title: Disrupted dynamic functional network connectivity among cognitive control networks in the progression of Alzheimer's disease

abstract:
BackgroundAlzheimers disease (AD) is the most common age-related dementia that promotes a decline in memory, thinking, and social skills. The initial stages of dementia can be associated with mild symptoms, and symptom progression to a more severe state is heterogeneous across patients. Recent work has demonstrated the potential for functional network mapping to assist in the prediction of symptomatic progression. However, this work has primarily used static functional connectivity (sFC) from rs-fMRI. Recently, dynamic functional connectivity (dFC) has been recognized as a powerful advance in functional connectivity methodology to differentiate brain network dynamics between healthy and diseased populations.

MethodsGroup independent component analysis was applied to extract 17 components within the cognitive control network (CCN) from 1385 individuals across varying stages of AD symptomology. We estimated dFC among 17 components within the CCN, followed by clustering the dFCs into 3 recurring brain states and then estimated a hidden Markov model and the occupancy rate for each subject. Finally, we investigated the link between CCN dFC connectivity features with AD progression.

ResultsProgression of AD symptoms were associated with increases in connectivity within the middle frontal gyrus. Also, the AD with mild and severer symptoms showed less connectivity within the inferior parietal lobule and between this region with the rest of CCN. Finally, comparing with mild dementia, we found that the normal brain spends significantly more time in a state with lower within middle frontal gyrus connectivity and higher connectivity between the hippocampus and the rest of CCN, highlighting the importance of assessing the dynamics of brain connectivity in this disease.

ConclusionOur results suggest that AD progress not only alters the CCN connectivity strength but also changes the temporal properties in this brain network. This suggests the temporal and spatial pattern of CCN as a biomarker that differentiates different stages of AD.

Impact StatementBy assuming that functional connectivity is static over time, many of previous studies have ignored the brain dynamic in Alzheimers disease progression. Here, a longitudinal resting-state functional magnetic resonance imaging data are used to explore the temporal changes of functional connectivity in the cognitive control network in Alzheimers disease progression. The result of this study would increase our understanding about the underlying mechanisms of Alzheimers Disease and help in finding future treatment of this neurological disorder.


title: Canonical features of human antibodies recognizing the influenza hemagglutinin trimer interface

abstract: Broadly reactive antibodies targeting the influenza A hemagglutinin (HA) head domain are thought to be rare and to require extensive somatic mutations or unusual structural features to achieve breadth against divergent HA subtypes. Here we describe common genetic and structural features of diverse human antibodies from several individuals recognizing the trimer interface (TI) of the influenza HA head, a recently identified site of vulnerability1-3. We examined the sequence of TI-reactive antibodies, determined crystal structures for TI antibody-antigen complexes, and analyzed the contact residues of the antibodies on HA to discover common genetic and structural features of TI antibodies. Our data reveal that many TI antibodies are encoded by a light chain variable gene segment incorporating a shared somatic mutation. In addition, these antibodies have a shared acidic residue in the heavy chain despite originating from diverse heavy chain variable gene segments. These studies show that the TI region of influenza HA is a major antigenic site with conserved structural features that are recognized by a common human B cell public clonotype. The canonical nature of this antibody-antigen interaction suggests that the TI epitope might serve as an important new target for structure-based vaccine design.

category: immunology


title: Paired heavy and light chain signatures contribute to potent SARS-CoV-2 neutralization in public antibody responses

abstract:
Understanding protective mechanisms of antibody recognition can inform vaccine and therapeutic strategies against SARS-CoV-2. We discovered a new antibody, 910-30, that targets the SARS-CoV-2 ACE2 receptor binding site as a member of a public antibody response encoded by IGHV3-53/IGHV3-66 genes. We performed sequence and structural analyses to explore how antibody features correlate with SARS-CoV-2 neutralization. Cryo-EM structures of 910-30 bound to the SARS-CoV-2 spike trimer revealed its binding interactions and ability to disassemble spike. Despite heavy chain sequence similarity, biophysical analyses of IGHV3-53/3-66 antibodies highlighted the importance of native heavy:light pairings for ACE2 binding competition and for SARS-CoV-2 neutralization. We defined paired heavy:light sequence signatures and determined antibody precursor prevalence to be ~1 in 44,000 human B cells, consistent with public antibody identification in several convalescent COVID-19 patients. These data reveal key structural and functional neutralization features in the IGHV3-53/3-66 public antibody class to accelerate antibody-based medical interventions against SARS-CoV-2.

HighlightsO_LIA molecular study of IGHV3-53/3-66 public antibody responses reveals critical heavy and light chain features for potent neutralization
C_LIO_LICryo-EM analyses detail the structure of a novel public antibody class member, antibody 910-30, in complex with SARS-CoV-2 spike trimer
C_LIO_LICryo-EM data reveal that 910-30 can both bind assembled trimer and can disassemble the SARS-CoV-2 spike
C_LIO_LISequence-structure-function signatures defined for IGHV3-53/3-66 class antibodies including both heavy and light chains
C_LIO_LIIGHV3-53/3-66 class precursors have a prevalence of 1:44,000 B cells in healthy human antibody repertoires
C_LI


title: A metagenomic-based stufy of two sites from the Barbadian reef system

abstract: We study the microbiome of sea water collected from two locations of the Barbadian coral reefs. The two sites differ in several environmental and ecological variables including their endogenous benthic community in addition to their proximity to urban development and runoffs from inland watersheds. The composition of the microbial community was estimated using whole genome DNA shotgun sequencing. Although both sites exhibit a similar degree of richness, the less urbanized site (Maycocks reef at Hangmans Bay) is strongly concentrated with phototrophs. In comparison, the more urbanized location (Bellairs Research Institute) is enriched for copiotrophs, macroalgal symbionts and marine-related disease-bearing organisms from taxa scattered across the tree of life. Overall, our samples and associated measurements of chemical and environmental qualities of the water are in line with previous marine microbiome profiles of warm ocean surface waters. This suggests our approach captures salient information regarding the state of each coral reef site and sets the stage for larger longitudinal studies of coral reef dynamics in Barbados.

category: microbiology


title: Real-time respiration changes as a viability indicator for rapid antibiotic susceptibility testing in a microfluidic chamber array

abstract: Rapid identification of a pathogen and the measurement of its antibiotic susceptibility are key elements in the diagnostic process of bacterial infections. Microfluidic technologies offer great control over handling and manipulation of low sample volumes with the possibility to study microbial cultures on the single-cell level. Downscaling the dimensions of cultivation systems directly results in a lower number of bacteria required for antibiotic susceptibility testing (AST) and thus in a reduction of the time to result. The developed platform presented in this work allows the reading of pathogen resistance profiles within 2-3 hours based on the changes of the dissolved oxygen levels during bacterial cultivation. The platform contains hundreds of individual growth chambers prefilled with a hydrogel containing oxygen-sensing nanoprobes and different concentrations of antibiotic compounds. The performance of the microfluidic platform is tested using quality control Escherichia coli strains (ATCC 25922 and ATCC 35218) in response to different clinically relevant antibiotics. The achieved results are in agreement with values given in clinical reference guides and independent measurements using a clinical AST protocol. Finally, the platform is successfully used for AST of an E. coli clinical isolate obtained from a patient blood culture.


title: A new method for improving extraction efficiency and purity of urine and plasma cell-free DNA

abstract: This study assessed three commercially available cell-free DNA (cfDNA) extraction kits and the impact of a PEG-based DNA cleanup procedure (DNApure) on cfDNA quality and yield. Six normal donor urine and plasma samples, and specimens from four pregnant (PG) women carrying male fetuses underwent extractions with the JBS cfDNA extraction kit (kit J), MagMAX Cell-Free DNA Extraction kit (kit M), and QIAamp Circulating Nucleic Acid Kit (kit Q). Recovery of a PCR product spike-in, endogenous TP53, and Y-chromosome DNA was used to assess kit performance. Nucleosomal-sized DNA profiles varied among the kits, with prominent multi-nucleosomal-sized peaks present in urine and plasma DNA isolated by kits J and M only. Kit J recovered significantly more spike-in DNA compared with kit M or Q (p<0.001) from urine, and similar amounts from plasma (p=0.12). Applying DNApure to kit M- and Q-isolated DNA significantly improved the amplification efficiency of spike-in DNA from urine (p<0.001) and plasma (p[≤]0.013). Furthermore, kit J isolated significantly more Y-chromosome DNA from PG urine compared to kit Q (p=0.05). We conclude that DNApure provides an efficient means of improving the yield and purity of cfDNA and minimizing effects of pre-analytical biospecimen variability on liquid biopsy assay performance.

category: molecular biology


title: RNA pull-down-Confocal Nanoscanning (RP-CONA) detects quercetin as pri-miR-7/HuR interaction inhibitor that decreases α-Synuclein levels

abstract: RNA-protein interactions are central to all gene expression processes and contribute to variety of human diseases. Therapeutic approaches targeting RNA-protein interactions have shown promising effects on some diseases that are previously regarded as  incurable. Here we developed a fluorescent on-bead screening platform: RNA pull-down-Confocal Nanoscanning (RP-CONA), to identify RNA-protein interaction modulators in eukaryotic cell extracts. Using RP-CONA, we identified small molecules that disrupt the interaction between HuR, an inhibitor of brain-enriched miR-7 biogenesis, and the conserved terminal loop of pri-miR-7-1. Importantly, miR-7s primary target is an mRNA of -Synuclein, which contributes to aetiology of Parkinsons disease. Our method identified a natural product quercetin as a molecule able to upregulate cellular miR-7 levels and downregulate the expression of -Synuclein. This opens up new therapeutic avenues towards treatment of Parkinsons disease as well as provides novel methodology to search for RNA-protein interaction modulators.


title: PD-L1+ and Hyal2+ myeloid cells in renal cell carcinoma: a case report

abstract: RCC patients frequently have increased numbers of immunosuppressive myeloid cells in circulation. High numbers of myeloid derived suppressor cells (MDSCs) in the blood are associated with immune suppression as well as with cancer-related inflammation which drives the mobilization of myeloid cells to tumor tissue. Here we show that peripheral blood from a previously untreated renal cell carcinoma patient has increased numbers of monocytic CD33+CD11b+ MDSCs, which also co-expressed PD-L1 and membrane-bound enzyme hyaluronidase 2 (Hyal2). PD-L1 expression is associated with immune suppression, whereas expression of Hyal2 is associated with inflammation, because Hyal2+ myeloid cells can degrade the extracellular hyaluronan (HA), leading to the accumulation of pro-inflammatory HA fragments with low molecular weight. These findings implicate the potential involvement of monocytic MDSCs in both tumor-associated immune suppression and cancer-related inflammation. Analysis of organoid-like tumor-tissue slice cultures prepared from cancer tissue of the same patient revealed the significant presence of PD-L1+ HLA-DR+ macrophage-like or dendritic cell-like antigen-presenting cells in tumor stroma. Interestingly that stroma-associated PD-L1+ cells frequently have intracellular hyaluronan. Collectively, data presented in this study suggest that the interplay between tumor-recruited myeloid cells and stromal hyaluronan may contribute to the inflammation and immune tolerance in cancer.

category: cell biology


title: Estimation of the Acetylcholinesterase activity of honey bees in Nepal

abstract: Decline in honey bee colonies possess a serious threat to biodiversity and agriculture. Prior detection of the stresses with the help of biomarkers and their management ensures honey bees survivability. Acetylcholinesterase (AChE) is a promising biomarker to monitor exposure of honey bees towards environmental pollutants. In this preliminary study, we measured AChE activity in forager honey bees collected from six districts of Nepal, Kathmandu, Bhaktapur, Lalitpur, Chitwan, Rupandehi and Pyuthan during autumn and winter seasons. We estimated AChE tissue and specific activities from bees heads using commercial kit based on Ellman assay and protein concentration using Lowry assay. In total, we collected 716 foragers belonging to A. cerana, A. mellifera and A. dorsata. A significant increase in all three parameters measured: AChE tissue activity, AChE specific activity and protein concentration was observed in winter samples. Both AChE tissue and specific activities were lower in A. mellifera compared to either A. cerana or A. dorsata. Protein concentration was higher in A. mellifera than in A. dorsata and lower than in A. cerana. We show correlation between both AChE tissue and specific activities and protein concentration across season and species and discuss possible factors contributing to the observations. Our results clearly indicate the presence of stress in the winter which is manifested through overexpression of the AChE. We recommend a detailed study to determine the factors accountable for the stresses for better management of honey bees in Nepal.

category: ecology


title: Diversity in olfactory receptor repertoires is associated with dietary specialization in a genus of frugivorous bat

abstract:
Mammalian olfactory receptors (ORs) are a diverse family of genes encoding proteins that directly interact with environmental chemical cues. ORs evolve via gene duplication in a birth-death fashion, neofunctionalizing and pseudogenizing over time. Olfaction is a primary sense used for food detection in plant-visiting bats, but the relationship between dietary specialization and OR repertoires is unclear. Within neotropical Leaf-nosed bats (Phyllostomidae), many lineages are plant specialists, and some have a distinct OR repertoire compared to insectivorous species. Yet, whether specialization on particular plant genera is associated with the evolution of more specialized OR repertoires has never been tested. Using targeted sequence capture, we sequenced the OR repertoires of three sympatric species of short-tailed leaf-nosed bats (Carollia), which vary in their degree of specialization on the fruits of Piper plants. We characterized orthologous versus duplicated receptors among Carollia species, and identified orthologous receptors and associated paralogs to explore the diversity and redundancy of the receptor gene repertoire. The most dedicated Piper specialist, Carollia castanea, had lower OR diversity compared to the two more generalist species (sowelli, perspicillata), but we discovered a few unique sets of ORs within C. castanea with exceptional redundancy of similar gene duplicates. These unique receptors potentially enable C. castanea to detect Piper fruit odorants to an extent that the other species cannot. C. perspicillata, the species with the most generalist diet, had a larger diversity of functional receptors, suggesting the ability to detect a wider range of odorant molecules. The variation among ORs may be a factor in the coexistence of these sympatric species, facilitating the exploitation of different plant resources. Our study sheds light on how gene duplication plays a role in dietary adaptations and underlies patterns of ecological interactions between bats and plants.

Impact Statement--though it asks for 3-4 sentencesThe sense of smell is essential to how many animals detect food, yet few studies have demonstrated how dietary evolution has shaped olfactory receptor genes, which encode proteins that bind to environmental scent cues, including food odorants. We compared the evolutionary history of olfactory receptor repertoires in three co-occurring neotropical bat species along a spectrum of dietary specialization on the fruits of Piper plants. We found the more generalist species possessed a more diverse olfactory receptor profile, potentially reflecting an ability to detect more diverse arrays of fruit scent compounds, while the specialist had a narrower profile that demonstrated more redundancy. By introducing creative approaches to measure diversity in large gene families and connecting diet specialization and molecular diversity, this study makes an unprecedented contribution to evolutionary biology.

category: evolutionary biology


title: Time-dependent pleiotropic phenotypes are caused by progressive DNA polymerase α deficiency in zebrafish

abstract: Pleiotropy caused by single-gene mutations is common and poorly understood. A zebrafish null mutant of DNA polymerase  subunit B, huli hutu (hht), evolves a complex pleiotropy associated with DNA damage and S phase arrest across multiple organ systems over 5-7 days, including nuclear atypia, a common cellular feature in human cancers and pre-cancers, in gastrointestinal organs, and nuclear fragmentation in the eye and brain. The pleiotropic pattern of hht phenotypes is explained by progressive loss of wild-type maternal pola2 function in homozygous mutant embryos whose pola2 mRNA becomes undetectable by 24 hours post-fertilization (hpf). Inhibition of DNA synthesis by aphidicolin or hydroxyurea in wild-type embryos from 24 hpf phenocopied the pleiotropic pattern of hht. These results are consistent with a model in which time-sensitive, reduced capacity for DNA synthesis results in cell death in fast-replicating cells, and nuclear atypia in tissues with fewer and larger cells.

category: genetics


title: Time- and cell-dependent atypia and cell death are caused by progressive deficiency in DNA replication


title: LAVA: An integrated framework for local genetic correlation analysis

abstract: Genetic correlation (rg) analysis is commonly used to identify traits that may have a shared genetic basis. Traditionally, rg is studied on a global scale, considering only the average of the shared signal across the genome; though this approach may fail to detect scenarios where the rg is confined to particular genomic regions, or show opposing directions at different loci. Tools dedicated to local rg analysis have started to emerge, but are currently restricted to analysis of two phenotypes. For this reason, we have developed LAVA, an integrated framework for local rg analysis which, in addition to testing the standard bivariate local rgs between two traits, can evaluate the local heritability for all traits of interest, and analyse conditional genetic relations between several traits using partial correlation or multiple regression. Applied to 20 behavioural and health phenotypes, we show considerable heterogeneity in the bivariate local rgs across the genome, which is often masked by the global rg patterns, and demonstrate how our conditional approaches can elucidate more complex, multivariate genetic relations between traits.


title: Comparing instance segmentation methods for analyzing clonal growth of single cells in microfluidic chips

abstract: Appropriately tailored segmentation techniques can extract detailed quantitative information from biological image datasets to characterize and better understand sample distributions. Practically, high-resolution characterization of biological samples such as cell populations can provide insights into the sources of variance in biomarker expression, drug resistance, and other phenotypic aspects, but it is still unclear what is the best method for extracting this information from large image-based datasets. We present a software pipeline and comparison of multiple image segmentation methods to extract single-cell morphological and fluorescence quantitation from time lapse images of clonal growth rates using a recently reported microfluidic system. The inputs in all pipelines consist of thousands of unprocessed images and the outputs are the detection of cell counts, chamber identifiers, and individual morphological properties of each clone over time detected through multi-channel fluorescence and bright field imaging. Our conclusion is that unsupervised learning methods for cell segmentation substantially outperform supervised statistical methods with respect to accuracy and have key advantages including individual cell instance detection and flexibility through model training. We expect this system and software to have broad utility for researchers interested in high-throughput single-cell biology.

category: bioengineering


title: Comprehensive profiling of genomic and transcriptomic  differences between risk groups of lung adenocarcinoma and lung squamous cell carcinoma

abstract: Lung cancer is the second frequently diagnosed cancer type and responsible for the highest number of cancer deaths worldwide. Lung adenocarcinoma and lung squamous cell carcinoma are subtypes of non-small cell lung cancer which has the highest frequency of lung cancer cases. We aimed to analyze genomic and transcriptomic variations including simple nucleotide variations (SNVs), copy number variations (CNVs) and differential expressed genes (DEGs) in order to find key genes and pathways for diagnostic and prognostic prediction for lung adenocarcinoma and lung squamous cell carcinoma. We performed univariate cox model and then lasso regularized cox model with leave-one-out cross-validation using TCGA gene expression data in tumor samples. We generated a 35-gene signature and a 33-gene signature for prognostic risk prediction based on the overall survival time of the patients with LUAD and LUSC, respectively. When we clustered patients into high-risk and low-risk groups, the survival analysis showed highly significant results with high prediction power for both training and test datasets. Then we characterized the differences including significant SNVs, CNVs, DEGs, active subnetworks, and the pathways. We described the results for the risk groups and cancer subtypes separately to identify specific genomic alterations between both high-risk groups and cancer subtypes. Both LUAD and LUSC high-risk groups have more down-regulated immune pathways and upregulated metabolic pathways. On the other hand, low-risk groups have both upregulated and downregulated genes on cancer-related pathways. Both LUAD and LUSC have important gene alterations such as CDKN2A and CDKN2B deletions with different frequencies. SOX2 amplification occurs in LUSC and PSMD4 amplification in LUAD. EGFR and KRAS mutations are mutually exclusive in LUAD samples. EGFR, MGA, SMARCA4, ATM, RBM10, and KDM5C genes are mutated only in LUAD but not in LUSC. CDKN2A, PTEN, and HRAS genes are mutated only in LUSC samples. Low-risk groups of both LUAD and LUSC, tend to have a higher number of SNVs, CNVs, and DEGs. The signature genes and altered genes have the potential to be used as diagnostic and prognostic biomarkers for personalized oncology.

category: bioinformatics


title: SANS serif: alignment-free, whole-genome based phylogenetic reconstruction

abstract:
SummarySANS serif is a novel software for alignment-free, whole-genome based phylogeny estimation that follows a pangenomic approach to efficiently calculate a set of splits in a phylogenetic tree or network.

Availability and ImplementationImplemented in C++ and supported on Linux, MacOS, and Windows. The source code is freely available for download at https://gitlab.ub.uni-bielefeld.de/gi/sans.

Contactandreas.rempel@uni-bielefeld.de


title: Wide occurrence of putative mobilized colistin resistance genes in the human gut microbiome

abstract:
BackgroundThe high incidence of bacterial genes that confer resistance to last-resort antibiotics, such as colistin caused by MCR genes, poses an unprecedented threat to our civilizations health. To understand the spread, evolution, and distribution of such genes among human populations, with the final goal of diminishing their occurrence in human environments should be a priority. To tackle this problem, we investigated the distribution and prevalence of potential mcr genes in the human gut microbiome we used a set of bioinformatics tools to screen the Unified Human Gastrointestinal Genome (UHGG) collection for the presence, synteny and phylogeny of putative mcr genes, and co-located antibiotic resistance genes.

ResultsA total of 2,079 ARGs were classified as different MCR in 2,046 Metagenome assembled genomes (MAGs), present in 1,596 individuals from 41 countries, of which 215 MCRs were identified in plasmidial contigs. The genera that presented the largest number of MCR-like genes were Suterella and Parasuterella, prevalent human gut bacteria of which Suterella wadsworthensis is associated with autism. Other potential pathogens carrying MCR genes belonged to the genus Vibrio, Escherichia and Campylobacter. Finally, we identified a total of 22,746 ARGs belonging to 21 different classes in the same 2,046 MAGs, suggesting multi-resistance potential in the corresponding bacterial strains, increasing the concern of ARGs impact in the clinical settings.

ConclusionThis study uncovers the diversity of MCR-like genes in the human gut microbiome. We showed the cosmopolitan distribution of these genes in individuals worldwide and the co-presence of other antibiotic resistance genes, including Extended-spectrum beta-lactamases (ESBL). Also, we described mcr-like genes fused to a PAP2-like domain in S. wadsworthensis. Although these novel sequences increase our knowledge about the diversity and evolution of mcr-like genes, their activity and a potential colistin resistance in the corresponding strains has to be experimentally validated.


title: Putative mobilized colistin resistance genes in the human gut microbiome


title: Cellular mechanisms of heterogeneity in NF2-mutant schwannoma

abstract: Schwannomas are common sporadic nervous system tumors and are diagnostic features of familial neurofibromatosis type 2 (NF2) that develop predominantly on cranial and spinal nerves and cause severe neurological deficits and significant morbidity. Virtually all schwannomas result from inactivation of the NF2 tumor suppressor gene with few, if any, cooperating mutations. Despite their genetic uniformity schwannomas exhibit remarkable clinical and therapeutic heterogeneity, which has impeded the success of early rational therapies. An understanding of how heterogeneity develops in NF2-mutant schwannomas is critically needed to improve therapeutic options for these patients. We have found that loss of the membrane:actin cytoskeleton-associated NF2 tumor suppressor protein, merlin, yields unstable intrinsic polarity and enables Nf2-/- Schwann cells to adopt distinct programs of coordinated ErbB ligand production and polarized signaling, suggesting a self-generated model of schwannoma heterogeneity. We validated the heterogeneous distribution of biomarkers of these programs in schwannoma tissue and cell lines from well-established mouse models, and then took advantage of the synchronous development of multiple lesions in a mouse model to establish a quantitative pipeline that can be used to study how schwannoma heterogeneity evolves and impacts nerve function and therapeutic response in mouse, and ultimately human schwannomas.

category: cancer biology


title: Massively parallel characterization of engineered transcript isoforms using direct RNA sequencing

abstract: Transcriptional terminators signal where transcribing RNA polymerases (RNAPs) should halt and disassociate from DNA. However, because termination is stochastic, two different forms of transcript could be produced: one ending at the terminator and the other reading through. An ability to control the abundance of these transcript isoforms would offer bioengineers a mechanism to regulate multi-gene constructs at the level of transcription. Here, we explore this possibility by repurposing terminators as  transcriptional valves which can tune the proportion of RNAP read-through. Using one-pot combinatorial DNA assembly we construct 1183 transcriptional valves for T7 RNAP and show how nanopore-based direct RNA sequencing (dRNA-seq) can be used to simultaneously characterize the entire pool at a nucleotide resolution in vitro and unravel genetic design principles to tune and insulate their function using nearby sequence context. This work provides new avenues for controlling transcription and demonstrates the value of long-read sequencing for exploring complex sequence-function landscapes.

category: synthetic biology


title: Distribution of Huntington's disease Haplogroups in Indian population

abstract: Huntingtons disease (HD), a rare neurodegenerative disorder, is inherited in an autosomal dominant manner, and caused by a pathological trinucleotide expansion at exon1 of the HTT locus. Previous studies have described the haplogroups at the HTT locus that can explain the differences in prevalence of HD. We have selected three informative SNPs (rs762855, rs3856973 and rs4690073) to study these haplogroups in an Indian sample. Our results show that the genotype frequencies are significantly different between cases and controls for these SNPs. More than 90% of both cases and controls belong to Haplogroup A which is the predominant European haplogroup.

category: neuroscience


title: Spontaneous and deliberate modes of creativity: Multitask eigen-connectivity analysis captures latent cognitive modes during creative thinking

abstract: Despite substantial progress in the quest of demystifying the brain basis of creativity, several questions remain open. One such issue concerns the relationship between two latent cognitive modes during creative thinking, i.e., deliberate goal-directed cognition and spontaneous thought generation. Although an interplay between deliberate and spontaneous thinking is often indirectly implicated in the creativity literature (e.g., dual-process models), a bottom-up data-driven validation of the cognitive processes associated with creative thinking is still lacking. Here, we attempted to capture the latent modes of creative thinking by utilizing a data-driven approach on a novel continuous multitask paradigm (CMP) that widely sampled a hypothetical two-dimensional cognitive plane of deliberate and spontaneous thinking in a single fMRI session. The CMP consisted of eight task blocks ranging from undirected mind wandering to goal-directed working memory task, while also including two of the widely used creativity tasks, i.e., alternate uses task (AUT) and remote association task (RAT). Using data-driven eigen-connectivity (EC) analysis on the multitask whole-brain functional connectivity (FC) patterns, we embedded the multitask FCs into a low-dimensional latent space. The first two latent components, as revealed by the EC analysis, broadly mapped onto the two cognitive modes of deliberate and spontaneous thinking, respectively. Further, in this low-dimensional space, both creativity tasks were located in the upper right corner of high deliberate and spontaneous thinking (creative cognitive space). Neuroanatomically, the creative cognitive space was represented by not only increased intra-network connectivity within executive control and default mode networks, but also by a higher inter-network coupling between the two. Further, individual differences reflected in the low-dimensional connectivity embeddings were related to differences in deliberate and spontaneous thinking abilities. Altogether, using a continuous multitask paradigm and data-driven approach, we provide direct empirical evidence for the contribution of both deliberate and spontaneous modes of cognition during creative thinking.


title: Colour Ambiguity In Real Scenes And The Role Of Perceptual Organisation

abstract: In this study we show a reproduction of the dress-ambiguity phenomenon in a real scene and we report quantitative measurements of the corresponding colour perceptions. The original, real dress, known from #thedress-illusion, was illuminated by combined short- and longwavelength broadband lights from two slide projectors. Test subjects viewing the dress reported to perceive the dress fabric and lace colours as blue & black, white & gold or light blue & brown; their corresponding perceptual matches were distributed along the blue/yellow cardinal axis, and exhibited a variability comparable to the ambiguity of the dress photograph. It is particularly noteworthy that the colour ambiguity emerged despite explicit knowledge of the observers about the direction of the light source. Manipulating the background of the real dress (change in chromaticity and luminance, or masking) revealed significant differences between the perceptual groups regarding lightness and colour of the dress. Our findings suggest that observer specific differences in the perceptual organisation of the visual scene are responsible for the colour ambiguity observed for the real dress; in particular, we conclude that colour computations of white & gold viewers focused onto the local region of the dress, whereas the colour processes of blue & black and light-blue & brown viewers were strongly influenced by contextual computations including the background. Our segmentation hypothesis extends existing explanations for the dress ambiguity and proposes image based (in the case of the real scene) and high level (in the case of the photograph) neural processes which control the spatial reach of contextual colour computations. The relation between the ambiguity in our real scene and the dress photograph is discussed.


title: In vivo super-resolution track-density imaging for thalamic nuclei identification

abstract: The development of novel techniques for the in vivo, non-invasive visualization and identification of thalamic nuclei has represented a major challenge for human neuroimaging research in the last decades. Thalamic nuclei have important implications in various key aspects of brain physiology and many of them show selective alterations in various neurologic and psychiatric disorders. In addition, both surgical stimulation and ablation of specific thalamic nuclei have been proven to be useful for the treatment of different neuropsychiatric diseases. The present work aimed at describing a novel protocol for histologically-guided delineation of thalamic nuclei based on short-tracks track-density imaging (stTDI), which is an advanced imaging technique that exploits high angular resolution diffusion tractography to obtain super-resolved white matter maps with high anatomical information. We tested this protocol on i) six healthy individual 3T MRI scans from the Human Connectome Project database, and on ii) a group population template reconstructed by averaging 100 unrelated healthy subjects scans from the same repository. We demonstrated that this approach can identify up to 13 distinct thalamic nuclei bilaterally with very high reliability (intraclass correlation coefficient: 0.996, 95% CI: 0.993-0.998; total accumulated overlap: 0.43) and that both subject-based and group-level thalamic parcellation show a fair share of similarity to a recent standard-space histological thalamic atlas. Finally, we showed that stTDI-derived thalamic maps can be successfully employed to study thalamic structural and functional connectivity, and may have potential implications both for basic and translational research, as well as for pre-surgical planning purposes.


title: Effects of chronic lithium treatment on anxious behaviors and serotonergic genes expression in the midbrain raphe nuclei in defeated male mice

abstract: There are experimental data that mixed anxiety/depression-like state induced by chronic social defeat stress is accompanied by development of anxiety and downregulation of serotonergic gene expression in the midbrain raphe nuclei of male mice. The paper aimed to study the effect of chronic lithium chloride (LiCl) on anxious behaviors and the expression of serotonergic genes (Tph2, Slc6a4, Htr1a, Htr5b) in the midbrain raphe nuclei of defeated mice. Slight anxiolytic effects of LiCl were found on the commucativeness in the partition test, and anxiogenic-like effects, estimated by the elevated plus-maze and social interactions tests. Chronic LiCl treatment induced overexpression of the serotonergic genes in the midbrain raphe nuclei of defeated mice. We can assume that effects of LiCl, rather anxiogenic, may be due to activation of serotonergic system induced by hyperexpression of serotonergic genes. Our findings will allow to understand the factors involved in the positive and side effects of lithium on anxiety and function of serotonergic genes which are involved into mechanisms of depression.


title: Specific cognitive signatures of information seeking in controllable environments

abstract:
In uncertain environments, seeking information about alternative choice options is essential for adaptive learning and decision-making. However, information seeking is usually confounded with changes-of-mind about the reliability of the preferred option. Here, we exploited the fact that information seeking requires control over which option to sample to isolate its behavioral and neurophysiological signatures. We found that changes-of-mind occurring with control require more evidence against the current option, are associated with reduced confidence, but are nevertheless more likely to be confirmed on the next decision. Multimodal neurophysiological recordings showed that these changes-of-mind are preceded by stronger activation of the dorsal attention network in magnetoencephalography (MEG), and followed by increased pupil-linked arousal during the presentation of decision outcomes. Together, these findings indicate that information seeking increases the saliency of evidence perceived as the direct consequence of ones own actions.

HighlightsO_LIExploration-exploitation dilemmas confound information seeking with changes-of-mind.
C_LIO_LIUnlike changes-of-mind, information seeking requires control over information sampling.
C_LIO_LIInformation seeking is associated with reduced confidence and active hypothesis testing.
C_LIO_LIStronger neurophysiological correlates of attention and arousal during information seeking.
C_LI


title: Controllability reveals defining features of information seeking


title: Controllability boosts neural and cognitive signatures of information seeking


title: Lithium ions display weak interaction with amyloid-beta (Aβ) peptides and have minor effects on their aggregation

abstract: Alzheimers disease (AD) is an incurable disease and the main cause of age-related dementia worldwide, despite decades of research. Treatment of AD with lithium (Li) has showed promising results, but the underlying mechanism is unclear. The pathological hallmark of AD brains is deposition of amyloid plaques, consisting mainly of amyloid-{beta} (A{beta}) peptides aggregated into amyloid fibrils. The plaques contain also metal ions of e.g. Cu, Fe, and Zn, and such ions are known to interact with A{beta} peptides and modulate their aggregation and toxicity. The interactions between A{beta} peptides and Li+ ions have however not been well investigated. Here, we use a range of biophysical techniques to characterize in vitro interactions between A{beta} peptides and Li+ ions. We show that Li+ ions display weak and non-specific interactions with A{beta} peptides, and have minor effects on A{beta} aggregation. These results indicate that possible beneficial effects of Li on AD pathology are not likely caused by direct interactions between A{beta} peptides and Li+ ions.

category: biochemistry


title: De novo germline mutation in the Dual Specificity Phosphatase 10 gene accelerates autoimmune diabetes in Non-Obese Diabetic (NOD) mice

abstract: Here we report the isolation by selective breeding of two sublines of Non-Obese Diabetic (NOD) mice exhibiting a significant difference in the incidence of autoimmune type 1 diabetes (T1D). Whole genome sequencing of the NOD/NckH (high T1D incidence) and NOD/NckL (low T1D incidence) revealed the presence of a limited number of variants specific to each subline. Treating the age of T1D onset as a quantitative trait and using automated meiotic mapping (AMM), enhanced susceptibility in the NOD/NckH subline was unambiguously attributed to a recessive allele of Dusp10 which encodes a dual specificity phosphatase. The causative effect of the mutation was verified with a high level of confidence by targeting Dusp10 with CRISPR/Cas9 in NOD/NckL mice: in these animals a higher incidence of diabetes was observed. Expression of wild-type Dusp10 correlated with higher levels of surface PD-L1 in the islets of NOD/NckL mice.


title: S. aureus-serine protease-like protein B (SplB) activates PAR2 and induces endothelial barrier dysfunction

abstract:
Staphylococcus aureus (S. aureus) is a major cause of life-threatening systemic infection in humans. To cause blood stream infections such as sepsis and endocarditis, the bacteria must overcome the hosts endothelial barrier. The serine protease-like proteins (Spls) of S. aureus are known to contribute to pneumonia and allergic airway inflammation in animal models, but their role in endothelial damage is unknown. Here we demonstrate that SplB induces proinflammatory cytokine release in primary human vascular endothelial cells (HUVECs) in vitro. Mechanistically, we show that SplB selectively cleaves and activates human proteinase-activated receptor-2 (PAR2), and induces biased signaling via G13, Gi1/oB (NF-k{beta}), and {beta}-arrestin-1/-2. This activation did not trigger Gq/11-mediated calcium release nor ERK phosphorylation. Inhibition of PAR2 in HUVECs reduced the SplB-mediated cytokine release. Intravital microscopy of cremaster muscles in mice demonstrated that administration of SplB causes microvascular leakage. Genetic deletion of PAR2 in mice or neutralization of SplB with a monoclonal antibody preserved the endothelial barrier. This study identifies PAR2 as a receptor and substrate for SplB and highlights its role in mediating endothelial damage.

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org.highwire.dtl.DTLVardef@16a60a2org.highwire.dtl.DTLVardef@ee4e41org.highwire.dtl.DTLVardef@153cd7borg.highwire.dtl.DTLVardef@d746eb_HPS_FORMAT_FIGEXP  M_FIG Graphical abstract C_FIG


title: Staphylococcus aureus-serine protease-like protein B (SplB) activates PAR2 and induces endothelial barrier dysfunction


title: 6-gingerol interferes with amyloid-beta (Aβ) peptide aggregation

abstract: Alzheimers disease (AD) is the most prevalent age-related cause of dementia. AD affects millions of people worldwide, and to date there is no cure. The pathological hallmark of AD brains is deposition of amyloid plaques, which mainly consist of amyloid-{beta} (A{beta}) peptides, commonly 40 or 42 residues long, that have aggregated into amyloid fibrils. Intermediate aggregates in the form of soluble A{beta} oligomers appear to be highly neurotoxic. Cell and animal studies have previously demonstrated positive effects of the molecule 6-gingerol on AD pathology. Gingerols are the main active constituents of the ginger root, which in many cultures is a traditional nutritional supplement for memory enhancement. Here, we use biophysical experiments to characterize in vitro interactions between 6-gingerol and A{beta}40 peptides. Our experiments with atomic force microscopy imaging, and nuclear magnetic resonance and Thioflavin-T fluorescence spectroscopy, show that the hydrophobic 6-gingerol molecule interferes with formation of A{beta}40 aggregates, but does not interact with A{beta}40 monomers. Thus, together with its favourable toxicity profile, 6-gingerol appears to display many of the desired properties of an anti-AD compound.


title: The engineered peptide construct NCAM1-Aβ inhibits aggregation of the human prion protein (PrP)

abstract: In prion diseases, the prion protein (PrP) becomes misfolded and forms fibrillar aggregates, which are resistant to proteinase degradation and become responsible for prion infectivity and pathology. So far, no drug or treatment procedures have been approved for prion disease treatment. We have previously shown that engineered cell-penetrating peptide constructs can reduce the amount of prion aggregates in infected cells. The molecular mechanisms underlying this effect are however unknown. Here, we use atomic force microscopy (AFM) imaging to show that the aggregation of the human PrP protein can be inhibited by equimolar amounts of the 25 residues long engineered peptide construct NCAM1-A{beta}.


title: An integrative model of plant gravitropism linking statoliths position and auxin transport

abstract: Gravity is a major cue for the proper growth and development of plants. The response of plants to gravity implies starch-filled plastids, the statoliths, which sediments at the bottom of the gravisensing cells, the statocytes. Statoliths are assumed to modify the transport of the growth hormone, auxin, by acting on specific auxin transporters, PIN proteins. However, the complete gravitropic signaling pathway from the intracellular signal associated to statoliths to the plant bending is still not well understood. In this article, we build on recent experimental results showing that statoliths do not act as gravitational force sensor, but as position sensor, to develop a bottom-up theory of plant gravitropism. The main hypothesis of the model is that the presence of statoliths modifies PIN trafficking close to the cell membrane. This basic assumption, coupled with auxin transport and growth in an idealized tissue made of a one-dimensional array of cells, recovers several major features of the gravitropic response of plants. First, the model provides a new interpretation for the response of a plant to a steady stimulus, the so-called sine-law of plant gravitropism. Second, it predicts the existence of a gravity-independent memory process as observed recently in experiments studying the response to transient stimulus. The model suggests that the timescale of this process is associated to PIN turnover, calling for new experimental studies.

category: biophysics


title: POT1 Stability and Binding Measured by Fluorescence Thermal Shift Assays

abstract: The protein POT1 (Protection of Telomeres 1) is an integral part of the shelterin complex that protects the ends of human chromosomes from degradation or end fusions. It is the only component of shelterin that binds single-stranded DNA. We describe here the application of two separate fluorescent thermal shift assays (FTSA) that provide quantitative biophysical characterization of POT1 stability and its interactions. The first assay uses Sypro Orange and monitors the thermal stability of POT1 and its binding under a variety of conditions. This assay is useful for the quality control of POT1 preparations, for biophysical characterization of its DNA binding and, potentially, as an efficient screening tool for binding of small molecule drug candidates. The second assay uses a FRET-labeled human telomeric G-quadruplex structure that reveals the effects of POT1 binding on thermal stability from the DNA frame of reference. These complementary assays provide efficient biophysical approaches for the quantitative characterization of multiple aspects of POT1 structure and function. The results from these assays provide thermodynamics details of POT1 folding, the sequence selectivity of its DNA binding and the thermodynamic profile for its binding to its preferred DNA binding sequence. Most significantly, results from these assays elucidate two mechanisms for the inhibition of POT1 - DNA interactions. The first is by competitive inhibition at the POT1 DNA binding site. The second is indirect and is by stabilization of G-quadruplex formation within the normal POT1 single-stranded DNA sequence to prevent POT1 binding.


title: Deciphering how naturally occurring sequence features impact the phase behaviors of disordered prion-like domains

abstract: Phase separation of intrinsically disordered prion-like low-complexity domains (PLCDs) derived from RNA-binding proteins enable the formation of biomolecular condensates in cells. PLCDs have distinct amino acid compositions, and here we decipher the physicochemical impact of conserved compositional biases on the driving forces for phase separation. We find that tyrosine residues make for stronger drivers of phase separation than phenylalanine. Depending on their sequence contexts, arginine residues enhance or weaken phase separation, whereas lysine residues weaken cohesive interactions within PLCDs. Increased net charge per residue (NCPR) weakens the driving forces for phase separation of PLCDs and this effect can be modeled quantitatively. The effects of NCPR also weaken known correlations between the dimensions of single chains in dilute solution and the driving forces for phase separation. We build on experimental data to develop a coarse-grained model for accurate simulations of phase separation that yield novel insights regarding PLCD phase behavior.


title: FAM134B-RHD Protein Clustering Drives Spontaneous Budding of Asymmetric Membranes

abstract:
Living cells constantly remodel the shape of their lipid membranes. In the endo-plasmic reticulum (ER), the reticulon homology domain (RHD) of the reticulophagy regulator 1 (RETR1/FAM134B) forms dense autophagic puncta that are associated with membrane removal by ER-phagy. In molecular dynamics (MD) simulations, we find that FAM134B-RHD spontaneously forms clusters, driven in part by curvature-mediated attraction. At a critical size, the FAM134B-RHD clusters induce the formation of membrane buds. The kinetics of budding depends sensitively on protein concentration and bilayer asymmetry. Our MD simulations shed light on the role of FAM134B-RHD in ER-phagy and show that membrane asymmetry can be used to modulate the kinetics barrier for membrane remodeling.

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title: Microsecond resolved infrared spectroscopy on non-repetitive protein reactions by applying caged-compounds and quantum cascade laser frequency combs

abstract: Infrared spectroscopy is ideally suited for the investigation of protein reactions at the atomic level. Many systems were investigated successfully by applying Fourier transform infrared (FTIR) spectroscopy. While rapid-scan FTIR spectroscopy is limited by time resolution (about10 ms with 16 cm-1 resolution), step-scan FTIR spectroscopy reaches a time-resolution of about 10 ns but is limited to cyclic reactions that can be repeated hundreds of times under identical conditions. Consequently, FTIR with high time resolution was only possible with photoactivable proteins that undergo a photocycle. The huge number of non-repetitive reactions, e.g. induced by caged compounds, were limited to the ms time domain. The advent of dual comb quantum cascade laser allows now for a rapid reaction monitoring in the s time domain. Here we investigate the potential to apply such an instrument to the huge class of G-proteins. We compare caged-compound induced reactions monitored by FTIR and dual comb spectroscopy, respectively, by applying the new technique to the  subunit of the inhibiting Gi protein and to the larger protein-protein complex of Gi with its cognate regulator of G-protein signaling (RGS). We observe good data quality with 4 s time resolution with a wavelength resolution comparable to FTIR. This is more than three orders of magnitude faster than any FTIR measurement on G-proteins in the literature. This study paves the way for infrared spectroscopic studies in the so far unresolvable s time regime for non-repetitive biological systems including all GTPases and ATPases.


title: Cryo-EM structure of the yeast TREX complex and coordination with the SR-like protein Gbp2

abstract: The evolutionarily conserved TREX complex plays central roles during mRNP (messenger ribonucleoprotein) maturation and export from the nucleus to the cytoplasm. In yeast, TREX is composed of the THO sub-complex (Tho2, Hpr1, Tex1, Mft1, and Thp2), the DEAD box ATPase Sub2, and Yra1. Here we present a 3.7 [A] cryo-EM structure of the yeast THO*Sub2 complex. The structure reveals the intimate assembly of THO revolving around its largest subunit Tho2. THO stabilizes a semi-open conformation of the Sub2 ATPase via interactions with Tho2. We show that THO interacts with the SR-like protein Gbp2 through both the N-terminal domain and RRM domains of Gbp2. Crosslinking mass spectrometry analysis supports the extensive interactions between THO and Gbp2, further revealing that RRM domains of Gbp2 are in close proximity to the C-terminal domain of Tho2. We propose that THO serves as a landing pad to configure Gbp2 to facilitate its loading onto mRNP.


title: Learning attention-controllable border-ownership for objectness inference and binding

abstract: Human visual systems can parse a scene composed of novel objects and infer their surfaces and occlusion relationships without relying on object-specific shapes or textures. Perceptual grouping can bind together spatially disjoint entities to unite them as one object even when the object is entirely novel, and bind other perceptual properties like color and texture to that object using object-based attention. Border-ownership assignment, the assignment of perceived occlusion boundaries to specific perceived surfaces, is an intermediate representation in the mammalian visual system that facilitates this perceptual grouping. Since objects in a scene can be entirely novel, inferring border ownership requires integrating global figural information, while dynamically postulating what the figure is, a chicken-and egg process that is complicated further by missing or conflicting local evidence regarding the presence of boundaries. Based on neuroscience observations, we introduce a model - the cloned Markov random field (CMRF)- that can learn attention-controllable representations for border-ownership. Higher-order contour representations that distinguish border-ownerships emerge as part of learning in this model. When tested with a cluttered scene of novel 2D objects with noisy contour-only evidence, the CMRF model is able to perceptually group them, despite clutter and missing edges. Moreover, the CMRF is able to use occlusion cues to bind disconnected surface elements of novel objects into coherent objects, and able to use top-down attention to assign border ownership to overlapping objects. Our work is a step towards dynamic binding of surface elements into objects, a capability that is crucial for intelligent agents to interact with the world and to form entity-based abstractions.


title: A Practical Guide to Sparse Clustering for Studying Molecular Development of the Human Brain

abstract: Studying the molecular development of the human brain presents unique challenges for selecting a data analysis approach. The rare and valuable nature of human postmortem brain tissue, especially for developmental studies, means the sample sizes are small (n), but the use of high throughput genomic and proteomic methods measure the expression levels for hundreds or thousands of variables (e.g. genes or proteins (p)) for each sample. This leads to a data structure that is high dimensional (p >> n) and introduces the curse of dimensionality, which poses a challenge for traditional statistical approaches. In contrast, high dimensional analyses, especially cluster analyses developed for sparse data, have worked well for analyzing genomic datasets where p >> n. Here we explore applying a lasso-based clustering method developed for high dimensional genomic data with small sample sizes. Using protein and gene data from the developing human visual cortex, we compared clustering methods. We identified an application of sparse K-means clustering (Robust Sparse K-means Clustering (RSKC)) that partitioned samples into age-related clusters that reflect lifespan stages from birth to aging. RSKC adaptively selects a subset of the genes or proteins contributing to partitioning samples into age-related clusters that progress across the lifespan. This approach addresses a problem in current studies that could not identify multiple postnatal clusters. Moreover, clusters encompassed a range of ages like a series of overlapping waves illustrating that chronological- and brain-age have a complex relationship. In addition, a recently developed workflow to create plasticity phenotypes (Balsor et al., 2020) was applied to the clusters and revealed neurobiologically relevant features that identified how the human visual cortex changes across the lifespan. These methods can help address the growing demand for multimodal integration, from molecular machinery to brain imaging signals, to understand the human brains development.


title: A Practical Guide to Sparse k-means Clustering for Studying Molecular Development of the Human Brain


title: More than expected: the abundance of yellow-legged gulls Larus michahellis breeding in the historic centre of Venice and the initial effects of the new waste collection policy on the population

abstract: Yellow-legged gull, Larus michahellis, has undergone widespread colonization of the urban environment in recent past. Starting in 2000 this affected the historical centre of Venice, 24 roof-nesting pairs being recorded in 2005, with this number increasing significantly in the last decade. In 2016, the waste management company of Venice established a new door to door garbage collection system to prevent the accumulation of rubbish in the streets and limit the trophic resources available for the species. The study provides an up-to-date estimate of the urban population of yellow-legged gulls, using Distance Sampling method. We also studied the effect of the new system on the species by comparing the population estimate before and after the change and by analysing the trend of individuals collected in the old town by the service of wildlife recovery during 2010-2018. Results estimate 440 breeding pairs (95s% confidence interval: 326-593) in June 2018 and show a 34% decrease of breeding pairs in 2018 with respect to 2017, as well as a decrease in number of 1-year birds and pulli collected by wildlife recovery service starting from 2016, year of the policy implementation. Our data did not show a significant decrease in the overall number of individuals, suggesting the new policy has a stronger effect on the breeding success of the species than on adult survival. This study emphasizes the importance of preventing rubbish accumulation in the streets as factor for reducing the abundance of urban yellow-legged gulls.


title: Viral competence data improves rodent reservoir predictions for American orthohantaviruses

abstract:
Identifying reservoir host species is crucial for understanding the risk of pathogen spillover from wildlife to people. Orthohantaviruses are zoonotic pathogens primarily carried by rodents that cause the diseases hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS) in humans. Given their diversity and abundance, many orthohantaviruses are expected to be undiscovered, and several host relationships remain unclear, particularly in the Americas. Despite the increasing use of predictive models for understanding zoonotic reservoirs, explicit comparisons between different evidence types for demonstrating host associations, and relevance to model performance in applied settings, have not been previously made. Using multiple machine learning methods, we identified phylogenetic patterns in and predicted unidentified reservoir hosts of New World orthohantaviruses based on evidence of infection (RT-PCR data) and competence (live virus isolation data). Infection data were driven by phylogeny, unlike competence data, and boosted regression tree (BRT) models using competence data displayed higher accuracy and a narrower list of predicted reservoirs than those using infection data. Eight species were identified by both BRT models as likely orthohantavirus hosts, with a total of 98 species identified by our infection models and 14 species identified by our competence models. Hosts predicted by competence models are concentrated in the northeastern United States (particularly Myodes gapperi and Reithrodontomys megalotis) and northern South America (several members of tribe Oryzomyini) and should be key targets for empirical monitoring. More broadly, these results demonstrate the value of infection competence data for predictive models of zoonotic pathogen hosts, which can be applied across a range of settings and host-pathogen systems.

Author SummaryHuman diseases with wildlife origins constitute a significant risk for human health. Orthohantaviruses are viruses found primarily in rodents that cause disease with high rates of mortality and other complications in humans. An important step in disease prevention is to identify which rodent species carry and transmit orthohantaviruses. By incorporating species relatedness and evidence of different levels of host capacity to be infected and transmit virus, we used predictive modeling to determine unidentified rodent hosts of orthohantaviruses. Models using host competence data outperformed models using host infection data, highlighting the importance of stronger data in model optimization. Our results highlighted roughly a dozen key target species to be monitored that are concentrated in two geographic regions--northeastern United States and northern South America. More broadly, the approaches used in this study can be applied to a variety of other host-pathogen systems that threaten public health.


title: Predicting The Yields Of Species Occupying A Single Trophic Level With Incomplete Information: Two Approximations Based On The Lotka-Volterra Generalized Equations

abstract:
The linear Lotka-Volterra generalized equations (LLVGE) serve for describing the dynamics of communities of species connected by negative as well as positive interspecific interactions.

Here we particularize these LLVGE to the case of a single trophic level community with S >2 species, either artificial or natural. In this case, by estimating the LLVGE parameters from the yields in monoculture and biculture experiments, the LLVGE are able to produce quite accurate predictions for species yields.

However, a common situation we face is that we dont know all the parameters appearing in the LLVGE. Indeed, for large values of S, only a fraction of the experiments necessary for estimating the model parameters is commonly carried out.

We then analyze which quantitative predictions are possible with an incomplete knowledge of the parameters. We discuss two approximations that allow using these LLVGE as a quantitative tool. First, when we only know a fraction of the model parameters, the mean field approximation allows making predictions on aggregate or average quantities. Second, for cases in which all the interaction parameters involving a particular species are available, we have the focal species approximation for predicting the yield of this focal species.


title: Distribution modeling of Lantana camara and identification of hotspot for future management of the species in the lower Shivalik region of Uttarakhand, India

abstract: Invasive alien species are one of the most significant threats to biodiversity of the earth ecosystem. Spatial modeling has played a vital role in predicting and mapping the suitable areas of the species habitat for management implementation. Lantana camara is one of the ten worst invasive weed enlisted by IUCN., and has its distribution in more than 154000 sq. km area in India. We predicted the distribution of Lantana camara using Ecological Niche Modeling (ENM) in MaxEnt software for Rajaji- Corbett landscape in the lower Shivalik region of the state of Uttarakhand, India. The predicted area for the invasion was classified into four categories high, good, medium, and low potential areas. The distribution hotspots were identified using Getis Ord G* method in ArcGIS 10.5 by calculating plot-wise species occurrence. Major hotspot areas under threat of high infestation are Dholkhand, Gohri, Ramgarh, Motichur, and Chilla from Rajaji Tiger Reserve, Palain, Mandal and Maidavan from Kalagarh Tiger Reserve and Bijrani, Dheela, Dhikala, Jhirna and Kalagarh from Corbett Tiger Reserve. This study provides a current status of the invasive species in the landscape with identified areas that need immediate actions to control the spread of the species. The study results can help the policymakers and stakeholders build an efficient and strategically weed management plan.


title: Identification of Discriminative Gene-level and Protein-level Features Associated with Gain-of-Function and Loss-of-Function Mutations

abstract: Identifying whether a given genetic mutation results in a gene product with increased (gain-of-function; GOF) or diminished (loss-of-function; LOF) activity is an important step toward understanding disease mechanisms as they may result in markedly different clinical phenotypes. Here, we generated the first extensive database of all currently known germline GOF and LOF pathogenic mutations by employing natural language processing (NLP) on the available abstracts in the Human Gene Mutation Database. We then investigated various gene- and protein-level features of GOF and LOF mutations by applying machine learning and statistical analyses to identify discriminative features. We found that GOF mutations were enriched in essential genes, autosomal dominant inheritance, protein binding and interaction domains, whereas LOF mutations were enriched in singleton genes, protein-truncating variants, and protein core regions. We developed a user-friendly web-based interface that enables the extraction of selected subsets from the GOF/LOF database by a comprehensive set of annotated features, and downloading up-to-date versions (https://itanlab.shinyapps.io/goflof/). These results could ultimately improve our understanding of how mutations affect gene/protein function thereby guiding future treatment options.


title: Moment-based approximations for the Wright-Fisher model of population dynamics under natural selection at two linked loci

abstract: Properly modelling genetic recombination and local linkage has been shown to bring significant improvement to the inference of natural selection from time series data of allele frequencies under a Wright-Fisher model. Existing approaches that can account for genetic recombination and local linkage are built on either the diffusion approximation or a moment-based approximation of the Wright-Fisher model. However, methods based on the diffusion approximation are likely to require much higher computational cost, whereas moment-based approximations may suffer from the distribution support issue: for example, the normal approximation can seriously affect computational accuracy. In the present work, we introduce two novel moment-based approximations of the Wright-Fisher model on a pair of linked loci, both subject to natural selection. Our key innovation is to extend existing methods to account for both the mean and (co)variance of the two-locus Wright-Fisher model with selection. We devise two approximation schemes, using a logistic normal distribution and a hierarchical beta distribution, respectively, by matching the first two moments of the Wright-Fisher model and the approximating model. As compared with the diffusion approximation, our approximations enable the approximate computation of the transition probabilities of the Wright-Fisher model at a far smaller computational cost. We can also avoid the distribution support issue found in the normal approximation.


title: The histologic phenotype of lung cancers may be driven by transcriptomic features rather than genomic characteristics

abstract: Histology plays an essential role in therapeutic decision-making for lung cancer patients. However, the molecular determinants of lung cancer histology are largely unknown. We conducted whole-exome sequencing(WES) and microarray profiling on 19 micro-dissected tumor regions of different histologic subtypes from 9 patients with lung cancers of mixed histology. A median of 68.9% of point mutations and 83% of copy number aberrations were shared between different histologic components within the same tumors. Furthermore, different histologic components within the tumors demonstrated similar subclonal architecture. On the other hand, transcriptomic profiling revealed shared pathways between the same histologic subtypes from different patients, which was supported by the analyses of the transcriptomic data from 141 cell lines and 343 lung cancers of different histologic subtypes. These data suggest that histology of lung cancers may be determined at the transcriptomic level rather than the genomic level.

category: genomics


title: Characterizing and correcting camera noises in back-illuminated sCMOS cameras

abstract: With promising properties of fast imaging speed, large field-of-view, relative low cost and many others, back-illuminated sCMOS cameras have been receiving intensive attentions for low-light imaging in the past several years. However, due to the pixel-to-pixel difference of camera noises (called noise non-uniformity) in sCMOS cameras, researchers may hesitate to use them in some application fields, and sometimes wonder whether they should optimize the noise non-uniformity of their sCMOS cameras before using them in a specific application scenario. In this paper, we systematically characterize the impact of different types of sCMOS noises on image quality and perform corrections to these sCMOS noises. We verify that it is possible to use appropriate correction methods to push the non-uniformity of major camera noises, including readout noise, offset, and photon response, to a satisfactory level for conventional microscopy and single molecule localization microscopy. We further find out that, after these corrections, global read noise becomes a major concern that limits the imaging performance of back-illuminated sCMOS cameras. We believe this study provides new insights into the understanding of camera noises in back-illuminated sCMOS cameras, and also provides useful information for future development of this promising camera technology.


title: Mining underutilized whole-genome sequencing projects to improve 16S rRNA databases

abstract: Current approaches to interpreting 16S rDNA amplicon data are hampered by several factors. Among these are database inaccuracy or incompleteness, sequencing error, and biased DNA/RNA extraction. Existing 16S rRNA databases source the majority of sequences from deposited amplicon sequences, draft genomes, and complete genomes. Most of the draft genomes available are assembled from short reads. However, repeated ribosomal regions are notoriously difficult to assemble well from short reads, and as a consequence the short-read-assembled 16S rDNA region may be an amalgamation of different loci within the genome. This complicates high-resolution community analysis, as a draft genomes 16S rDNA sequence may be a chimera of multiple loci; in such cases, the draft-derived sequences in a database may not represent a 16S rRNA sequence as it occurs in biology. We present Focus16, a pipeline for improving 16S rRNA databases by mining NCBIs Sequence Read Archive for whole-genome sequencing runs that could be reassembled to yield additional 16S rRNA sequences. Using riboSeed (a genome assembly tool for correcting rDNA misassembly), Focus16 provides a way to augment 16S rRNA databases with high-quality re-assembled sequences. In this study, we augmented the widely-used SILVA 16S rRNA database with the novel sequences disclosed by Focus16 and re-processed amplicon sequences from several benchmarking datasets with DADA2. Using this augmented SILVA database increased the number of amplicon sequence variants that could be assigned taxonomic annotations. Further, fine-scale classification was improved by revealing ambiguities. We observed, for example, that amplicon sequence variants (ASVs) may be assigned to a specific genus where Focus16-correction would indicate that the ASV is represented in two or more genera. Thus, we demonstrate that improvements can be made to taxonomic classification by incorporating these carefully re-assembled 16S rRNA sequences, and we invite the community to expand our work to augment existing 16S rRNA reference databases such as SILVA, GreenGenes, and RDP.


title: Machine Learning to Summarize and Provide Context for Sleep and Eating Schedules.

abstract:
The relative timing of sleep and of eating within the circadian day is important for human health. Despite much data on sleep, and a growing data set for eating, there remains a need for an interpretative framework for the understanding of this data for health decisions. This study provides a new statistical and machine learning analysis of more than 500 participants in the Daily24 project. From their data, and the analysis, we propose a framework for determining the classification of participants into different chronotypes and with that the ability to realize the potential impact of daily circadian habits on health. We propose that our resulting distribution curves could be used, similar to NHANES (National Health and Nutrition Examination Survey) data for pediatric growth, as a measure for circadian misalignment and used to help guide re-entrainment schedules.

Author summaryDaily habits can be positive, negative or neutral for human health. Generally sleep and eating schedules are assumed without thought for their potential to help or interfere with health. In this study we propose a framework, based on data from more than 500 participants, for evaluating the relative timing of meals and sleep schedules. This evaluation, similar to pediatric growth charts, can guide clinical suggestions for those at the extremes, while helping others to realize that they are unusual relative to the population average


title: HOPMA: Boosting protein functional dynamics with colored contact maps

abstract:
In light of the recent very rapid progress in protein structure prediction, accessing the multitude of functional protein states is becoming more central than ever before. Indeed, proteins are flexible macromolecules, and they often perform their function by switching between different conformations. However, high-resolution experimental techniques such as X-ray crystallography and cryogenic electron microscopy can catch relatively few protein functional states. Many others are only accessible under physiological conditions in solution. Therefore, there is a pressing need to fill this gap with computational approaches.

We present HOPMA, a novel method to predict protein functional states and transitions using a modified elastic network model. The method exploits patterns in a protein contact map, taking its 3D structure as input, and excludes some disconnected patches from the elastic network. Combined with nonlinear normal mode analysis, this strategy boosts the protein conformational space exploration, especially when the input structure is highly constrained, as we demonstrate on a set of more than 400 transitions. Our results let us envision the discovery of new functional conformations, which were unreachable previously, starting from the experimentally known protein structures.

The method is computationally efficient and available at https://github.com/elolaine/HOPMA and https://team.inria.fr/nano-d/software/nolb-normal-modes.


title: Algorithm optimization for weighted gene co-expression network analysis: accelerating the calculation of Topology Overlap Matrices with OpenMP and SQLite

abstract:
MotivationWeighted gene co-expression network analysis (WGCNA) is an R package that can search highly related gene modules. The most time-consuming step of the whole analysis is to calculate the Topological Overlap Matrix (TOM) from the Adjacency Matrix in a single thread. This study changes it to multithreading.

ResultsThis paper uses SQLite for multi-threaded data transfer between R and C++, uses OpenMP to enable multi-threading and calculates the TOM via an adjacency matrix on a Shared-memory MultiProcessor (SMP) system, where the calculation time decreases as the number of physical CPU cores increases.

Availability and implementationThe source code is available at https://github.com/do-somethings-haha/fast_calculate_TOM_of_WGCNA

Contactchenxin@cdutcm.edu.cn


title: Identification of Common Molecular Signatures Shared between Alzheimer's and Parkinson's Diseases and Therapeutic Agents Exploration: An Integrated Genomics Approach

abstract: Alzheimers disease (AD) and Parkinsons disease (PD) are two most prevalent age-related dementias that severely affect a large number of elderly people around the globe. Poor understanding of pathogenesis of these neurological diseases imposes challenge to discover therapeutic measures and effective diagnosis methods. In this study, a network-based approach was utilized to identify potential common molecular signatures and therapeutic agents for AD and PD. Protein-protein interaction analysis revealed NCK1, UBC, CDH1, CDC20, ACTB, PSMA7, PRPF8, RPL7, XRCC6 and HSP90AB1 as the best proteome signatures. Different regulatory transcriptional signatures i.e., YY1, NFKB1, BRCA1, TP53, GATA2, SREBF2, E2F1, FOXC1, RELA and NFIC and post-transcriptional signatures i.e., hsa-mir-186-5p, hsamir-92a-3p, hsa-mir-615-3p, hsa-let-7c-5p, hsa-mir-100-5p, hsa-mir-93-3p, hsa-mir-5681a, hsamir-484, hsa-mir-193b-3p and hsa-mir-16p-5p were identified from other interaction network. Drug-gene interaction study revealed possible therapeutic agents which may reverse the AD and PD condition. The scientific approach of this study should contribute to identify potential biomarkers, drug targets and therapeutic agents against AD and PD which should in turn advance the present efforts of scientists to secure effective diagnosis and therapeutic options. However, further in vivo and in vitro experiments might be required to validate the outcomes of this study.


title: Statistical and machine learning models for classification of human wear and delivery days in accelerometry data

abstract:
PurposeAccelerometers are increasingly utilized in healthcare research to assess human activity. Accelerometry data are often collected by mailing accelerometers to participants, who wear the accelerometers to collect data on their activity. The devices are then mailed back to the laboratory for analysis. We develop models to classify days in accelerometry data as activity from actual human wear or the delivery process. These models can be used to automate the cleaning of accelerometry datasets that are adulterated with activity from delivery.

MethodsFor the classification of delivery days in accelerometry data, we developed statistical and machine learning models in a supervised learning context using a large human activity and delivery labeled accelerometry dataset. We extracted several features, which were included to develop random forest, logistic regression, mixed effects regression, and multilayer perceptron models, while convolutional neural network, recurrent neural network, and hybrid convolutional recurrent neural network models were developed without feature extraction. Model performances were assessed using Monte Carlo cross-validation.

ResultsWe found that a hybrid convolutional recurrent neural network performed best in the classification task with an F1 score of 0.960 but simpler models such as logistic regression and random forest also had excellent performance with F1 scores of 0.951 and 0.957, respectively.

ConclusionThe models developed in this study can be used to classify days in accelerometry data as either human or delivery activity. An analyst can weigh the larger computational cost and greater performance of the convolutional recurrent neural network against the faster but slightly less powerful random forest or logistic regression. The best performing models for classification of delivery data are publicly available on the open source R package, PhysicalActivity.


title: FLT3-ITD transduces autonomous growth signals during its biosynthetic trafficking in acute myelogenous leukemia cells.

abstract: FMS-like tyrosine kinase 3 (FLT3) in hematopoietic cells binds to its ligand at the plasma membrane (PM), then transduces growth signals. FLT3 gene alterations that lead the kinase to assume its permanently active form, such as internal tandem duplication (ITD) and D835Y substitution, are found in 30~40% of acute myelogenous leukemia (AML) patients. Thus, the drugs for molecular targeting of FLT3 mutants have been developed for the treatment of AML. Several groups have reported that compared with wild-type FLT3 (FLT3-wt), FLT3 mutants are retained in organelles, resulting in low levels of PM localization of the receptor. However, the precise subcellular localization of mutant FLT3 remains unclear, and the relationship between oncogenic signaling and the mislocalization is not completely understood. In this study, we show that in cell lines established from AML patients, endogenous FLT3-ITD but not FLT3-wt clearly accumulates in the perinuclear region. Our co-immunofluorescence assays demonstrate that Golgi markers are co-localized with the perinuclear region, indicating that FLT3-ITD mainly localizes to the Golgi region in AML cells. FLT3-ITD biosynthetically traffics to the Golgi apparatus and remains there in a manner dependent on its tyrosine kinase activity. A tyrosine kinase inhibitor midostaurin (PKC412) markedly decreases in FLT3-ITD retention and increases in the PM levels of the mutant. FLT3-ITD activates downstream in the endoplasmic reticulum (ER) and the Golgi apparatus during its biosynthetic trafficking. Results of our trafficking inhibitor treatment assays show that FLT3-ITD in the ER activates STAT5, whereas that in the Golgi can cause the activation of AKT and ERK. We provide evidence that FLT3-ITD signals from the early secretory compartments before reaching the PM in AML cells.


title: Effects of Hydrogen Peroxide on Organically Fertilized Hydroponic Lettuce (Lactuca sativa L.)

abstract: Hydroponic production typically uses conventional fertilizers and information is lacking on the use of organic hydroponic fertilizers. Development of biofilm is a common problem with organic hydroponics which can reduce dissolved oxygen availability to roots. One potential solution is the use of hydrogen peroxide, H2O2 which can reduce microbial populations and decomposes to form oxygen. However, information is lacking on the impact of hydrogen peroxide on hydroponic crops. The aim of this study was to determine the effects of H2O2 concentrations in deep water culture hydroponics by assessing how it affects plant size and yield in lettuce (Lactuca sativa L.)  Rouxai. In this experiment, three different treatments consisting of a control without H2O2, and the application of 37.5 mg/L or 75 mg/L of hydrogen peroxide were added to aerated 4-L reservoirs that contained either organic (4-4-1) or inorganic nutrients (21-5-20), both applied at 150 mg{middle dot}L-1 N. Three replicates for each treatment and each fertilizer were prepared resulting in a total of eighteen mini hydroponic containers each with one head of lettuce. When added to conventional fertilizers, concentrations of 37.5 mg/L and 75 mg/L of H2O2 led to stunted growth or death lettuce plants. However, when 37.5 mg/L of H2O2 was applied to organic fertilizers, the lettuce yield nearly matched that of the conventionally fertilized control, demonstrating that the application of H2O2 has the potential to make organic hydroponic fertilization a more viable method in the future.

category: plant biology


title: 12-Lipoxygenase Governs the Innate Immune Pathogenesis of Islet Inflammation and Autoimmune Diabetes

abstract: Macrophages and related myeloid cells are innate immune cells that participate in the early islet inflammation of type 1 diabetes (T1D). The inflammatory signals and antigen presentation by these cells may be inducers of the adaptive immune response that is the hallmark of T1D. The enzyme 12-lipoxygenase (12-LOX) catalyzes the formation of pro-inflammatory eicosanoids from membrane-derived phospholipids, but its role and mechanisms in the pathogenesis of islet inflammation have not been elucidated. Leveraging a model of T1D-like islet inflammation in zebrafish, we show here that macrophages contribute significantly to the loss of {beta}-cells and the subsequent development of hyperglycemia. Depletion or inhibition of 12-LOX in this model resulted in significantly reduced macrophage infiltration into islets with preservation of {beta}-cell mass. In mice, we deleted the gene encoding 12-LOX (Alox15) in the myeloid lineage in the non-obese diabetic (NOD) model of T1D. Myeloid cell-specific Alox15 knockout NOD mice demonstrated reduced insulitis and T-cell responses, preserved {beta} cell mass, and almost complete protection from the development of T1D. A critical effect of 12-LOX depletion appeared secondary to a defect in myeloid cell migration, a function required for immune surveillance and tissue injury responses. This effect on migration appeared to be secondary to the loss of the chemokine receptor CXCR3. Transgenic expression of the gene encoding CXCR3 rescued the migrator defect in zebrafish 12-LOX morphants. Taken together, our results reveal a formative role for innate immune myeloid cells in the early pathogenesis of T1D and identify 12-LOX as a necessary enzyme to promote their pro-diabetogenic phenotype in the context of autoimmunity.


title: Testing the efficacy of hyperspectral (AVIRIS-NG), multispectral (Sentinel-2) and radar (Sentinel-1) remote sensing images to detect native and invasive non-native trees

abstract:
Invasive alien species (IAS) threaten tropical grasslands and native biodiversity and impact ecosystem service delivery, ecosystem function, and associated human livelihoods. Tropical grasslands have been dramatically and disproportionately lost to invasion by trees. The invasion continues to move rapidly into the remaining fragmented grasslands impacting various native grassland-dependent species and water streamflow in tropical montane habitats. The Shola Sky Islands of the Western Ghats host a mosaic of native grasslands and forests; of which the grasslands have been lost to exotic tree invasion (Acacias, Eucalyptus and Pines) since the 1950s. The invasion intensities, however, differ between these species wherein Acacia mearnsii and Pinus patula are highly invasive in contrast to Eucalyptus globulus. These disparities necessitate distinguishing these species for effective grassland restoration. Further, these invasive alien trees are highly intermixed with native species, thus requiring high discrimination abilities to native species apart from the non-native species.

Here we assess the accuracy of various satellite and airborne remote sensing sensors and machine learning classification algorithms to identify the spatial extent of native habitats and invasive trees. Specifically, we test Sentinel-1 SAR and Sentinel-2 multispectral data and assess high spatial and spectral resolution AVIRIS-NG imagery identifying invasive species across this landscape. Sensor combinations thus include hyperspectral, multispectral and radar data and present tradeoffs in associated costs and ease of procurement. Classification methods tested include Support Vector Machine (SVM), Classification and Regression Trees (CART) and Random Forest (RF) algorithms implemented on the Google Earth Engine platform. Results indicate that AVIRIS-NG data in combination with SVM recover the highest classification skill (Overall -98%, Kappa-0.98); while CART and RF yielded < 90% accuracy. Fused Sentinel-1 and Sentinel-2 produce 91% accuracy, while Sentinel-2 alone yielded 91% accuracy with RF and SVM classification; but only with higher coverage of ground control points. AVIRIS-NG imagery was able to accurately (97%) demarcate the Acacia invasion front while Sentinel-1 and Sentinel-2 data failed. Our results suggest that Sentinel-2 images could be useful for detecting the native and non-native forests with more ground truth points, but hyperspectral data (AVIRIS-NG) permits distinguishing, native and non-native tree species and recent invasions with high precision using limited ground truth points. We suspect that large areas will have to be mapped and assessed in the coming years by conservation managers, NGOs to plan restoration, or to assess the success of restoration activities, and several data procurement and analysis steps may have to be simplified.


title: A conserved HSF:miR169:NF-YA loop involved in tomato and Arabidopsis heat stress tolerance

abstract: Regulatory feedbacks are at the basis of different stress and developmental networks in plants. Here, we report that tomato and Arabidopsis plants improve their heat stress tolerance through Heat stress transcription factor (HSF)-mediated transcriptional regulation of MIR169 and post-transcriptional regulation of NF-YA transcription factors. We show that HSFs recognize tomato and Arabidopsis MIR169 promoters using yeast-one-hybrid/ChIP-qPCR. Silencing tomato HSFs using virus-induced-gene-silencing (VIGS) reduce Sly-MIR169 levels and enhance Sly-NF-YA9/A10 target expression. Further, tomato transgenic plants overexpressing Sly-MIR169 and Sly-NF-YA9/A10-VIGS knock-down tomato plants as well as Arabidopsis plants overexpressing At-MIR169d and At-nf-ya2 mutants showed a link with increased heat tolerance. In contrast, Arabidopsis plants overexpressing At-NF-YA2, or those expressing a non-cleavable At-NF-YA2 form (miR169-resistant At-NF-YA2) as well as plants inhibited for At-miRNA169d regulation (miR169d mimic plants) were more sensitive to heat stress, highlighting NF-YA as negative regulator of heat tolerance. Furthermore, post-transcriptional cleavage of NF-YA by elevated miR169 levels result in alleviating the repression of heat stress effectors HSFA7a/b in tomato and Arabidopsis revealing a retroactive control of HSFs by the miR169:NF-YA node. Hence, a regulatory feedback loop involving HSFs, miR169s and NF-YAs plays a critical role in the regulation of heat stress response in tomato and Arabidopsis plants.


title: Mapping the temporal and spatial dynamics of the human endometrium in vivo and in vitro

abstract: The endometrium, the mucosal lining of the uterus, undergoes dynamic changes throughout the menstrual cycle in response to ovarian hormones. We have generated single-cell and spatial reference maps of the human uterus and 3D endometrial organoid cultures. We dissect the signalling pathways that determine cell fate of the epithelial lineages in the lumenal and glandular microenvironments. Our benchmark of the endometrial organoids highlights common pathways regulating the differentiation of secretory and ciliated lineage in vivo and in vitro. We show in vitro that downregulation of WNT or NOTCH pathways increases the differentiation efficiency along the secretory and ciliated lineages, respectively. These mechanistic insights provide a platform for future development of treatments for a range of common endometrial disorders including endometriosis and carcinoma.


title: Priming mycobacterial ESX-secreted protein B to form a channel-like structure

abstract: ESX-1 is a major virulence factor of Mycobacterium tuberculosis, a secretion machinery directly involved in the survival of the microorganism from the immune system defence. It disrupts the phagosome membrane of the host cell through a contact-dependent mechanism. Recently, the structure of the inner-membrane core complex of the homologous ESX-3 and ESX-5 was resolved; however, the elements involved in the secretion through the outer membrane or those acting on the host cell membrane are unknown. Protein substrates might form this missing element. Here, we describe the oligomerisation process of the ESX-1 substrate EspB, which occurs upon cleavage of its C-terminal region and is favoured by an acidic environment. Cryo-electron microscopy data are presented which show that EspB from different mycobacterial species have a conserved quaternary structure, except for the non-pathogenic species M. smegmatis. EspB assembles into a channel with dimensions and characteristics suitable for the transit of ESX-1 substrates, as shown by the presence of another EspB trapped within. Our results provide insight into the structure and assembly of EspB, and suggests a possible function as a structural element of ESX-1.


title: Assessment of Polarized Piezoelectric SrBi4Ti4O15 Nanoparticles as an alternative antibacterial agent

abstract: Strontium bismuth titanate nanoparticles (SrBi4Ti4O15/SBT NPs,) and their polarized counterparts were prepared to assess their antibacterial efficacy on biomaterials. The structural properties of the SBT NPs were performed by X-ray diffraction and the antibacterial efficacy was evaluated against Staphyllococcus aureus (S. aureus) pathogenic bacteria. Significant antibacterial activity of polarized SBT specimen was observed against S. aureus bacteria. Results presented in this work confirmed that polarized SBT can effectively combat bacterial growth and prevent biofilm formation activity of pathogenic bacteria and hence they can be used as alternative antimicrobial agents.


title: LocusZoom.js: Interactive and embeddable visualization of genetic association study results

abstract:
LocusZoom.js is a JavaScript library for creating interactive web-based visualizations of genetic association study results. It can display one or more traits in the context of relevant biological data (such as gene models and other genomic annotation), and allows interactive refinement of analysis models (by selecting linkage disequilibrium reference panels, identifying sets of likely causal variants, or comparisons to the GWAS catalog). It can be embedded in web pages to enable data sharing and exploration. Views can be customized and extended to display other data types such as phenome-wide association study (PheWAS) results, chromatin co-accessibility, or eQTL measurements. A new web upload service harmonizes datasets, adds annotations, and makes it easy to explore user-provided result sets.

AvailabilityLocusZoom.js is open-source software under a permissive MIT license. Code and documentation are available at: https://github.com/statgen/locuszoom/. Installable packages are also distributed via NPM. Additional features are provided as standalone libraries to promote reuse. Use with your own GWAS results at https://my.locuszoom.org/.

Contactlocuszoom@googlegroups.com


title: Measurement of curvature and twist of microtubule bundles in the mitotic spindle

abstract: The highly ordered spatial organization of microtubule bundles in the mitotic spindle is crucial for its proper functioning. The recent discovery of twisted shapes of microtubule bundles and spindle chirality suggests that the bundles extend along curved paths in three dimensions, rather than being confined to a plane. This in turn implies that rotational forces exist in the spindle in addition to the widely studied linear forces. However, studies of spindle architecture and forces are impeded by a lack of a robust method for the geometric quantification of microtubule bundles in the spindle. In this paper, we describe a simple method for measuring and evaluating the shapes of microtubule bundles, by characterizing them in terms of their curvature and twist. By using confocal microscopy, we obtain three-dimensional images of spindles, which allow us to trace the entire microtubule bundles. For each traced bundle, we first fit a plane, and then fit a circle lying in that plane. With this easily reproducible method, we extract the curvature and twist, which represent the geometric information characteristic for each bundle. As the bundle shapes reflect the forces within them, this method is valuable for the understanding of forces that act on chromosomes during mitosis.


title: Non-clinical safety profile and pharmacodynamics of two formulations of the anti-sepsis drug candidate Rejuveinix

abstract: Here, we demonstrate that the two distinct formulations of our anti-sepsis drug candidate Rejuveinix (RJX) have a very favorable safety profile in Wistar Albino rats at dose levels comparable to the projected clinical dose levels. 14-day treatment with RJX-P or RJX-B similarly elevated the day 15 tissue levels of the antioxidant enzyme superoxide dismutase (SOD) as well as ascorbic acid in both the lungs and liver in a dose-dependent fashion. The activity of SOD and ascorbic acid levels were significantly higher in tissues of RJX-P or RJX-B treated rats than vehicle-treated control rats (p <0.0001). There was no statistically significant difference between tissues SOD activity or ascorbic acid levels of rats treated with RJX-P vs. rats treated with RJX-B (p >0.05). The observed elevations of the SOD and ascorbic acid levels were transient and were no longer detectable on day 28 following a 14-day recovery period. These results demonstrate that RJX-P and RJX-B are bioequivalent relative to their pharmacodynamic effects on tissue SOD and ascorbic acid levels.

category: pharmacology and toxicology