bluuebunny/crossref_metadata_2025 huggingface dataset:
Human scalp hair as a thermoregulatory adaptation
Authors: Lasisi Tina , Smallcombe James W , Kenney W. Larry , Shriver Mark D. , Zydney Benjamin , Jablonski Nina G. , Havenith George
Published: January 2023

Humans are unique among mammals in having a functionally naked body with a hair-covered scalp. Scalp hair is exceptionally variable across populations withinHomo sapiens. Neither the function of human scalp hair nor the consequences of variation in its morphology have been studied within an evolutionary framework. A thermoregulatory role for human scalp hair has been previously suggested. Here, we present experimental evidence on the potential evolutionary function of human scalp hair and variation in its morphology. Using a thermal manikin and human hair wigs at different wind speeds in a temperature and humidity-controlled environment, with and without simulated solar radiation, we collected data on the convective, radiative, and evaporative heat fluxes to and from the scalp in relation to properties of a range of hair morphologies, as well as a naked scalp. We find evidence for a significant reduction in solar radiation influx to the scalp in the presence of hair. Maximal evaporative heat loss potential from the scalp is reduced by the presence of hair, but the amount of sweat required on the scalp to balance the incoming solar heat (i.e. zero heat gain) is reduced in the presence of hair. Particularly, we find that hair that is more tightly curled offers increased protection against heat gain from solar radiation.

Significance

The evolution of human scalp hair might be explained by thermoregulation pressures experienced in hot and arid environments. Bipedal posture and a hairless body may have necessitated the development of scalp hair to minimize heat gain from solar radiation, particularly in hominins with large brains. We used a thermal manikin and human-hair wigs to examine this thermoregulatory hypothesis. We found that scalp hair reduces heat gain from solar radiation; tightly curled hair is most protective. Specifically, our results show that hair protects the scalp from solar radiation while minimizing the amount of sweat required to offset heat gain, with tightly curled hair providing the most protection.
Sustained release Resolvin D1 liposomes are effective in the treatment of osteoarthritis in obese mice
Authors: Dravid Ameya A. , Dhanabalan Kaamini M. , Naskar Soumyadeep , Vashistha Akshi , Agarwal Smriti , Padhan Bhagyashree , Dewani Mahima , Agarwal Rachit
Published: January 2023

Osteoarthritis (OA) is the most common joint disorder and currently affects > 500 million patients worldwide, with ~60% of them also suffering from obesity. There is no drug approved for human use that changes the course of OA progression. OA is one of the most common comorbidities of obesity, and obesity-related OA (ObOA) is a serious health concern because it shows heightened severity of tissue damage and also predominantly affects the working population. Unresolved inflammation is a major driver of ObOA, thus, resolving disease-associated inflammation is a viable strategy to treat ObOA. Resolvins are highly potent molecules that play a role in the resolution of inflammation and promote tissue healing. However, small molecules (like Resolvin D1; RvD1) have to be administered frequently or prior to injury because they lose theirin vivoactivity rapidly either by lymphatic clearance, or oxidation-mediated deactivation. In this study, we have encapsulated RvD1 in liposomes and established its efficacy in the mouse model of ObOA at much lower dosages than freely administered RvD1. Liposomal RvD1 (lipo-RvD1) acted as a source of the RvD1 molecules for ~11 daysin vitroin synovial fluid derived from patients. When administered prophylactically or therapeutically, lipo-RvD1 suppressed cartilage damage in male C57BL/6 mice compared to untreated and free RvD1 treatments. This efficacy was achieved by increasing the proportion of the proresolution M2 macrophages over proinflammatory M1 macrophages in the synovial membrane. These results show the potential of lipo-RvD1 as an anti-OA agent.Graphical abstract:

Mechanism of working of lipo-RvD1 in ObOA joint.
End-to-End Explainable AI: Derived Theory-of-Mind Fingerprints to Distinguish Between Autistic and Typically developing and Social Symptom Severity
Authors: Bhavna Km , Banerjee Romi , Roy Dipanjan
Published: January 2023

Theory-of-Mind (ToM) is an evolving ability that significantly impacts human learning and cognition. Early development of ToM ability allow one to comprehend other people’s aims and ambitions, as well as thinking that differs from one’s own. Autism Spectrum Disorder (ASD) is the prevalent pervasive neurodevelopmental disorder in which participants’ brains appeared to be marked by diffuse variations throughout large-scale brain systems made up of functionally connected but physically separated brain areas that got abnormalities in willed action, self-monitoring and monitoring the intents of others, often known as ToM. Although functional neuroimaging techniques have been widely used to establish the neural correlates implicated in ToM, the specific mechanisms still need to be clarified. The availability of current Big data and Artificial Intelligence (AI) frameworks paves the way for systematically identifying Autistics from typically developing by identifying neural correlates and connectome-based features to generate accurate classifications and predictions of socio-cognitive impairment. In this work, we develop an Ex-AI model that quantifies the common sources of variability in ToM brain regions between typically developing and ASD individuals. Our results identify a feature set on which the classification model can be trained to learn characteristics differences and classify ASD and TD ToM development more distinctly. This approach can also estimate heterogeneity within ASD ToM subtypes and their association with the symptom severity scores based on socio-cognitive impairments. Based on our proposed framework, we obtain an average accuracy of more than 90 % using Explainable ML (Ex-Ml) models and an average of 96 % classification accuracy using Explainable Deep Neural Network (Ex-DNN) models. Our findings identify three important sub-groups within ASD samples based on the key differences and heterogeneity in resting state ToM regions’ functional connectivity patterns and predictive of mild to severe atypical social cognition and communication deficits through early developmental stages.
BiFCo: Visualising cohesin assembly/disassembly cycle in living cells
Authors: González-Martín Emilio , Jiménez Juan , Tallada Víctor A.
Published: January 2023

Cohesin is a ring-shaped protein complex highly conserved in evolution that is composed in all eukaryotes of at least two SMC proteins (Structural Maintenance of Chromosomes) SMC1 and SMC3 in humans (Psm1 and Psm3 in fission yeast), and the kleisin RAD21 (Rad21 in fission yeast). Mutations in its components or its regulators cause genetic syndromes (known as cohesinopathies) and several types of cancer. It has been shown in a number of organisms that only a small fraction of each subunit is assembled into complexes. Therefore, the presence of an excess of soluble components hinders dynamic chromatin loading/unloading studies using fluorescent fusionsin vivo. Here, we present a system based on bimolecular fluorescent complementation in the fission yeastSchizosaccharomyces pombe, named Bi-molecular Fluorescent Cohesin (BiFCo) that selectively excludes signal from individual proteins to allow monitoring the complex assembly/disassembly within a physiological context during a whole cell cycle in living cells. This system may be expanded and diversified in different genetic backgrounds and other eukaryotic models, including human cells.
Tracking coreceptor switch of the transmitted/founder HIV-1 identifies co-evolution of HIV-1 antigenicity, coreceptor usage and CD4 subset targeting
Authors: Marichannegowda Manukumar Honnayakanahalli , Zemil Michelle , Wieczorek Lindsay , Sanders-Buell Eric , Bose Meera , O’Sullivan Anne Marie , King David , Francisco Leilani , Diaz-Mendez Felisa , Setua Saini , Chomont Nicolas , Phanuphak Nittaya , Ananworanich Jintanat , Hsu Denise , Vasan Sandhya , Michael Nelson L. , Eller Leigh Anne , Tovanabutra Sodsai , Tagaya Yutaka , Robb Merlin L. , Polonis Victoria R. , Song Hongshuo
Published: January 2023

The CCR5 (R5) to CXCR4 (X4) coreceptor switch in natural HIV-1 infection is associated with faster progression to AIDS, but the underlying mechanisms remain unclear. The difficulty in capturing the earliest moment of coreceptor switchin vivolimits our understanding of this phenomenon. Here, by tracking the evolution of the transmitted/founder (T/F) HIV-1 in a prospective cohort of individuals at risk for HIV-1 infection identified very early in acute infection, we investigated this process with high resolution. The earliest X4 variants evolved from the R5 tropic T/F strains. Strong X4 usage can be conferred by a single mutation. The mutations responsible for coreceptor switch can confer escape to neutralization and drive X4 variants to replicate mainly in the central memory and naïve CD4+ T cells. We propose a novel concept to explain the co-evolution of virus antigenicity and entry tropism termed “escape by shifting”. This concept posits that for viruses with receptor or coreceptor flexibility, entry tropism alteration represents a mechanism of immune evasionin vivo.
Distinct mutational processes shape selection of MHC class I and class II mutations across primary and metastatic tumors
Authors: Mumphrey Michael B. , Hosseini Noshad , Parolia Abhijit , Geng Jie , Zou Weiping , Raghavan Malini , Chinnaiyan Arul , Cieslik Marcin
Published: January 2023

Disruption of antigen presentation via loss of MHC expression is a strategy whereby cancer cells escape immune surveillance and develop resistance to immunotherapy. We developed the personalized genomics algorithm Hapster and accurately called somatic mutations within the MHC genes of 10,001 primary and 2,199 metastatic tumors, creating a catalog of 1663 nonsynonymous mutations that provide key insights into MHC mutagenesis. We found that MHC-I genes are among the most frequently mutated genes in both primary and metastatic tumors, while MHC-II mutations are more restricted. Recurrent deleterious mutations are found within haplotype and cancer-type specific hotspots associated with distinct mutational processes. Functional classification of MHC residues revealed significant positive selection for mutations disruptive to the B2M, peptide, and T-cell binding interfaces, as well as MHC chaperones. At the cohort level, all cancers with positive selection for MHC mutations are responsive to immune checkpoint inhibitors, underscoring the translational relevance of our findings.
Knocking out CD70 rescues CD70-specific nanoCAR T cells from antigen induced exhaustion
Authors: De Munter Stijn , Buhl Juliane , De Cock Laurenz , Van Parys Alexander , Daneels Willem , Pascal Eva , Deseins Lucas , Ingels Joline , Goetgeluk Glenn , Billiet Lore , Pille Melissa , Vandamme Niels , Van Dorpe Jo , Offner Fritz , Depla Erik , Tavernier Jan , Kerre Tessa , Drost Jarno , Vandekerckhove Bart
Published: January 2023

CD70 is an attractive target for chimeric antigen receptor (CAR) T cell therapy as treatment for both solid and liquid malignancies. However, functionality of CD70-specific CARs is only modest. Here, we optimized a CD70-specific VHH based CAR (nanoCAR). We evaluated the nanoCARs in clinically relevant modelsin vitro, using co-cultures of CD70-specific nanoCAR T cells with malignant rhabdoid tumor organoids, andin vivoby using a diffuse large B cell lymphoma (DLBCL) patient-derived xenograft (PDX) model. Whereas the nanoCAR T cells were highly efficient in organoid co-cultures, they showed only modest efficacy in the PDX model. Knocking out CD70 expression by the nanoCAR T cells resulted in dramatically enhanced functionality in the PDX model, suggesting that endogenous CD70 interaction with the nanoCAR induces exhaustion. Through single-cell transcriptomics, we obtained evidence that CD70KO CD70-specific nanoCAR T cells are protected from antigen induced exhaustion. Our data shows that CARs targeted to endogenous T cell antigens, negatively affect CAR T cell functionality by inducing an exhausted state which can be overcome by knocking out the specific target, in this case CD70.
ApTOLL, a new therapeutic aptamer for cytoprotection and (re)myelination after Multiple Sclerosis
Authors: Fernández-Gómez Beatriz , Marchena Miguel A. , Piñeiro David , Gómez-Martín Paula , Sánchez Estefanía , Laó Yolanda , Valencia Gloria , Nocera Sonia , Benítez-Fernández Rocío , Castaño-León Ana M. , Lagares Alfonso , Hernández-Jiménez Macarena , de Castro Fernando
Published: January 2023

ApTOLL is an aptamer specifically designed to antagonize Toll-Like Receptor 4 (TLR4), a relevant actor for innate immunity involved in inflammatory responses in multiple sclerosis (MS) and other diseases. MS is a primary demyelinating, chronic, inmune and neurodegenerative disease of the central nervous system that normally debuts in young adults. The currently available therapeutic arsenal to treat MS is composed of immunomodulators but, to date, there are no (re)myelinating drugs available in clinics. Our present study shows cells expressing TLR4 in demyelinating lesions of MS patients (postmortemsamples from cerebral cortex) and, as a derivative, we studied the effect of TLR4 inhibition with ApTOLL in animal models of MS (experimental autoimmune encephalomyelitis -EAE- and the cuprizone). The treatment with ApTOLL positively impacted the clinical symptomatology, and this was associated with better preservation plus restoration of myelin and oligodendrocytes in the demyelinated lesions of these animals, which suggests not only an immunomodulatory but also a remyelinating effect of the treatment with ApTOLL. This latter was corroborated on purified cultures of rodent and adult human oligodendrocyte precursor cells (OPCs), confirming the expression of TLR4 in this cell type. Altogether, the molecular nature of ApTOLL and its mechanism/s of action strongly supports this compound as a novel candidate to treat MS and other demyelinating scenarios.
Genomic and Proteomic Analysis of Patients with Reoccurring Discrete Subaortic Stenosis
Authors: Birla Ravi K. , Singampalli Kavya L. , Nieuwsma Asela , Brimmer Sunita , Kaul Aditya , Wadhwa Lalita , Jung Sung Y. , Mezquita Dereck , Grimm Sandra , Balaji Swathi , Coarfa Cristian , Caldarone Christopher , Grande-Allen Jane , Keswani Sundeep G.
Published: January 2023

Discrete subaortic stenosis (DSS) is a pediatric condition in which a fibrotic membrane forms within the left ventricular outflow track. The fibrotic membrane is removed surgically; however, there is a high rate of reoccurrence which requires a second surgery. There are currently no tools available to predict the risk of reoccurrence in DSS patients, a limitation addressed by this study. In this study, we analyzed resected fibrotic membranes for DSS patients at the time of first surgery for non-recurrent and recurrent patients, and at the time of second surgery for recurrent patients. RNA-sequencing was conducted to obtain a global screen of changes in RNA expression while mass spectrometry was used to obtain a global screen of changes in protein expression. The results from the RNA-sequencing and mass spectrometry provide valuable insight into genes and the proteins that are differentially regulated in recurrent vs non-recurrent DSS patients.
Distinct neural components of visually guided grasping during planning and execution
Authors: Klein Lina K. , Maiello Guido , Stubbs Kevin M. , Proklova Daria , Chen Juan , Paulun Vivian C. , Culham Jody C. , Fleming Roland W.
Published: January 2023

Selecting suitable grasps on three-dimensional objects is a challenging visuomotor computation, which involves combining information about an object (e.g., its shape, size, and mass) with information about the actor’s body (e.g., the optimal grasp aperture and hand posture for comfortable manipulation). Here we used functional magnetic resonance imaging to investigate brain networks associated with these distinct aspects during grasp planning and execution. Human participants viewed and then executed preselected grasps on L-shaped objects made of wood and/or brass. By leveraging a computational approach that accurately predicts human grasp locations, we selected grasp points that disentangled the role of multiple grasp-relevant factors: grasp axis, grasp size, and object mass. Representational Similarity Analysis revealed that grasp axis was encoded along dorsal-stream regions during grasp planning. Grasp size was first encoded in ventral-stream areas during grasp planning, then in premotor regions during grasp execution. Object mass was encoded in ventral-stream and (pre)motor regions only during grasp execution. Premotor regions further encoded visual predictions of grasp comfort, whereas the ventral stream encoded grasp comfort during execution, suggesting its involvement in haptic evaluation. These shifts in neural representations thus capture the sensorimotor transformations that allow humans to grasp objects.

Significance Statement

Grasping requires integrating object properties with constraints on hand and arm postures. Using a computational approach that accurately predicts human grasp locations by combining such constraints, we selected grasps on objects that disentangled the relative contributions of object mass, grasp size, and grasp axis during grasp planning and execution in a neuroimaging study. Our findings reveal a greater role of dorsal-stream visuomotor areas during grasp planning, and surprisingly, increasing ventral stream engagement during execution. We propose that during planning, visuomotor representations initially encode grasp axis and size. Perceptual representations of object material properties become more relevant instead as the hand approaches the object and motor programs are refined with estimates of the grip forces required to successfully lift the object.
Capturing the dynamics of microbiomes using individual-specific networks
Authors: Yousefi Behnam , Melograna Federico , Galazzo Gianluca , van Best Niels , Mommers Monique , Penders John , Schwikowski Benno , van Steen Kristel
Published: January 2023

Background

Longitudinal analysis of multivariate individual-specific microbiome profiles over time or across conditions remains a daunting task. The vast majority of statistical tools and methods available to study the microbiota are based upon cross-sectional data. Over the past few years, several attempts have been made to model the dynamics of bacterial species over time or across conditions. However, the field needs novel views on how to incorporate individual-specific microbial associations in temporal analyses when the focus lies on microbial interactions.

Results

Here, we propose a novel data analysis framework, called MNDA, to uncover taxon neighbourhood dynamics that combines representation learning and individual-specific microbiome co-occurrence networks. We show that tracking local neighbourhood dynamics in microbiome interaction or co-occurrence networks can yield complementary information to standard approaches that only use microbial abundances or pairwise microbial interactions. We use cohort data on infants for whom microbiome data was available at 6 and 9 months after birth, as well as information on mode of delivery and diet changes over time. In particular, MNDA-based prediction models outperform traditional prediction models based on individual-specific abundances, and enable the detection of microbes whose neighbourhood dynamics are informative of clinical variables. We further show that similarity analyses of individuals based on microbial neighbourhood dynamics can be used to find subpopulations of individuals with potential relevance to clinical practice. The annotated source code for the MNDA framework can be downloaded from:https://github.com/H2020TranSYS/microbiome_dynamics

Conclusions

MNDA extracts information from matched microbiome profiles and opens new avenues to personalized prediction or stratified medicine with temporal microbiome data.
Mitochondrial citrate metabolism and efflux regulates trophoblast differentiation
Authors: Mahr Renee M. , Jena Snehalata , Nashif Sereen K. , Nelson Alisa B. , Rauckhorst Adam J. , Rome Ferrol I. , Sheldon Ryan D. , Hughey Curtis C. , Puchalska Patrycja , Gearhart Micah D. , Taylor Eric B. , Crawford Peter A. , Wernimont Sarah A.
Published: January 2023

Cytotrophoblasts fuse to form and renew syncytiotrophoblasts necessary to maintain placental health throughout gestation. During cytotrophoblast to syncytiotrophoblast differentiation, cells undergo regulated metabolic and transcriptional reprogramming. Mitochondria play a critical role in differentiation events in cellular systems, thus we hypothesized that mitochondrial metabolism played a central role in trophoblast differentiation. In this work, we employed static and stable isotope tracing untargeted metabolomics methods along with gene expression and histone acetylation studies in an established cell culture model of trophoblast differentiation. Trophoblast differentiation was associated with increased abundance of the TCA cycle intermediates citrate and α-ketoglutarate. Citrate was preferentially exported from mitochondria in the undifferentiated state but was retained to a larger extent within mitochondria upon differentiation. Correspondingly, differentiation was associated with decreased expression of the mitochondrial citrate transporter (CIC). CRISPR/Cas9 disruption of the mitochondrial citrate carrier showed that CIC is required for biochemical differentiation of trophoblasts. Loss of CIC resulted in broad alterations in gene expression and histone acetylation. These gene expression changes were partially rescued through acetate supplementation. Taken together, these results highlight a central role for mitochondrial citrate metabolism in orchestrating histone acetylation and gene expression during trophoblast differentiation.
Modeling of African population history usingf-statistics can be highly biased and is not addressed by previously suggested SNP ascertainment schemes
Authors: Flegontov Pavel , Işıldak Ulaş , Maier Robert , Yüncü Eren , Changmai Piya , Reich David
Published: January 2023

f-statistics have emerged as a first line of analysis for making inferences about demographic history from genome-wide data. These statistics can provide strong evidence for either admixture or cladality, which can be robust to substantial rates of errors or missing data.f-statistics are guaranteed to be unbiased under “SNP ascertainment” (analyzing non-randomly chosen subsets of single nucleotide polymorphisms) only if it relies on a population that is an outgroup for all groups analyzed. However, ascertainment on a true outgroup that is not co-analyzed with other populations is often impractical and uncommon in the literature. In this study focused on practical rather than theoretical aspects of SNP ascertainment, we show that many non-outgroup ascertainment schemes lead to false rejection of true demographic histories, as well as to failure to reject incorrect models. But the bias introduced by common ascertainments such as the 1240K panel is mostly limited to situations when more than one sub-Saharan African and/or archaic human groups (Neanderthals and Denisovans) or non-human outgroups are co-modelled, for example,f4-statistics involving one non-African group, two African groups, and one archaic group. Analyzing panels of SNPs polymorphic in archaic humans, which has been suggested as a solution for the ascertainment problem, cannot fix all these problems since for some classes off-statistics it is not a clean outgroup ascertainment, and in other cases it demonstrates relatively low power to reject incorrect demographic models since it provides a relatively small number of variants common in anatomically modern humans. And due to the paucity of high-coverage archaic genomes, archaic individuals used for ascertainment often act as sole representatives of the respective groups in an analysis, and we show that this approach is highly problematic. By carrying out large numbers of simulations of diverse demographic histories, we find that bias in inferences based onf-statistics introduced by non-outgroup ascertainment can be minimized if the derived allele frequency spectrum in the population used for ascertainment approaches the spectrum that existed at the root of all groups being co-analyzed. Ascertaining on sites with variants common in a diverse group of African individuals provides a good approximation to such a set of SNPs, addressing the great majority of biases and also retaining high statistical power for studying population history. Such a “pan-African” ascertainment, although not completely problem-free, allows unbiased exploration of demographic models for the widest set of archaic and modern human populations, as compared to the other ascertainment schemes we explored.
A dual sgRNA library design to probe genetic modifiers using genome-wide CRISPRi screens
Authors: Guna Alina , Page Katharine R. , Replogle Joseph M. , Esantsi Theodore K. , Wang Maxine L. , Weissman Jonathan S. , Voorhees Rebecca M.
Published: January 2023

Mapping genetic interactions is essential for determining gene function and defining novel biological pathways. We report a simple to use CRISPR interference (CRISPRi) based platform, compatible with Fluorescence Activated Cell Sorting (FACS)-based reporter screens, to query epistatic relationships at scale. This is enabled by a flexible dual-sgRNA library design that allows for the simultaneous delivery and selection of a fixed sgRNA and a second randomized guide, comprised of a genome-wide library, with a single transduction. We use this approach to identify epistatic relationships for a defined biological pathway, showing both increased sensitivity and specificity than traditional growth screening approaches.
Dynamics of Changes in Cadmium Levels in Environmental Objects and its Impact on the Bio-Elemental Composition of Living Organisms
Authors: Nechytailo Larysa , Danyliv Svitlana , Kuras Liliia , Shkurashivska Svitlana , Buchko Aleksandra
Published: January 2023

As a result of intensive anthropogenic impact in the biosphere there is a rapid process of accumulation of heavy metal salts. They have led to the aggravation of problems associated with the pollution of ecosystems and basic food products of plant and animal origin. Environmental pollution by these compounds is caused by their persistence in environmental objects, migration ability, accumulation by plants. This contributes to their accumulation in the human environment. A number of studies have shown that heavy metals have mutagenic, toxic effects and affect the intensity of biochemical processes. Therefore, the presence of heavy metals in the environment is extremely undesirable. Moreover, the ecological state of the environment is directly related to changes in the human internal environment. Deficiency or excess of certain bioelements in soils and drinking water or non-compliance with its stable chemical composition causes the development of dysmicroelementosis. The ecological situation of the Carpathian region is closely related to the state of soils and water resources. In this regard, it is advisable to study and control the level of cadmium compounds in the environment of the region. The study of the effect of cadmium intoxication on the macro- and microelement composition of the brain and myocardium of experimental animals is also worthwhile.

Materials and methods

Soils and drinking water of the plain, foothill and mountainous zones of the region, as well as organs and tissues of experimental animals served as the object of research. Cadmium levels in drinking water and myocardial tissues and brain of experimental animals have been measured by atomic absorption spectroscopy.

Results and discussion

The study of soils in the Prykarpattia region has revealed an increase in the toxic element cadmium. Its content is 1.1-1.5 times higher than background levels. The analysis of drinking water allowed to establish that a significant number of people living in the plain and foothill zone of the region consume water with a high content of cadmium. The main stages of cadmium intake and accumulation in plants have been analyzed.

Significant disorders in the body of experimental animals under conditions of excessive intake of cadmium compounds have been revealed. It was accompanied by the accumulation of cadmium in the myocardium and brain, on the background of redistribution of vital macronutrients calcium and magnesium along with micronutrients copper and zinc. Thus, excessive intake of cadmium salts causes the development of dysmicroelementosis, which is accompanied by a violation of the homeostasis of a living organism. It is suggested to conduct continuous monitoring of the level of toxicants in the ecosystem as an integral component of environmental monitoring.
Division and Spreading of Attention across Colour
Authors: Martinovic Jasna , Boyanova Antoniya , Andersen Søren K.
Published: January 2023

Biological systems must allocate limited perceptual resources to relevant elements in their environment. This often requires simultaneous selection of multiple elements from the same feature dimension (e.g., colour). To establish the determinants of divided attentional selection of colour, we conducted an experiment that used multicoloured displays with four overlapping random dot kinematograms that differed only in hue. We manipulated (1) requirement to focus attention to a single colour or divide it between two colours; (2) distances of distractor hues from target hues in a perceptual colour space. We conducted a behavioural and an electroencephalographic experiment, in which each colour was tagged by a specific flicker frequency and driving its own steady-state visual evoked potential. Behavioural and neural indices of attention showed several major consistencies. Concurrent selection halved the neural signature of target enhancement observed for single targets, consistent with an approximately equal division of limited resources between two hue-selective foci. Distractors interfered with behavioural performance in a context-dependent fashion but their effects were asymmetric, indicating that perceptual distance did not adequately capture attentional distance. These asymmetries point towards an important role of higher-level mechanisms such as categorisation and grouping-by-colour in determining the efficiency of attentional allocation in complex, multi-coloured scenes.
Early frequency-specific contributions to serial-effects in audition
Authors: Lieder I. , Sulem A. , Ahissar M.
Published: January 2023

Recent stimuli affect the perception of current stimuli, referred to as serial effects. These effects were mainly studied in the visual modality, where it was suggested that perceptual biases towards previous stimuli (contraction) stems from high-level processing stages, and promotes object-level stability. We now asked whether high object-level stages underlie contraction also in the auditory modality. We administered a two-tone pitch discrimination task using both pure and complex tones. Both have pitch, but they are perceived as different timbre categories. Pitch contraction was observed to be largest between tones of the same timbre-category, in line with the object-level account. To decipher the role of early, frequency-specific, category-indifferent processing-stages we used complex tones with missing fundamental. They differ in their low-level frequency components yet have the same pitch. Hence, a high-level account predicts that pitch contraction will remain. Surprisingly, we observed no contraction to the missing fundamental frequency. Rather, pitch was contracted to the physically-present frequencies. Supporting the low-level contribution, we found that though attention enhances contraction, it is not necessary. These observations suggest that contraction bias is an inherent part of the various stages of the auditory hierarchy of sensory processing.
Using inbreeding to test the contribution of non-additive genetic effects to additive genetic variance: a case study inDrosophila serrata
Authors: Dugand Robert J. , Blows Mark W. , McGuigan Katrina
Published: January 2023

Additive genetic variance,VA, is the key parameter for predicting adaptive and neutral phenotypic evolution. Changes in demography (e.g., increased close-relative inbreeding) can alterVA, but how depends on the, typically unknown, gene action and allele frequencies across many loci. For example,VAincreases proportionally with the inbreeding coefficient when allelic effects are additive, but larger (or smaller) increases can occur when allele frequencies are unequal at causal loci with dominance effects. Here, we describe an experimental approach to assess the potential for rare, recessive alleles to inflateVAunder inbreeding. Applying a powerful paired pedigree design inDrosophila serrata, we measured 11 wing traits on half-sibling families bred via either random or sibling mating, differing only in homozygosity (not allele frequency). Despite close inbreeding and substantial power to detect smallVA, we detected no deviation from the expected additive effect of inbreeding on genetic (co)variances. Our results suggest the average dominance coefficient is very small relative to the additive effect, or that allele frequencies are relatively equal at loci affecting wing traits. We outline the further opportunities for this paired pedigree approach to reveal the characteristics ofVA, providing insight into historical selection and future evolutionary potential.
Solution-state NMR Assignment and Secondary Structural Propensities of the Full-Length and Minimalistic-Truncated Prefibrillar Monomeric Form of Biofilm-Forming Functional-Amyloid FapC fromPseudomonas aeruginosa
Authors: Byeon Chang-Hyeock , Wang Pang C. , Byeon In-Ja L. , Akbey Ümit
Published: January 2023

Functional bacterial amyloids provide structural scaffolding to bacterial biofilms. In contrast to the pathological amyloids, they have a rolein vivoand are tightly regulated. Their presence is essential to the integrity of the bacterial communities surviving in biofilms and may cause serious health complications. Targeting amyloids in biofilms could be a novel approach to prevent chronic infections. However, structural information is very scarce on them in both soluble monomeric and insoluble fibrillar forms, hindering our molecular understanding and strategies to fight biofilm related diseases. Here, we present solution-state NMR assignment of 250 amino acid long biofilm-forming functional-amyloid FapC fromPseudomonas aeruginosa. We studied the full-length and shorter minimalistic-truncated FapC constructs without signal-sequence that is required for secretion. 91% and 100% backbone NH resonance assignment for FL and short constructs, respectively, indicates that soluble monomeric FapC is predominantly disordered, with sizeable secondary structural propensities mostly as PP2 helices, but also as α-helices and β-sheets highlighting hotspots for fibrillation initiation interface. Shorter construct showing almost identical NMR chemical shifts highlights the promise of utilizing it for more demanding solid-state NMR studies that requires methods to alleviate signal redundancy due to almost identical repeat units. This study provides key NMR resonance assignment for future structural studies of soluble, pre-fibrillar and fibrillar forms of FapC.
Accurate and interpretable gene expression imputation on scRNA-seq data using IGSimpute
Authors: Xu Ke , Cheong ChinWang , Veldsman Werner Pieter , Lyu Aiping , Cheung William K. , Zhang Lu
Published: January 2023

Single-cell RNA-sequencing (scRNA-seq) enables the quantification of gene expression at the transcriptomic level with single-cell resolution, enhancing our understanding of cellular heterogeneity. However, the excessive missing values present in scRNA-seq data (termed dropout events) hinder downstream analysis. While numerous imputation methods have been proposed to recover scRNA-seq data, high imputation performance often comes with low or no interpretability. Here, we present IGSimpute, an accurate and interpretable imputation method for recovering missing values in scRNA-seq data with an interpretable instance-wise gene selection layer. IGSimpute outperforms ten other state-of-the-art imputation methods on nine tissues of the Tabula Muris atlas with the lowest mean squared error as the chosen benchmark metric. We demonstrate that IGSimpute can give unbiased estimates of the missing values compared to other methods, regardless of whether the average gene expression values are small or large. Clustering results of imputed profiles show that IGSimpute offers statistically significant improvement over other imputation methods. By taking the heart-and-aorta and the limb muscle tissues as examples, we show that IGSimpute can also denoise gene expression profiles by removing outlier entries with unexpected high expression values via the instance-wise gene selection layer. We also show that genes selected by the instance-wise gene selection layer could indicate the age of B cells from bladder fat tissue of the Tabula Muris Senis atlas. IGSimpute has linear time-complexity with respect to cell number, and thus applicable to large datasets.
Antithetic effects of agonists and antagonists on the structural fluctuations of TRPV1 channel
Authors: Sumino Ayumi , Zhao Yimeng , Mukai Daichi , Sumikama Takashi , Puppulin Leonardo , Hattori Motoyuki , Shibata Mikihiro
Published: January 2023

Transient receptor potential vanilloid member 1 (TRPV1) is a heat and capsaicin receptor that allows cations to permeate and cause pain. As the molecular basis for temperature sensing, the heat capacity (ΔCp) model (D. E. Clapham, C. Miller,Proc. Natl. Acad. Sci. U. S. A.108, 19492–19497 (2011).) has been proposed and experimentally supported. Theoretically, heat capacity is proportional to a variance in enthalpy, presumably related to structural fluctuation; however, the fluctuation of TRPV1 has not been directly visualized. In this study, we directly visualized single-molecule structural fluctuations of the TRPV1 channels in a lipid bilayer with the ligands resiniferatoxin (RTX: agonist, 1000 times hotter than capsaicin) and capsazepine (CPZ: antagonist) by high-speed atomic force microscopy (HS-AFM). We observed the structural fluctuations of TRPV1 in an apo state and found that RTX binding enhances structural fluctuations, while CPZ binding suppresses fluctuations. These ligand-dependent differences in structural fluctuation would play a key role in the gating of TRPV1.
Correcting dilated cardiomyopathy with fibroblast-targeted p38 deficiency
Authors: Bretherton Ross C. , Reichardt Isabella M. , Zabrecky Kristin A. , Goldstein Alex J. , Bailey Logan R.J. , Bugg Darrian , McMillen Timothy S. , Kooiker Kristina B. , Flint Galina V. , Martinson Amy , Gunaje Jagdambika , Koser Franziska , Plaster Elizabeth , Linke Wolfgang A. , Regnier Michael , Moussavi-Harami Farid , Sniadecki Nathan J. , DeForest Cole A. , Davis Jennifer
Published: January 2023

Inherited mutations in contractile and structural genes, which decrease cardiomyocyte tension generation, are principal drivers of dilated cardiomyopathy (DCM)– the leading cause of heart failure1,2. Progress towards developing precision therapeutics for and defining the underlying determinants of DCM has been cardiomyocyte centric with negligible attention directed towards fibroblasts despite their role in regulating the best predictor of DCM severity, cardiac fibrosis3,4. Given that failure to reverse fibrosis is a major limitation of both standard of care and first in class precision therapeutics for DCM, this study examined whether cardiac fibroblast-mediated regulation of the heart’s material properties is essential for the DCM phenotype. Here we report in a mouse model of inherited DCM that prior to the onset of fibrosis and dilated myocardial remodeling both the myocardium and extracellular matrix (ECM) stiffen from switches in titin isoform expression, enhanced collagen fiber alignment, and expansion of the cardiac fibroblast population, which we blocked by genetically suppressing p38α in cardiac fibroblasts. This fibroblast-targeted intervention unexpectedly improved the primary cardiomyocyte defect in contractile function and reversed ECM and dilated myocardial remodeling. Together these findings challenge the long-standing paradigm that ECM remodeling is a secondary complication to inherited defects in cardiomyocyte contractile function and instead demonstrate cardiac fibroblasts are essential contributors to the DCM phenotype, thus suggesting DCM-specific therapeutics will require fibroblast-specific strategies.
Novel Pipeline for Large-Scale Comparative Population Genetics
Authors: Majoros S.E. , Adamowicz S.J. , Cottenie K.
Published: January 2023

This study determined population genetic structure measures, compared these measures across species with different biological traits; and created efficient, reproducible, reusable programming modules that are publicly available for future research. Cytochrome C Oxidase subunit I gene sequences from Diptera (true fly) species from Greenland and Canada were used as a case study and proof of concept. We hypothesized that population genetic structure measures will be influenced by the biological traits of organisms. Data were pulled from public databases, as well as taxon-specific literature. The R pipeline includes fifteen modules that can be adapted and applied to a diverse set of animal groups, geographic regions, genes, and traits. Habitat, larval diet, geographical distance, latitude, and longitude were all significantly related to population genetic structure in Diptera. Overall, this study has created efficient, reusable bioinformatics modules, as well as provided insight into the factors affecting population genetic structure in Northern fly communities.
Data Driven Taxonomy for Antipsychotic Medication: A New Classification System
Authors: McCutcheon Robert A. , Harrison Paul J. , Howes Oliver D. , McGuire Philip K. , Taylor David , Pillinger Toby
Published: January 2023

Background

There are over 25 licensed antipsychotic medications with diverse pharmacological and clinical profiles. Antipsychotics are commonly described as either ‘typical’ or ‘atypical’, but this does not accurately reflect pharmacological profiles. There is thus a need for a data driven antipsychotic classification scheme suitable for clinicians and researchers which maps onto both pharmacological and clinical effects.

Method

We analysed affinities of 27 antipsychotics for 42 receptors from 3,325 receptor binding studies. We used a clustering algorithm to group antipsychotics based on their pattern of receptor affinity. Using a machine learning model, we examined the ability of this grouping to predict antipsychotic-induced side effects quantified according to an umbrella review of clinical trial and treatment guideline data.

Results

Clustering resulted in four groups of antipsychotics. The predominant receptor affinity and effect/side effect ‘fingerprints’ of these four groups were defined, as follows:

Group 1 - Muscarinic (M3-M5) receptor antagonism; Cholinergic and metabolic side effects.

Group 2 - Dopamine (D2) partial agonism and adrenergic antagonism; Globally low side effect burden.

Group 3 - Serotonergic and dopaminergic antagonism; Globally moderate side effect burden.

Group 4 - Dopaminergic antagonism; Extrapyramidal and motor side effects.

Groups 1 and 4 were more efficacious than clusters 2 and 3. The novel classification was superior to existing approaches when predicting side effects.

Conclusions

A receptor affinity-based grouping not only reflects compound pharmacology but also detects meaningful clinical differences to a greater extent than existing approaches. The approach has the potential to benefit both patients and researchers by guiding treatment and informing drug development.
Low frequency optogenetic deep brain stimulation of nucleus accumbens dopamine D1 or D2 receptor-containing neurons attenuates cocaine seeking selectively in male rats in part by reversing synaptic plasticity deficits
Authors: Swinford-Jackson Sarah E. , Rich Matthew T. , Huffman Phillip J. , Knouse Melissa C. , Thomas Arthur S. , Mankame Sharvari , Worobey Samantha J. , Pierce R. Christopher
Published: January 2023

Background

Clinically, deep brain stimulation (DBS) utilizes relatively high frequencies (>100 Hz). In preclinical models, 160 Hz stimulation of the nucleus accumbens in rodents prevents relapse of drug seeking. However, the ability of varied frequencies of accumbens DBS to attenuate drug seeking, and the neuronal subtype specificity of this effect, is unclear.

Methods

The present study examined the effect of DBS in the nucleus accumbens on neuronal plasticity and cocaine-primed reinstatement of cocaine seeking behavior in rats.

Results

Electrical DBS of the accumbens shell attenuated cocaine primed reinstatement across a range of frequencies in male rats, including as low as 12 Hz. The majority of nucleus accumbens neurons are medium spiny neurons (MSNs), which can be differentiated in terms of projections and effects on cocaine-related behaviors by expression of dopamine D1 receptors (D1DRs) or D2DRs. In slice electrophysiology experiments, 12 Hz electrical stimulation evoked long term potentiation (LTP) in eYFP labeled D1DR-MSNs and D2DR-MSNs from cocaine naive male and female rats. However, in rats that self-administered cocaine and underwent extinction training, a paradigm identical to our reinstatement experiments, electrical DBS only elicited LTP in D2DR-MSNs from male rats; this effect was replicated by optical stimulation in rats expressing Cre-dependent ChR2 in D2DR-MSNs. Low-frequency optogenetic-DBS in D1DR-containing or D2DR-containing neurons attenuated cocaine-primed reinstatement of cocaine seeking in male but not female rats.

Conclusions

These results suggest that administering DBS in the nucleus accumbens shell at lower frequencies effectively, but sex-specifically, suppresses cocaine craving, perhaps in part by reversing synaptic plasticity deficits selectively in D2DR-MSNs.
Structural insights into the mechanism of the human SGLT2–MAP17 glucose transporter
Authors: Hiraizumi Masahiro , Akashi Tomoya , Murasaki Kouta , Kishida Hiroyuki , Kumanomidou Taichi , Torimoto Nao , Nureki Osamu , Miyaguchi Ikuko
Published: January 2023

Selective sodium-glucose cotransporter 2 (SGLT2) plays an important role in glucose reabsorption. SGLT2 inhibitors suppress glucose reabsorption from the kidneys, thus reducing blood glucose levels in type 2 diabetes patients. We and other groups have developed several SGLT2 inhibitors starting from a natural product, phlorizin, but their action mechanisms remain unknown. Here, we elucidated the physiological hSGLT2–MAP17 complex structures bound to five SGLT2 inhibitors using single-particle cryo-electron microscopy. Canagliflozin, dapagliflozin, TA-1887, and sotagliflozin were bound in the outward-facing structure, whereas phlorizin was bound in the inward-open structure. The phlorizin–hSGLT2 interaction biochemically exhibited biphasic binding. Phlorizin weakly binds, via the phloretin motif, from its intracellular side near the Na+-binding site, while strongly interacts from its extracellular side. Unexpectedly, bound Na+stabilizes the outward-open conformation, while its release allows the transporter to adopt inward-open state. Our results first visualized the Na+-binding and inward-open conformation of hSGLT2–MAP17, clarifying the unprecedented Na+-dependent sugar transport mechanism with MAP17 acting as a scaffold, and may pave the way for development of next-generation SGLT inhibitors.