentate gyrus granule cells. We found that each of intrinsic, synaptic, and structural heterogeneities independently yielded heterogeneous plasticity profiles obtained with two different induction protocols. However, prior predictions about strong relationships between neuronal intrinsic excitability and plasticity emerged only when adult-neurogenesis-induced structural heterogeneities were accounted for. Strikingly, despite the concomitant expression of heterogeneities in structural, synaptic, and intrinsic neuronal properties, similar plasticity profiles were attainable through synergistic interactions among these heterogeneities. Importantly, consequent to strong relationships with intrinsic excitability measurements, we found that synaptic plasticity in the physiological range was achieved in immature cells despite their electrophysiologically-observed weak synaptic strengths. Together, our analyses unveil the dominance of neurogenesis-induced structural heterogeneities in driving plasticity heterogeneity in granule cells. Broadly, these analyses emphasize that the mechanistic origins of and the implications for plasticity heterogeneities need quantitative characterization across brain regions, particularly focusing on context-specific encoding of learned behavior.


title: Neprilysin-sensitive amyloidogenic Aβ versus IDE-sensitive soluble Aβ: a probable mechanistic cause for sporadic Alzheimer's disease

abstract: Neprilysin (NEP) and insulin-degrading enzyme (IDE) are considered the two major catabolic enzymes that degrade amyloid {beta} peptide (A{beta}), the primary cause of Alzheimers disease (AD). However, their roles in A{beta} metabolism in vivo have never been compared in an impartial and side-by-side manner. Here, we crossbred single App knock-in mice with NEP (Mme) KO mice and with IDE (Ide) KO mice to generate double mutants that were analyzed for their biochemical and A{beta} pathology properties. We found that NEP is responsible for the metabolism of amyloidogenic insoluble A{beta} whereas IDE affects soluble A{beta}. A deficiency of NEP, but not of IDE, augmented the formation of A{beta} plaques, dystrophic neurites, and astrocytic and microglial activation, all of which are key pathological events in the development of AD. In addition, a deficiency of NEP had no significant impact on the levels of various neuropeptides (somatostatin, substance P, cholecystokinin, and neuropeptide Y), well known to be in vitro substrates for NEP, presumably because NEP is expressed in secretory vesicles and on the presynaptic membranes of excitatory neurons while most if not all neuropeptides are secreted from inhibitory neurons. This argues against the concern that NEP up-regulation for treatment of preclinical AD would reduce the levels of these neuropeptides. These findings indicate that NEP relatively selectively degrades A{beta} in the brain. Whereas familial AD (FAD) is unambiguously caused by an increased anabolism of A{beta}, and of A{beta} 42 and A{beta} 43 in particular, the anabolism of A{beta} appears unaffected before its deposition in the brain that subsequently leads to the onset of sporadic AD (SAD). These observations thus suggest that NEP-sensitive amyloidogenic A{beta} likely plays a primary pathogenic role in the etiology of SAD. Our findings are consistent with the aging-dependent decline of NEP expression in human brain and with recent genome-wide association studies (GWAS) indicating that variants of the gene encoding NEP (MME) are associated with the risk of SAD development. Taken together, our results imply that the aging-associated decrease in NEP expression is a primary cause of SAD and could thus be a target for the treatment of preclinical AD once other factors such as apolipoprotein E genotypes have also been considered.


title: An isogenic panel of single App knock-in mouse models of Alzheimer's disease confers differential profiles of β-secretase inhibition and endosomal abnormalities

abstract: We previously developed single App knock-in mouse models of Alzheimers disease (AD) that harbor the Swedish and Beyreuther/Iberian mutations with or without the Arctic mutation (AppNL- G-F and AppNL-F mice). These models showed the development of amyloid {beta} peptide (A{beta}) pathology, neuroinflammation and cognitive impairment with aging. We have now generated App knock-in mice devoid of the Swedish mutations (AppG-F mice) and some additional mutants to address the following two questions: [1] Do the Swedish mutations influence the mode of {beta}-secretase inhibitor action in vivo? [2] Does the quantity of C-terminal fragment of amyloid precursor protein (APP) generated by {beta}-secretase (CTF-{beta}) affect endosomal properties as previously reported as well as other pathological events? A{beta} pathology was exhibited by AppG-F mice from 6 to 8 months of age, and was accompanied by microglial and astrocyte activation. We found that a {beta}-secretase inhibitor, verubecestat, inhibited A{beta} production in AppG-F mice, but not in AppNL-G-F mice, indicating that the AppG-F mice are more suitable for preclinical studies of {beta}-secretase inhibition given that most AD patients do not carry Swedish mutations. We also found that the quantity of CTF-{beta} generated by various App knock-in mutants failed to correlate with endosomal alterations or enlargement, implying that CTF-{beta}, endosomal abnormalities, or both are unlikely to play a major role in AD pathogenesis. This is the first AD mouse model ever described that recapitulates amyloid pathology in the brain without the presence of Swedish mutations and without relying on the overexpression paradigm. Thus, experimental comparisons between different App knock-in mouse lines will potentially provide new insights into our understanding of the etiology of AD.


title: FEDERATED MORPHOMETRY FEATURE SELECTION FOR HIPPOCAMPAL MORPHOMETRY ASSOCIATED BETA-AMYLOID AND TAU PATHOLOGY

abstract: Amyloid-{beta} (A{beta}) plaques and tau protein tangles in the brain are now widely recognized as the defining hallmarks of Alzheimers disease (AD), followed by structural atrophy detectable on brain magnetic resonance imaging (MRI) scans. One of the particular neurodegenerative regions is the hippocampus to which the influence of A{beta}/tau on has been one of the research focuses in the AD pathophysiological progress. This work proposes a novel framework, Federated Morphometry Feature Selection (FMFS) model, to examine subtle aspects of hippocampal morphometry that are associated with A{beta}/tau burden in the brain, measured using positron emission tomography (PET). FMFS is comprised of hippocampal surface-based feature calculation, patch-based feature selection, federated group LASSO regression, federated screening rule-based stability selection, and region of interest (ROI) identification. FMFS was tested on two ADNI cohorts to understand hippocampal alterations that relate to A{beta}/tau depositions. Each cohort included pairs of MRI and PET for AD, mild cognitive impairment (MCI) and cognitively unimpaired (CU) subjects. Experimental results demonstrated that FMFS achieves an 89x speedup compared to other published state-of-the-art methods under five independent hypothetical institutions. In addition, the subiculum and cornu ammonis 1 (CA1 subfield) were identified as hippocampal subregions where atrophy is strongly associated with abnormal A{beta}/tau. As potential biomarkers for A{beta}/tau pathology, the features from the identified ROIs had greater power for predicting cognitive assessment and for survival analysis than five other imaging biomarkers. All the results indicate that FMFS is an efficient and effective tool to reveal associations between A{beta}/tau burden and hippocampal morphometry.


title: Soil inoculum identity and rate jointly steer plant and belowground communities in the field

abstract: The importance of soil inoculation to engineer soil microbiomes and ultimately entire ecosystems is becoming widely acknowledged. Inoculation with soil from different ecosystems can induce directional changes in soil and plant communities and promote the restoration of degraded ecosystems. However, it is unknown how such inoculations influence the soil microbiome, how much inoculum is needed, and whether inocula collected from similar ecosystems will steer the microbiome in different directions. We conducted a three-year soil inoculation field experiment at a degraded grassland and used two different soil inocula both from grasslands with three inoculation rates. Our results show that inoculation with soil that originates from different donor grasslands steers the soil microbiome as well as the plant communities at the inoculated site which was a degraded grassland into different directions and that these effects were stronger with increasing amount of soil used to inoculate. Inoculation with upland meadow soil introduced more keystone genera and resulted in more complex biotic networks in the soil than inoculation with meadow steppe soil. Our experiment highlights that soil inoculation can steer soil microbiomes in the field and that the direction and speed of development depend on the origin and the amount of soil inoculum used.


title: Soil inoculum identity and rate jointly steer microbiomes and plant communities in the field


title: Ease of de novo gene birth through spontaneous mutations predicted in a parsimonious model

abstract: Phylostratigraphy suggests that new genes are continually born de novo from non-genic sequences, and the genes that persist found new lineages, contributing to the adaptive evolution of organisms. While recent evidence supports the view that de novo gene birth is frequent and widespread, the mechanisms underlying this process are yet to be discovered. Here we hypothesize and examine a potential general mechanism of gene birth driven by the accumulation of beneficial mutations at non-genic loci. To demonstrate this possibility, we model this mechanism within the boundaries set by current knowledge on mutation effects. Estimates from this analysis are in line with observations of recurrent and extensive gene birth in genomics studies. Thus, we propose that, rather than being inactive and silent, non-genic regions are likely to be dynamic storehouses of potential genes.


title: de novo gene birth as an inevitable consequence of adaptive evolution


title: Influence of condensation domains on activity and specificity of adenylation domains

abstract: Many clinically used natural products are produced by non-ribosomal peptide synthetases (NRPSs), which due to their modular nature should be accessible to modification and engineering approaches. While the adenylation domain (A) plays the key role in substrate recognition and activation, the condensation domain (C) which is responsible for substrate linkage and stereochemical filtering recently became the subject of debate - with its attributed role as a "gatekeeper" being called into question. Since we have thoroughly investigated different combinations of C-A didomains in a series of in vitro, in vivo, and in situ experiments suggesting an important role to the C-A interface for the activity and specificity of the downstream A domain and not the C domain as such, we would like to contribute to this discussion. The role of the C-A interface, termed  extended gatekeeping, due to structural features of the C domains, can also be transferred to other NRPSs by engineering, was finally investigated and characterised in an in silico approach on 30 wild-type and recombinant C-A interfaces. With these data, we not only would like to offer a new perspective on the specificity of C domains, but also to revise our previously established NRPS engineering and construction rules.

category: bioengineering


title: EXPLORING HUB GENES IN LUNG CANCER USING INTEGRATED BIOINFORMATICS ANALYSIS

abstract: Lung cancer is a serious health issue worldwide causing death men than women. The environmental and genetic factored in metastasis primary lung cancer. The survival rate patient improved by identification hub genes lung cancer with bioinformatics tools. The present study was to determine the biological pathway and PPI network by identification the biomarker hub genes lung cancer. The GSE84797, GSE28827, and GSE115456 were retrieved from GEO attained upregulated and downregulated by GEO2R tool. Enrichment analysis DEGs analyzed used DAVID server. PPI network and hub genes was constructed by STRING, Cytoscape and cytoHubba. The OS and expression level were retrieved by KM plotter server and GEPIA2. Results obtained 3 DEGs dataset by GEO2R with -1.0 [≤] logFC[≥]1.0.Upregulated and downregulated DEGs presence for GO and pathway enrichment analysis.The PPI network and hub genes identification done with cutoff >0.9 obtained KRT5, KRT13, KRT17, KRTI6 KRTI5, C5, PPBP, CXCL2, CCR9, and CCR7 .The OS done analyzed showed hazard ratio while expression level presented the different gene of LUSC/LUAD and normal tissues.The hub genes help in understanding the system biology of cancer through the identification network of protein interaction and hub gene identification lung cancer for classified the medicine and early diagnosis cancer.


title: Multi-omics integration and regulatory inference for unpaired single-cell data with a graph-linked unified embedding framework

abstract: With the ever-increasing amount of single-cell multi-omics data accumulated during the past years, effective and efficient computational integration is becoming a serious challenge. One major obstacle of unpaired multi-omics integration is the feature discrepancies among omics layers. Here, we propose a computational framework called GLUE (graph-linked unified embedding), which utilizes accessible prior knowledge about regulatory interactions to bridge the gaps between feature spaces. Systematic benchmarks demonstrated that GLUE is accurate, robust and scalable. We further employed GLUE for various challenging tasks, including triple-omics integration, model-based regulatory inference and multi-omics human cell atlas construction (over millions of cells) and found that GLUE achieved superior performance for each task. As a generalizable framework, GLUE features a modular design that can be flexibly extended and enhanced for new analysis tasks. The full package is available online at https://github.com/gao-lab/GLUE for the community.


title: A universal approach for integrating super large-scale single-cell transcriptomes by exploring gene rankings

abstract: Advancement in single-cell RNA sequencing leads to exponential accumulation of single-cell expression data. However, there is still lack of tools that could integrate these unlimited accumulation of single-cell expression data. Here, we presented a universal approach iSEEEK for integrating super large-scale single-cell expression via exploring expression rankings of top-expressing genes. We developed iSEEEK with 13.7 million single-cells. We demonstrated the efficiency of iSEEEK with canonical single-cell downstream tasks on five heterogenous datasets encompassing human and mouse samples. iSEEEK achieved good clustering performance benchmarked against well-annotated cell labels. In addition, iSEEEK could transfer its knowledge learned from large-scale expression data on new dataset that was not involved in its development. iSEEEK enables identification of gene-gene interaction networks that are characteristic of specific cell types. Our study presents a simple and yet effective method to integrate super large-scale single-cell transcriptomes and would facilitate translational single-cell research from bench to bedside.


title: Exploring ensemble structures of Alzheimer's amyloid β (1-42) monomer using linear regression for the MD simulation and NMR chemical shift

abstract:
Aggregation of intrinsically disordered amyloid {beta} (A{beta}) is a hallmark of Alzheimers disease. Although complex aggregation mechanisms have been increasingly revealed, structural ensembles of A{beta} monomers with heterogeneous and transient properties still hamper detailed experimental accesses to early events of amyloidogenesis. We herein developed a new mathematical tool based on multiple linear regression to obtain the reasonable ensemble structures of A{beta} monomer by using the solution nuclear magnetic resonance (NMR) and molecular dynamics simulation data. Our approach provided the best-fit ensemble to two-dimensional NMR chemical shifts, also consistent with circular dichroism and dynamic light scattering analyses. The major monomeric structures of A{beta} including {beta}-sheets in both terminal and central hydrophobic core regions and the minor partially-helical structures suggested initial structure-based explanation on possible mechanisms of early molecular association and nucleation for amyloid generation. A wide-spectrum application of the current approach was also indicated by showing a successful utilization for ensemble structures of folded proteins. We propose that multiple linear regression in combination to experimental results will be highly promising for studies on protein misfolding diseases and functions by providing a convincing template structure.

Graphic abstract

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category: biophysics


title: Defining the components of the miRNA156-SPL-miR172 aging pathway in pea and their expression relative to changes in leaf morphology

abstract: The timing of developmental phase transitions is crucial for plant reproductive success, and two microRNAs (miRNA), miR156 and miR172, are implicated in the control of these changes, together with their respective SQUAMOSA promoter binding-like (SPL) and APETALA2 (AP2)-like targets. While their patterns of regulation have been studied in a growing range of species, to date they have not been examined in pea (Pisum sativum), an important legume crop and model species. We analysed the recently-released pea genome and defined nine miR156, 21 SPL, four miR172, and five AP2-like genes. Phylogenetic analysis of the SPL genes in pea, Medicago and Arabidopsis confirmed the eight previously defined clades, and identified a ninth potentially legume-specific SPL clade in pea and Medicago. Among the PsSPL, 14 contain a miR156 binding site and all five AP2-like transcription factors in pea include a miR172 binding site. Phylogenetic relationships, expression levels and temporal expression changes identified PsSPL2a/3a/3c/6b/9a/9b/13b/21, PsmiR156d/j and PsmiR172a/d as the most likely of these genes to participate in phase change in pea. Comparisons with leaf morphology suggests that vegetative phase change is unlikely to be definitively marked by a change in leaflet number. In addition, the timing of FT gene induction suggests that the shift from the juvenile to the adult vegetative phase may occur within fourteen days in plants grown under inductive conditions, and calls into question the contribution of miR172/AP2 to the floral transition. This work provides the first insight into the nature of vegetative phase change in pea, and an important foundation for future functional studies.


title: Genome-wide development of lncRNA-derived-SSR markers for Dongxiang wild rice (Oryza rufipogon Griff.)

abstract: Dongxiang wild rice (Oryza rufipogon Griff., DXWR) is the northernmost distributed common wild rice found in the world. It contains a large number of agronomically valuable genes, which makes it a natural gene pool for rice breeding. Molecular markers, especially simple repeat sequence (SSR) markers, play important roles in crop breeding. Although a large number of SSR markers have been developed, most of them are derived from the genome coding sequences, rarely from non-coding sequences. Meanwhile, long non-coding RNAs (lncRNAs), which are derived from the transcription of non-coding sequences, play vital roles in plant growth, development and stress responses. In this study, 1878 SSR loci were detected from the lncRNA sequences of DXWR, and 1258 lncRNA-derived-SSR markers were developed on the genome-wide scale. To verify the validity and applicability of these markers, 72 pairs of primers were randomly selected to test 44 rice materials. The results showed that 42 (58.33%) pairs of primers have abundant polymorphism among these rice materials; the polymorphism information content (PIC) values ranged from 0.04 to 0.87 with an average of 0.50; the genetic diversity index of SSR loci varied from 0.04 to 0.88 with an average of 0.56; and the number of alleles per marker ranged from 2 to 11 with an average of 4.36. Thus, we concluded that these lncRNA-derived-SSR markers are a very useful source for future basic and applied research, including genetic diversity analysis, QTL mapping, and molecular breeding programs, to make good use of the elite lncRNA genes from DXWR.


title: DIVERGENT EFFECT OF CENTRAL INCRETIN RECEPTORS INHIBITION IN A RAT MODEL OF SPORADIC ALZHEIMER'S DISEASE

abstract: The incretin system is an emerging new field that might provide valuable contributions to the research of both pathophysiology and therapeutic strategies in the treatment of diabetes, obesity, and neurodegenerative disorders. This study aimed to explore the role of central glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) on cell metabolism and energy in the brain as well as on the levels of these incretins, insulin and glucose, by inhibiting the central incretins receptors following intracerebroventricular administration of the respective antagonists in healthy rats and a streptozotocin-induced rat model of sporadic Alzheimers disease (sAD). Chemical ablation of the central GIP receptor (GIPR) or GLP-1 receptor (GLP-1R) in healthy and diseased animals indicated a region-dependent role of incretins in the brain cell energy and metabolism and central incretin-dependent modulation of peripheral hormone secretion, markedly after GIPR inhibition, as well as a dysregulation of the GLP-1 system in experimental sAD.


title: Electrophysiological markers of fairness and selfishness revealed by a combination of Dictator and Ultimatum Games

abstract: AO_SCPLOWBSTRACTC_SCPLOWEvent Related Potentials (ERPs) were recorded from 39 participants who played the role of Allocators in a Dictator Game (DG) and Responders in an Ultimatum Game (UG). Most participants expressed very low levels of altruistic decision making, and two homogeneous groups could be identified, one formed by fair (N = 10) individuals and another by selfish (N = 8) individuals. At fronto-central cortical sites, the ERP early negativity (N1) was reduced in selfish participants with a latency about 10 ms earlier than in fair participants. In fair DG players, the features of the subsequent positive wave P2 suggested that more cognitive resources were required when they allocated the least gains to the other party. P2 latency and amplitude in the selfish group supported the hypothesis that these participants tended to maximize their profit, as expected by a rational Homo economicus. During UG, we observed that a medial frontal negativity (MFN) occurred earlier and with greater amplitude when selfish participants rejected less favorable endowment shares. In this case, all players received zero payoffs, which showed that MFN in selfish participants was associated with a spiteful punishment. At posterior-parietal sites we found that the greater the selfishness, the greater the amplitude of the late positive component (LPC). Our results bring new evidence to the existence of specific somatic markers associated with the activation of distinct cerebral circuits by the evaluation of fair and unfair proposals in participants characterized by different expressions of perceived fairness, thus suggesting that particular brain dynamics could be associated with moral decisions.


title: Insulin Signaling Attenuates GLUT4 Endocytosis in Muscle Cells via GSK3a-Dyn2-Bin1 Interplay

abstract: Insulin-induced translocation of glucose transporter 4 (GLUT4) to the plasma membrane of skeletal muscle is critical for postprandial glucose uptake; however, whether the internalization of GLUT4 into cells is also regulated by insulin signaling remains unclear. Here, we discover that the activity of dynamin-2 (Dyn2), pivotal GTPase catalyzing GLUT4 internalization, is regulated by insulin signaling in muscle cells. The membrane fission activity of Dyn2 is inhibited in muscle cells through binding with the SH3 domain-containing protein Bin1. Phosphorylation of Serine848 on Dyn2 by GSK3 or the mutations of Bin1-SH3 in patients with centronuclear myopathy, elevate the activity of Dyn2 due to reduced binding affinity toward Bin1. The augmented Dyn2 fission activity in muscle cells leads to GLUT4 internalization and Bin1-tubule vesiculation. Together, our findings reveal a new role of insulin signaling in glucose metabolism and muscle physiology via attenuating Dyn2 activity thus regulating GLUT4 endocytosis in muscle cell.

category: cell biology


title: Parity-induced changes to mammary epithelial cells control NKT cell expansion and mammary oncogenesis

abstract: Pregnancy reprograms the epigenome of mammary epithelial cells (MECs) in a manner that control responses to pregnancy hormone re-exposure and the rate of carcinoma progression. However, the influence of pregnancy on the tissue microenvironment of the mammary gland is less clear. Here, we used single-cell RNA sequencing to comparatively profile the composition of epithelial and non-epithelial cells in mammary tissue from nulliparous and parous female mice. Our analysis revealed an expansion of {gamma}{delta} Natural Killer T (NKT) immune cells following pregnancy, in association with upregulation of immune signal molecules in post-pregnancy MECs. We show that expansion of NKT cells following pregnancy is due to elevated expression of the antigen presenting molecule CD1d protein, which is known to induce NKT activation. Accordingly, loss of CD1d expression on post-pregnancy MECs, or overall lack of activated NKT cells, accompanied the development of mammary oncogenesis in response to cMYC overexpression and loss of Brca1 function. Collectively, our findings illustrate how pregnancy-induced epigenetic changes modulate the communication between MECs and the mammary immune microenvironment, and establish a causal link between pregnancy, the immune microenvironment, and mammary oncogenesis.


title: Genetic coupling of life-history and aerobic performance in juvenile Atlantic salmon

abstract: A better understanding of the genetic and phenotypic architecture underlying life-history variation is a longstanding aim in biology. Theories suggest energy metabolism determines life-history variation by modulating resource acquisition and allocation trade-offs, but the genetic underpinnings of the relationship and its dependence on ecological conditions have rarely been demonstrated. The strong genetic determination of age-at-maturity by two unlinked genomic regions (vgll3 and six6) makes Atlantic salmon (Salmo salar) an ideal model to address these questions. Using more than 250 juveniles in common garden conditions, we quantified the covariation between metabolic phenotypes -standard and maximum metabolic rates (SMR and MMR), and aerobic scope (AS) - and the life-history genomic regions and tested if food availability modulates the relationships. We found that the early maturation genotype in vgll3 was associated with higher MMR and consequently AS. Additionally, MMR exhibited physiological epistasis; it was decreased when late maturation genotypes co-occurred in both genomic regions. Contrary to our expectation, the life-history genotypes had no effects on SMR. Further, food availability had no effect on the genetic covariation, suggesting a lack of genotype-by-environment interactions. Our results provide insights on the key organismal processes that link energy use at the juvenile-stage to age-at-maturity, indicating potential mechanisms by which metabolism and life-history can coevolve.


title: Genetic coupling of life-history and aerobic performance in Atlantic salmon indicates potential constrains on life-history evolution


title: Genetic coupling of life-history and aerobic performance in Atlantic salmon indicates potential for coevolution across life-stages


title: Genetic coupling of life-history and aerobic performance in Atlantic salmon


title: Correlation analysis among single nucleotide polymorphisms in thirteen language genes and culture/education parameters from twenty-six countries

abstract: Language is a vital feature of any human culture, but whether language gene polymorphisms have meaningful correlations with some cultural characteristics during the long-run evolution of human languages largely remains obscure (uninvestigated). This study would be an endeavor example to find evidences for the above questions answer. In this study, the collected basic data include 13 language genes and their randomly selected 111 single nucleotide polymorphisms (SNPs), SNP profiles, 29 culture/education parameters, and estimated cultural context values for 26 representative countries. In order to undertake principal component analysis (PCA) for correlation search, SNP genotypes, cultural context and all other culture/education parameters have to be quantitatively represented into numerical values. Based on the above conditions, this study obtained its preliminary results, the main points of which contain: (1) The 111 SNPs contain several clusters of correlational groups with positive and negative correlations with each other; (2) Low cultural context level significantly influences the correlational patterns among 111 SNPs in the principal component analysis diagram; and (3) Among 29 culture/education parameters, several basic characteristics of a language (the numbers of alphabet, vowel, consonant and dialect) demonstrate least correlations with 111 SNPs of 13 language genes.


title: A Recurring Chemogenetic Switch for Chimeric Antigen Receptor T Cells

abstract: As a revolutionary cancer treatment, the chimeric antigen receptor (CAR) T cell therapy suffers from complications such as cytokine release syndromes and T cell exhaustion. Their mitigation desires controllable activation of CAR-T cells that is achievable through regulatory display of CARs on the T cell surface. By embedding the hepatitis C virus NS3 protease (HCV-NS3) in an anti-CD19 CAR between the anti-CD19 single-chain variable fragment (scFv) and the hinge domain, we showed that the display of anti-CD19 scFv on CAR-T cells was positively correlated to the presence of a clinical HCV-NS3 inhibitor asunaprevir (ASV). This novel CAR design that allows the display of anti- CD19 scFv on the T cell surface in the presence of ASV and its removal in the absence of ASV effectuates a practically recurring chemical switch for CAR-T cells. We demonstrated that the intact CAR on T cells was repeatedly turn on and off by controlling the presence of ASV. The dose dependent manner of the intact CAR display on T cells with regard to the ASV concentration enables delicate modulation of CAR-T cell activation during cancer treatment. In a mouse model, we showed different treatment prospects when ASV was provided at different doses to mice that were infused with both human CD19+ lymphoma and the switchable CAR-T cells.


title: Dandelion pappus morphing is actuated by radially patterned material swelling

abstract: Plants can generate motion by absorbing and releasing water. Such motion often facilitates reproductive success through the dispersal of seeds and fruits or their self-burial into the soil. Asteraceae plants, such as the dandelion, often have a hairy pappus attached to their fruits to allow them to fly and in many cases, these can open and close depending on moisture levels to modify dispersal. Here we demonstrate the relationship between structure, composition and function of the underlying hygroscopic actuator. By investigating the structure and properties of the actuator cell walls we have identified the mechanism by which the dandelion pappus closes and developed a structural computational model that can capture observed pappus closing. This model was used to explore the contribution of differential material domains in the actuator function and the critical design features. We find that the actuator relies on the radial arrangement of vascular bundles and surrounding tissues including cortex and the floral podium around a central cavity. This allows heterogeneous swelling in a radially symmetric manner to co-ordinate precise movements of the pappus hairs attached at the upper flank. This actuator is a derivative of bilayer structures, but is radial and can synchronise the movement of a planar or lateral attachment. The simple, material-based mechanism presents a promising biomimetic potential in robotics and functional materials.


title: Comprehensive Analysis of Co-Mutations Identifies Cooperating Mechanisms of Tumorigenesis

abstract: Somatic mutations are one of the most important factors in tumorigenesis and are the focus of most cancer sequencing efforts. The co-occurrence of multiple mutations in one tumor has gained increasing attention as a means of identifying cooperating mutations or pathways that contribute to cancer.Using multi-omics, phenotypical, and clinical data from 29,559 cancer subjects and 1,747 cancer cell lines covering 78 distinct cancer types, we show that co-mutations are associated with prognosis, drug sensitivity, and disparities in sex, age, and race. Some co-mutation combinations displayed stronger effects than their corresponding single mutations. For example, co-mutation TP53:KRAS in pancreatic adenocarcinoma is significantly associated with disease specific survival (hazard ratio = 2.87, adjusted p-value = 0.0003) and its prognostic predictive power is greater than either TP53 or KRAS as individually mutated genes. Functional analyses revealed that co-mutations with higher prognostic values have higher potential impact and cause greater dysregulation of gene expression. Furthermore, many of the prognostically significant co-mutations caused gains or losses of binding sequences of RNA binding proteins or micro RNAs with known cancer associations. Thus, detailed analyses of co-mutations can identify mechanisms that cooperate in tumorigenesis.

category: cancer biology


title: Cyclic loading regime considered beneficial does not protect injured and interleukin-1-inflamed cartilage from post-traumatic osteoarthritis

abstract: Post-traumatic osteoarthritis is a degenerative musculoskeletal condition where homeostasis of articular cartilage is perturbated by lesions and inflammation, leading to abnormal tissue-level loading. These mechanisms have rarely been included simultaneously in in vitro osteoarthritis models. We modeled the early disease progression in bovine cartilage regulated by the coaction of (1) mechanical injury, (2) pro-inflammatory interleukin-1 challenge, and (3) cyclic loading mimicking walking and considered beneficial (15% strain, 1 Hz). Surprisingly, cyclic loading did not protect cartilage from accelerated glycosaminoglycan loss over 12 days of interleukin-1-culture despite promoting aggrecan biosynthesis. Our time-dependent data suggest that this loading regime could be beneficial in the first days following injury but later turn detrimental in interleukin-1-inflamed cartilage. Consequently, early anti-catabolic drug intervention may inhibit, whereas cyclic loading during chronic inflammation may promote osteoarthritis progression. Our data on the early stages of post-traumatic osteoarthritis could be utilized in the development of countermeasures for disease progression.

category: pathology


abstract:
TitleResearch Funding for Male Reproductive Health and Infertility in the UK and USA [2016 - 2019]

Study questionWhat is the research funding for male reproductive health and infertility in the UK and US between 2016 to 2019?

Summary answerThe average funding for a research project in male reproductive health and infertility was not significantly different to that for female-based projects ({pound}653,733 in the UK and $779,707 in the US). However, only 0.07% and 0.83% of government funds from NIHR (UK) and NICHD (USA) was granted for male reproductive health, respectively.

What is known alreadyThere is a marked paucity of data on research funding for male reproductive health.

Study design, size, durationExamined government databases over a total 4-year period from January 2016 to December 2019.

Participants/materials, setting, methodsInformation on the funding provided to male-based and female-based research was collected using public accessed web-databases from the UKRI-GTR, the NIHRs Open Data Summary, and the US NIH RePORT. Funded projects that began research activity between January 2016 to December 2019 were recorded, along with their grant and project details. Strict inclusion-exclusion criteria were followed for both UK and US data with a primary research focus of male infertility, reproductive health and disorders, and contraception development. Funding support was divided into three research groups: male-based, female-based, and not-specified research. Between the 4-year period, the UK is divided into 5 funding periods, starting from 2015/16 to 2019/20, and the US is divided into 5 fiscal years, from 2016 to 2020.

Main results and the role of chanceBetween January 2016 to December 2019, UK agencies awarded a total of {pound}11,767,190 to 18 projects for male-based research and {pound}29,850,945 to 40 projects for female-based research. There was no statistically significant difference in funding average between the two research groups (P=0.56, W=392). The US NIH funded 76 projects totaling $59,257,746 for male-based research and 99 projects totaling $83,272,898 for female-based research. There was no statistically significant difference in funding average between the two groups (P=0.83, W=3834).

Limitations, reasons for cautionThe findings of this study cannot be used to generalize and reflect global funding trends towards infertility and reproductive health as the data collected followed a narrow funding timeframe from government agencies and only two countries. Other funding sources such as charities, industry and major philanthropic organizations were not evaluated.

Wider implications of the findingsThis is the first study examining funding granted by main government research agencies from the UK and US for male reproductive health. This study should stimulate further discussion of the challenges of tackling male infertility and reproductive health disorders and formulate appropriate investment strategies.

Study funding/competing interest(s)CLRB is Editor for RBMO and has received lecturing fees from Merck, Pharmasure, and Ferring. His laboratory is funded by Bill and Melinda Gates Foundation, CSO, Genus. No other authors declare a conflict of interest.


title: Prior expectations in visual speed perception predict encoding characteristics of neurons in area MT

abstract:
Bayesian inference provides an elegant theoretical framework for understanding the characteristic biases and discrimination thresholds in visual speed perception. However, the framework is difficult to validate due to its flexibility and the fact that suitable constraints on the structure of the sensory uncertainty have been missing. Here, we demonstrate that a Bayesian observer model constrained by efficient coding not only well explains human visual speed perception but also provides an accurate quantitative account of the tuning characteristics of neurons known for rep-resenting visual speed. Specifically, we found that the population coding accuracy for visual speed in area MT ("neural prior") is precisely predicted by the power-law, slow-speed prior extracted from fitting the Bayesian model to psychophysical data ("behavioral prior") to the point that the two priors are indistinguishable in a cross-validation model comparison. Our results demonstrate a quantitative validation of the Bayesian observer model constrained by efficient coding at both the behavioral and neural levels.

Significance StatementStatistical regularities of the environment play an important role in shaping both neural representations and perceptual behavior. Most previous works addressed these two aspects independently. Here we present a quantitative validation of a theoretical framework that makes joint predictions for neural coding and behavior, based on the assumption that neural representations of sensory information are efficient but also optimally used in generating a percept. Specifically, we demonstrate that the neural tuning characteristics for visual speed in brain area MT are precisely predicted by the statistical prior expectations extracted from psychophysical data. As such, our results provide a normative link between perceptual behavior and the neural representation of sensory information in the brain.


title: Repurposing melanoma chemotherapy to activate inflammasomes in treatment of BRAF/MAPK inhibitor-resistant melanoma

abstract: The development of resistance to treatments of melanoma is commonly associated with upregulation of the MAPK pathway and development of an undifferentiated state. Prior studies have suggested that melanoma with these resistance characteristics may be susceptible to innate death mechanisms such as pyroptosis triggered by activation of inflammasomes. In the present studies we have taken cell lines from patients before and after development of resistance to BRAF V600 inhibitors and exposed the resistant melanoma to temozolomide (a commonly used chemotherapy) with and without chloroquine to inhibit autophagy. It was found that melanoma with an inflammatory undifferentiated state appeared susceptible to this combination when tested in vitro and in vivo against xenografts in NSG mice. Translation of the latter results into patients would promise durable responses in patients treated by the combination. The inflammasome and death mechanism involved appeared to vary between melanoma and involved either AIM2, NLRP3 or NLRC4 inflammasomes and gasdermin D or E. These preliminary studies have raised questions as to the selectivity for different inflammasomes in different melanoma and their selective targeting by chemotherapy. They also question whether the inflammatory state of melanoma may be used as biomarkers to select patients for inflammasome targeted therapy.