bluuebunny/crossref_metadata_2025 huggingface dataset:
Parallel Synapses with Transmission Nonlinearities Enhance Neuronal Classification Capacity
Authors: Song Yuru , Benna Marcus K.
Published: July 2024

Cortical neurons often establish multiple synaptic contacts with the same postsynaptic neuron. To avoid functional redundancy of these parallel synapses, it is crucial that each synapse exhibits distinct computational properties. Here we model the current to the soma contributed by each synapse as a sigmoidal transmission function of its presynaptic input, with learnable parameters such as amplitude, slope, and threshold. We evaluate the classification capacity of a neuron equipped with such nonlinear parallel synapses, and show that with a small number of parallel synapses per axon, it substantially exceeds that of the Perceptron. Furthermore, the number of correctly classified data points can increase superlinearly as the number of presynaptic axons grows.

When training with an unrestricted number of parallel synapses, our model neuron can effectively implement an arbitrary aggregate transmission function for each axon, constrained only by monotonicity. Nevertheless, successful learning in the model neuron often requires only a small number of parallel synapses.

We also apply these parallel synapses in a feedforward neural network trained to classify MNIST images, and show that they can increase the test accuracy. This demonstrates that multiple nonlinear synapses per input axon can substantially enhance a neuron’s computational power.
The relationship between microbial community succession, decay, and anatomical character loss in non-biomineralised animals
Authors: Clements Thomas , Goodall Robert , Gabbott Sarah , Murdock Duncan , Clokie Martha , Millard Andrew , Turkington Christopher , Bath-Enright Orla , Purnell Mark
Published: July 2024

A fundamental assumption of hypothesis-driven decay experiments is that, during decay, the loss of anatomy follows a sequence broadly controlled by the intrinsic compositional properties of tissues. Recent work investigating the succession of postmortem endogenous microbial communities (thanatomicrobiome) challenges this assumption. These studies suggest the thanatomicrobiome exhibits a predictable, clock-like succession in response to physical and chemical environmental changes within a carcass. Therefore, it is possible that reproducible sequences of character loss during decay are controlled by thanatomicrobiome succession dynamics. If so, exceptionally preserved fossil anatomy would reflect a succession of ancient contemporaneous microbial communities, about which we know nothing, rendering decay experiments uninformative. Here, we investigate two questions: (1) what is the role of exogenous and endogenous bacteria during formation of the thanatomicrobiome and (2) do thanatomicrobiome successions control the sequence of anatomical character loss within a decaying carcass? Our analysis shows that the thanatomicrobiome is dominated by endogenous bacteria and that, even in the presence of inoculum, exogenous bacteria do not invade the carcass and replace native bacteria (while the carcass is intact). This confirms that the use of environmental inoculum in decay experiments introduces an inadvisable confounding variable. Secondly, we find no correlation between thanatomicrobiome successions and the sequence of anatomical character loss, supporting that fossil non-biomineralised characters correlate with their propensity to decay in extant relatives. These findings indicate that the inability to model ancient bacteria does not invalidate decay experiments. We also present a synthesis of the role of bacteria in non-biomineralised fossilisation.
Reduction of Deformed Wing Virus-B levels in Colonies of the Honey beeApis melliferaafter Queen Vaccination with inactivatedPaenibacillus larvae
Authors: Weinberg Isaac , Floyd Amy , Reid Nathan , Swift Nigel
Published: July 2024

Deformed wing virus (DWV) is a virulent and ubiquitous disease that affects honey bee colonies. DWV infects bees at all life stages, but is most noticeable in adult bees, where clinical symptoms include shriveled, non-functional wings, and a drastically shortened lifespan. DWV is recorded in upwards of 90% of honey bee colonies worldwide, and has been linked to colony loss in symptomatic hives. DWV is primarily spread byVarroa destructormites, who feed on the fat bodies of honey bee adults and pupae. There is currently no direct treatment or preventative for DWV, with the primary method of reduction being vector control using acaracides. In this study, we tested the effect that vaccinating honey bee queens using killedPaenibacillus larvaebacterin, the causative agent of the honey bee disease American Foulbrood, had on deformed wing virus load in honey bee colonies. We placed vaccinated queens in 200 honey bee colonies, and unvaccinated queens in 200 colonies, and measured quantities of DWV-B in both groups immediately before, and 4 months after vaccination. We found that levels of DWV-B were identical before vaccination, but were significantly reduced in colonies 4 months post vaccination. This change was found despite no difference in mite quantities between groups. Overall, these data provide evidence that vaccination of queens withP. larvaebacterin is an effective method for reduction of DWV-B quantities in honey bee colonies in a commercially relevant field setting.
Comparative analysis of the syncytiotrophoblast in placenta tissue and trophoblast organoids using snRNA sequencing
Authors: Keenen Madeline M , Yang Liheng , Liang Huan , Farmer Veronica J , Worota Rizban E , Singh Rohit , Gladfelter Amy S , Coyne Carolyn B
Published: July 2024

The outer surface of chorionic villi in the human placenta consists of a single multinucleated cell called the syncytiotrophoblast (STB). The unique cellular ultrastructure of the STB presents challenges in deciphering its gene expression signature at the single-cell level, as the STB contains billions of nuclei in a single cell. There are many gaps in understanding the molecular mechanisms and developmental trajectories involved in STB formation and differentiation. To identify the underlying control of the STB, we performed comparative single nucleus (SN) and single cell (SC) RNA sequencing on placental tissue and tissue-derived trophoblast organoids (TOs). We found that SN RNA sequencing was essential to capture the STB population from both tissue and TOs. Differential gene expression and pseudotime analysis of TO-derived STB identified three distinct nuclear subtypes reminiscent of those recently identifiedin vivo. These included a juvenile nuclear population that exhibited both CTB and STB marker expression, a population enriched in genes involved in oxygen sensing, and finally a subtype enriched in transport and GTPase signaling molecules. Notably, suspension culture conditions of TOs that restore the native orientation of the STB (STBout) showed elevated expression of canonical STB markers and pregnancy hormones, along with a greater proportion of the STB nucleus subtype specializing in transport and GTPase signaling, compared to those cultivated with an inverted STB polarity (STBin). Gene regulatory analysis identified novel markers of STB differentiation conserved in tissue and TOs, including the chromatin remodeler RYBP, that exhibited STB-specific RNA and protein expression. CRISPR/Cas9 knockout of RYBP in STBinTOs did not impact cell-cell fusion; however, bulk RNA sequencing revealed downregulation of the pregnancy hormone CSH1 and upregulation of multiple genes associated with the oxygen-sensing STB nuclear subtype. Finally, we compared STB gene expression signatures amongst first trimester tissue, full-term tissue, and TOs, identifying many commonalities but also notable variability across each sample type. This indicates that STB gene expression is responsive to its environmental context. Our findings emphasize the utility of TOs to accurately model STB differentiation and the distinct nuclear subtypes observedin vivo, offering a versatile platform for unraveling the molecular mechanisms governing STB functions in placental biology and disease.
The metabolic benefits of thermogenic stimulation are preserved in aging
Authors: Natarajan Duraipandy , Plakkot Bhuvana , Tiwari Kritika , Ekambaram Shoba , Wang Weidong , Rudolph Michael , Mohammad Mahmoud A. , Chacko Shaji K. , Subramanian Madhan , Tarantini Stefano , Yabluchanskiy Andriy , Ungvari Zoltan , Csiszar Anna , Balasubramanian Priya
Published: July 2024

Adipose thermogenesis has been actively investigated as a therapeutic target for improving metabolic dysfunction in obesity. However, its applicability to middle-aged and older populations, which bear the highest obesity prevalence in the US (approximately 40%), remains uncertain due to age-related decline in thermogenic responses. In this study, we investigated the effects of chronic thermogenic stimulation using the β3-adrenergic (AR) agonist CL316,243 (CL) on systemic metabolism and adipose function in aged (18-month-old) C57BL/6JN mice. Sustained β3-AR treatment resulted in reduced fat mass, increased energy expenditure, increased fatty acid oxidation and mitochondrial activity in adipose depots, improved glucose homeostasis, and a favorable adipokine profile. At the cellular level, CL treatment increased uncoupling protein 1 (UCP1)-dependent thermogenesis in brown adipose tissue (BAT). However, in white adipose tissue (WAT) depots, CL treatment increased glycerol and lipid de novo lipogenesis (DNL) and turnover suggesting the activation of the futile substrate cycle of lipolysis and reesterification in a UCP1-independent manner. Increased lipid turnover was also associated with the simultaneous upregulation of proteins involved in glycerol metabolism, fatty acid oxidation, and reesterification in WAT. Further, a dose-dependent impact of CL treatment on inflammation was observed, particularly in subcutaneous WAT, suggesting a potential mismatch between fatty acid supply and oxidation. These findings indicate that chronic β3-AR stimulation activates distinct cellular mechanisms that increase energy expenditure in BAT and WAT to improve systemic metabolism in aged mice. Our study provides foundational evidence for targeting adipose thermogenesis to improve age-related metabolic dysfunction.
CRISPR-GEM: A Novel Machine Learning Model for CRISPR Genetic Target Discovery and Evaluation
Authors: Graham Josh P. , Zhang Yu , He Lifang , Gonzalez-Fernandez Tomas
Published: July 2024

CRISPR gene editing strategies are shaping cell therapies through precise and tunable control over gene expression. However, achieving reliable therapeutic effects with improved safety and efficacy requires informed target gene selection. This depends on a thorough understanding of the involvement of target genes in gene regulatory networks (GRNs) that regulate cell phenotype and function. Machine learning models have been previously used for GRN reconstruction using RNA- seq data, but current techniques are limited to single cell types and focus mainly on transcription factors. This restriction overlooks many potential CRISPR target genes, such as those encoding extracellular matrix components, growth factors, and signaling molecules, thus limiting the applicability of these models for CRISPR strategies. To address these limitations, we have developed CRISPR-GEM, a multi-layer perceptron (MLP)-based synthetic GRN constructed to accurately predict the downstream effects of CRISPR gene editing. First, input and output nodes are identified as differentially expressed genes between defined experimental and target cell/tissue types respectively. Then, MLP training learns regulatory relationships in a black-box approach allowing accurate prediction of output gene expression using only input gene expression. Finally, CRISPR-mimetic perturbations are made to each input gene individually and the resulting model predictions are compared to those for the target group to score and assess each input gene as a CRISPR candidate. The top scoring genes provided by CRISPR-GEM therefore best modulate experimental group GRNs to motivate transcriptomic shifts towards a target group phenotype. This machine learning model is the first of its kind for predicting optimal CRISPR target genes and serves as a powerful tool for enhanced CRISPR strategies across a range of cell therapies.
Redox signaling by hydrogen peroxide modulates axonal microtubule organization and induces a specific phosphorylation signature of microtubule proteins distinct from distress
Authors: Conze Christian , Trushina Nataliya I. , Monteiro-Abreu Nanci , Villar Romero Daniel , Wienbeuker Eike , Schwarze Anna-Sophie , Holtmannspötter Michael , Bakota Lidia , Brandt Roland
Published: July 2024

Many life processes are regulated by physiological redox signals, referred to as oxidative eustress. However, excessive oxidative stress can damage biomolecules and contribute to disease. The neuronal microtubule system is critically involved in axon homeostasis, regulation of axonal transport, and neurodegenerative processes. However, whether and how physiological redox signals affect axonal microtubules is largely unknown. Using live cell imaging and super- resolution microscopy, we show that subtoxic concentrations of the central redox metabolite hydrogen peroxide increase axonal microtubule dynamics, alter the structure of the axonal microtubule array, and affect the efficiency of axonal transport. We report that the mitochondria-targeting antioxidant SkQ1 and the microtubule stabilizer EpoD abolish the increase in microtubule dynamics. We found that oxidative eustress and distress specifically modulate the phosphorylation state of the microtubule system and induce a largely non- overlapping phosphorylation pattern of MAP1B as the main target. Cell-wide phosphoproteome analysis revealed that different signaling pathways are inversely activated by oxidative eustress and distress. Signaling via casein kinase (CK2) and pyruvate dehydrogenase kinases (PDK) is activated during eustress and signaling via mammalian target of rapamycin (mTOR) and serum/glucocorticoid-regulated protein kinase (SGK) is activated during distress. The results suggest that the redox metabolite and second messenger hydrogen peroxide induces rapid and local reorganization of the microtubule array in response to mitochondrial activity or as a messenger from neighboring cells by activating specific signaling cascades.
Altered dynamic functional connectivity in antagonistic state in first-episode, drug-naive patients with major depressive disorder
Authors: Wang Min , Chen Tao , He Zhongyi , Chan Lawrence Wing-Chi , Guo Qinger , Cai Shuyang , Duan Jingfeng , Zhang Danbin , Wang Xunda , Fang Yu , Yang Hong
Published: July 2024

Major depressive disorder (MDD) is characterized by disrupted functional network connectivity (FNC), with unclear underlying dynamics. We investigated both static FNC (sFNC) and dynamic FNC (dFNC) on resting-state fMRI data from drug-naive first-episode MDD patients and healthy controls (HC). MDD patients exhibited lower sFNC within and between sensory and motor networks than HC. Four dFNC states were identified, including a globally-weakly-connected state, a cognitive-control-dominated state, a globally-positively-connected state, and an antagonistic state. The antagonistic state was marked by strong positive connections within the sensorimotor domain and their anti-correlations with the executive-motor control domain. Notably, MDD patients exhibited significantly longer time dwelling in the globally-weakly-connected state, at the cost of significantly shorter time dwelling in the antagonistic state. Further, only the mean dwell time of this antagonistic state was significantly anticorrelated to disease severity measures. Our study highlights the altered dynamics of the antagonistic state as a fundamental aspect of disrupted FNC in early MDD.
Impaired contour object perception in psychosis
Authors: Kamath Rohit S. , Weldon Kimberly B. , Moser Hannah R. , Montoya Samantha , Abdullahi Kamar S. , Burton Philip C. , Sponheim Scott R. , Olman Cheryl A. , Schallmo Michael-Paul
Published: July 2024

Contour integration, the process of joining spatially separated elements into a single unified line, has consistently been found to be impaired in schizophrenia. Recent work suggests that this deficit could be associated with psychotic symptomatology, rather than a specific diagnosis such as schizophrenia. Examining a transdiagnostic sample of participants with psychotic psychopathology, we obtained quantitative indices of contour perception in a psychophysical behavioral task. We found impaired contour discrimination performance among people with psychotic psychopathology (PwPP, n = 62) compared to healthy controls (n = 34) and biological relatives of PwPP (n = 44). Participants with schizophrenia (n = 31) showed impaired task performance compared to participants with bipolar disorder (n = 18). We also measured responses during an analogous task using ultra-high field (7T) functional MRI and found higher responses in the lateral occipital cortex of PwPP compared to controls. Using task-based functional connectivity analyses, we observed abnormal connectivity between visual brain areas during contour perception among PwPP. These connectivity differences only emerged when participants had to distinguish the contour object from background distractors, suggesting that a failure to suppress noise elements relative to contour elements may underlie impaired contour processing in PwPP. Our results are consistent with impaired contour integration in psychotic psychopathology, and especially schizophrenia, that is related to cognitive dysfunction, and may be linked to impaired functional connectivity across visual regions.
Effect of parents’ country of birth on the relationship between socioeconomic status and childhood overweight and obesity in Southwest Sydney, Australia: learnings from the Growing Healthy Kids population prevalence survey
Authors: Kovai Vilas , Chong Shanley , Tang Janice , Jalaludin Bin , Thomas Margaret , Camilleri Michelle , Williams Mandy
Published: July 2024

Background

Childhood obesity is a major public health concern in Australia and the multicultural population of South-West Sydney. This study examined the influence of parents’ country of birth (COB) on the association between family socio-economic status (SES), assessed by area-level disadvantage and annual household income, and childhood obesity.

Methods

The analysis of data from the cross-sectional Growing Healthy Kids in Southwest Sydney (GHK-SWS) baseline survey of 1,815 children aged 5-16 years living in South Western Sydney, Australia employed generalised linear multinomial mixed models, with results presented as odds ratio and 95% confidence intervals.

Results

This study found a significant relationship between SES measures and the risk of overweight and obesity in the study population. The risks of childhood obesity are greatest in lower socioeconomic groups (across both SES metrics) regardless of their parents’ COB status. However, the overweight results are inconsistent across SES metrics and COB status. The risk of being overweight was lower for Australian-born parents living in disadvantaged areas but higher for those reporting lower income; and higher for Overseas-born parents living in disadvantaged areas but lower for those reporting low household income.

Conclusion

Parents’ SES is a consistent predictor of childhood obesity, and this relationship is not modified by parents’ COB. However, the likelihood of a child being overweight varied between the parents’ SES measures and COB. Prioritisation of the target population for area-level preventive public health interventions to modify obesogenic factors is recommended for a) obese children living in most disadvantaged areas and moderate disadvantaged areas regardless of their parents’ COB; b) overweight and obese children of moderate disadvantaged areas regardless of their parents’ COB.
“It’s his cheerfulness that gives me hope”: A Qualitative Analysis of Access to Pediatric Cancer Care in Northern Tanzania
Authors: Metcalf Madeline , Kajoka Happiness D. , Majaliwa Esther , Tupetz Anna , Staton Catherine A. , Vissoci João Ricardo , Espinoza Pamela , Cotache-Condor Cesia , Rice Henry E. , Mmbaga Blandina T. , Smith Emily R.
Published: July 2024

Background

Pediatric cancer is a significant and growing burden in low- and middle-income countries. The objective of this project was to describe the factors influencing access to pediatric cancer care in Northern Tanzania using the Three Delays Model.

Methods

This was a cross-sectional qualitative study conducted between June and September 2023 at Kilimanjaro Christian Medical Centre (KCMC). Parents and caregivers of children obtaining pediatric cancer care at KCMC were approached for participation in in-depth interviews (IDIs) and a demographic survey. All IDIs were facilitated in Swahili by a bilingual research coordinator. Thirteen IDIs and surveys were completed during the study period. Analysis utilized inductive and deductive coding approaches to identify dominant themes and sub-themes impacting access to pediatric oncology care.

Results

Participants reported significant financial barriers to accessing pediatric cancer care along the entire care continuum. Early delays were impacted by waiting for symptoms to resolve or worsen. The most substantial delays resulted from health infrastructure at mid-level health facilities, misdiagnoses, and delayed referral to KCMC for treatment. Participants did not describe delays after arrival to KCMC and rather offered perspective on their child’s cancer diagnosis, their concerns while obtaining care, and their hopes for the future. Financial support provided by the Tanzanian government was the only facilitator noted by participants.

Conclusions

We suggest targeted interventions including 1) empowerment of CHWs and local traditional healers to advocate for earlier care seeking behavior, 2) implementation of clinical structures and training at intermediary medical centers aimed at earlier referral to a treatment facility, 3) incorporation of support and education initiatives for families of children with a cancer diagnosis. Lastly, we suggest that national health plans include pediatric cancer care.
Effect of children’s BMI on the association between parents’ socio-demographic and economic characteristics, and Parental perceptions of their child’s weight status in South-western Sydney: The Growing Healthy Kids Survey, Australia
Authors: Kovai Vilas , Chong Shanley , Jalaludin Bin , Tang Janice , Camilleri Michelle , Thomas Margaret , Fox Francis , Williams Mandy
Published: July 2024

Background

Parents’ perception of children’s weight status has been recognised as one of the influencing factors when planning childhood overweight and obesity prevention programs. We aimed to examine whether children’s BMI modified the association between parents’ socio-demographic and economic characteristics and their perceptions of their children’s weight status in South Western Sydney Local Health District.

Methods

We analysed 1,353 parents’ perceptions of their child’s weight status using the ‘Growing Healthy Kids-Population Health Survey’ baseline data. Generalised linear multinomial mixed models were used to determine the associations. Results are presented as odds ratio and associated 95% confidence intervals by BMI.

Results

This study found that the weight status of about 23% of healthy-weight children, 65% of overweight children and 55% of obese children was incorrectly perceived by parents. Father as the primary parent and parents who completed ≤12 years of school education were less likely to perceive their overweight or obese children as overweight. Parents who lived in more disadvantaged areas were more likely to perceive their obese children as overweight. Parents who lived in moderate disadvantaged areas were less likely to perceive their overweight children as overweight. Parents who had reported an annual household income between $52,000-$103,999 were more likely to perceive their overweight children as of healthy weight and parents who reported an annual household income below $103,999 were twice as likely to perceive their obese children as having a healthy weight.

Conclusion

The findings suggest that there may be benefit in designing interventions that focus on improving parents’ misperception of children’s weight status. The groups of parents who should be prioritised for preventive public health interventions to modify the parental misperceptions of their child’s weight status include a) fathers, b) parents who completed ≤12 years of school education and parents who had Trade, TAFE or Diploma as educational qualification, c) parents living in moderately disadvantaged areas and d) parents with low and high household-income.
Tissue expression in surgically retrieved cam deformity and capsule from patient hips with Cam-type Femoroacetabular Impingement Syndrome
Authors: Yuh Catherine , Malloy Philip , Mell Steven P , Khan Zeeshan , Nho Shane J. , Pourzal Robin , Chahla Jorge , Hall Deborah J
Published: July 2024

Introduction

Cam-type femoroacetabular impingement syndrome (FAIS) is a pre-arthritic hip condition, defined as a bony growth on the proximal femur that causes abnormal joint contact. The tissue presentation of the cam deformity and capsule in FAIS remains understudied. The purpose of this study was to 1) evaluate histopathological features in cam deformity and capsule from FAIS patients, 2) assess the extent of local inflammation within the capsule, and 3) determine relationships between cam deformity tissue composition versus α angle and patient factors.

Methods

Cam deformity and capsular tissues were collected from FAIS patients undergoing arthroscopic surgery. Samples were histologically processed, imaged using light and polarized light microscopy, and assessed with point counting. Correlation-based statistics were performed to identify features correlated with α angle and patient factors.

Results

Across 21 cam deformity samples assessed, a total of 16,259 points were counted. The tissue within the cam deformity was observed to be heterogeneous between specimens, comprised of 16 distinct structures spanning different states of viability. In samples with articular cartilage, the tissue was highly disrupted and/or calcified. The presence of fibrocartilage, necrotic cartilage, and vasculature had significant low-moderate correlations with α angle. During assessment of capsular tissue quality, synovitis was observed in most samples.

Conclusion

The cam deformity is complex and heterogeneous, both within individual cam deformities and between individuals with FAIS. Several cam deformity tissue features were correlated with α angle, age, sex, and BMI. The heterogeneity observed in these samples indicates that tissue properties within the cam deformity varies between patients with FAIS, which may contribute to outcomes of hip arthroscopic surgery and a patient’s level of risk for the subsequent development of osteoarthritis. Our findings suggest distinct tissue phenotypes of FAIS exist, which may be an important consideration for FAIS treatment strategies.
Exploring Comorbidity Networks in Mild Traumatic Brain Injury Subjects through Graph Theory: A Traumatic Brain Injury Model Systems Study
Authors: Mehta Kaustav , Sudhakar Shyam Kumar
Published: July 2024

Traumatic brain injuries (TBIs) are characterized by myriad comorbidities that affect the functioning of the affected individuals. The comorbidities that TBI subjects experience span a wide range, ranging from psychiatric diseases to those that affect the various systems of the body. This is compounded by the fact that the problems that TBI subjects face could span over an extended period post-primary injury. Further, no drug exists to prevent the spread of secondary injuries after a primary impact. In this study, we employed graph theory to understand the patterns of comorbidities after mild TBIs. Upon application of network analysis and a novel clustering algorithm, we discovered interesting associations between comorbidities in young and old subjects with the condition. Specifically, bipolar disorder was seen as related to cardiovascular comorbidities, a pattern that was observed only in the young subjects. Similar associations between obsessive-compulsive disorder and rheumatoid arthritis were observed in young subjects. Psychiatric comorbidities exhibited differential associations with non-psychiatric comorbidities depending on the age of the cohort. The study results might have implications for effective surveillance and the management of comorbidities post mild TBIs.
A VgrG2b fragment cleaved by caspase-11/4 promotesPseudomonas aeruginosainfection through suppressing the NLRP3 inflammasome
Authors: Qian Yan , Liu Qiannv , Cheng Xiangyun , Wang Chunlei , Kong Chun , Li Mengqian , Ren Chao , Jiang Dong , Wang Shuo , Xia Pengyan
Published: July 2024

The T6SS ofPseudomonas aeruginosaplays an essential role in the establishment of chronic infections. Inflammatory cytokines mediated by inflammasomes are crucial for the body to resist bacterial infections. Here we found that during the infection ofP. aeruginosa, non-canonical inflammasome was activated in macrophages, but the activation of downstream NLRP3 inflammasome was inhibited. The VgrG2b ofP. aeruginosais recognized and cleaved by caspase-11, generating a free C-terminal fragment. The VgrG2b C-terminus can bind to NLRP3, inhibiting the activation of the NLRP3 inflammasome by rejecting NEK7 binding to NLRP3. Administrating a specific peptide that inhibits the cleavage of VgrG2b by caspase-11 to mice can significantly improve their survival rate during infection. Our discovery elucidates a mechanism by whichP. aeruginosainhibits host immune response, providing a new approach for the future clinical treatment ofP. aeruginosainfections.
BiRNA-BERT allows efficient RNA language modeling with adaptive tokenization
Authors: Tahmid Md Toki , Shahgir Haz Sameen , Mahbub Sazan , Dong Yue , Bayzid Md. Shamsuzzoha
Published: July 2024

Recent advancements in Transformer-based models have spurred interest in their use for biological sequence analysis. However, adapting models like BERT is challenging due to sequence length, often requiring truncation for proteomics and genomics tasks. Additionally, advanced tokenization and relative positional encoding techniques for long contexts in NLP are often not directly transferable to DNA/RNA sequences, which require nucleotide or character-level encodings for tasks such as 3D torsion angle prediction. To tackle these challenges, we propose an adaptive dual tokenization scheme for bioinformatics that utilizes both nucleotide-level (NUC) and efficient BPE tokenizations. Building on the dual tokenization, we introduce BiRNA-BERT, a 117M parameter Transformer encoder pretrained with our proposed tokenization on 28 billion nucleotides across 36 million coding and non-coding RNA sequences. The learned representation by BiRNA-BERT generalizes across a range of applications and achieves state-of-the-art results in long-sequence downstream tasks and achieves a performance comparable to 6× larger models in short-sequence tasks with 27×less pre-training compute. BiRNA-BERT can dynamically adjust its tokenization strategy based on sequence lengths, utilizing NUC for shorter sequences and switching to BPE for longer ones, thereby offering, for the first time, the capability to efficiently handle arbitrarily long DNA/RNA sequences.1
Genomic Signatures of Domestication in a Fungus Obligately Farmed by Leafcutter Ants
Authors: Leal-Dutra Caio A. , Vizueta Joel , Baril Tobias , Kooij Pepijn W. , Rødsgaard-Jørgensen Asta , Schantz-Conlon Benjamin H. , Croll Daniel , Shik Jonathan Z.
Published: July 2024

The naturally selected fungal crop (Leucoagaricus gongylophorus) farmed by leafcutter ants shows striking parallels with artificially selected plant crops domesticated by humans (e.g., polyploidy, engorged nutritional rewards, dependence on cultivation). To date, poorly resolvedL. gongylophorusgenomes based on short-read sequencing have constrained hypotheses about how millions of years under cultivation by ants shaped the fungal crop genome and potentially drove domestication. We use PacBio HiFi sequencing ofL. gongylophorusfrom the leafcutter antAtta colombicato identify 18 putatively novel biosynthetic gene clusters that likely cemented life as a cultivar (e.g., plant fragment degradation, ant-farmer communication, antimicrobial defense). Comparative analyses with cultivated and free-living fungi showed genomic signatures of stepwise domestication transitions: 1) free-living to ant-cultivated: loss of genes conferring stress response and detoxification, 2) hyphal food to engorged nutritional rewards: expansions of genes governing cellular homeostasis, carbohydrate metabolism, and siderophore biosynthesis, and 3) detrital provisioning to freshly cut plant fragments: gene expansions promoting cell wall biosynthesis, fatty acid metabolism, and DNA repair. Comparisons acrossL. gongylophorusfungi farmed by three leafcutter ant species highlight genomic signatures of exclusively vertical clonal propagation and widespread transposable element activity. These results show how natural selection can shape domesticated cultivar genomes towards long-term ecological resilience of farming systems that have thrived across millennia.
Allopatric speciation in cattails: Genomic landscapes of divergence acrossTyphaspp. suggest balancing selection, introgressions, and the absence of adaptive divergence
Authors: Aleman Alberto , Freeland Joanna R. , Shafer Aaron B. A. , Dorken Marcel E.
Published: July 2024

Determining the evolutionary forces which result in the accumulation of genetic divergence between closely related species can yield important insights into speciation. Genetic divergence can be understood by two broad non-mutually exclusive frameworks: genetic drift under allopatry and natural selection under ecological divergence. Genetic regions that are highly differentiated or conserved between closely related species can be used to infer the types of selection driving speciation. We tested the role of selection in promoting species divergence inTypha, an old, widespread plant genus characterised by high levels of intra- and interspecific gene flow. Using genome-wide data, we scanned the genomes of multiple individuals from fiveTyphaspecies to identify how selection influenced their levels of genetic divergence. We also tested whether past admixture or contemporary introgression events have contributed to the genetic variation within and among species. The genomic landscapes of divergence were predominantly neutral, including regions of exceptional differentiation, and we observed contemporary genetic introgressions with no evidence of historical hybridisation. The absence of adaptive divergence and historical hybridisation are consistent with patterns expected under allopatric speciation and genetic divergence driven primarily by drift, followed by range expansion and secondary contact leading to contemporary hybridisation and recent genetic introgressions. For all species pairs, most genomic regions associated with adaptive divergence were valleys of balancing selection, in which the maintenance of ancestral polymorphisms causes reduced levels of divergence. Reproductive isolation among multipleTyphaspecies remains incomplete, and balancing selection and recent introgressions have contributed to their standing genetic variation.
Transcriptional landscape of a hypoxia response identifies cell-specific pathways for adaptation
Authors: Kong Ji Na , Dipon Ghosh D. , Savvidis Achilleus , Sando Steve R. , Droste Rita , Robert Horvitz H.
Published: July 2024

How the HIF-1 (Hypoxia-Inducible) transcription factor drives and coordinates distinct responses to low oxygen across diverse cell types is poorly understood. We present a multi-tissue single-cell gene-expression atlas of the hypoxia response of the nematodeCaenorhabditis elegans. This atlas highlights how cell-type-specific HIF-1 responses overlap and diverge among and within neuronal, intestinal, and muscle tissues. Using the atlas to guide functional analyses of candidate muscle-specific HIF-1 effectors, we discovered that HIF-1 activation drives downregulation of thetspo-1(TSPO,Translocator Protein) gene in vulval muscle cells to modulate a hypoxia-driven change in locomotion caused by contraction of body-wall muscle cells. We further showed that in human cardiomyocytes HIF-1 activation decreases levels of TSPO and thereby alters intracellular cholesterol transport and the mitochondrial network. We suggest that TSPO-1 is an evolutionarily conserved mediator of HIF-1-dependent modulation of muscle and conclude that our gene-expression atlas can help reveal how HIF-1 drives cell-specific adaptations to hypoxia.
TDP43 autoregulation gives rise to shortened isoforms that are tightly controlled by both transcriptional and post-translational mechanisms
Authors: Dykstra Megan M. , Weskamp Kaitlin , Gómez Nicolás B. , Waksmacki Jacob , Tank Elizabeth , Glineburg M. Rebecca , Snyder Allison , Pinarbasi Emile , Bekier Michael , Li Xingli , Bai Jen , Shahzad Shameena , Nedumaran Juno , Wieland Clare , Stewart Corey , Willey Sydney , Grotewold Nikolas , McBride Jonathon , Moran John J. , Suryakumar Aditya V. , Lucas Michael , Tessier Peter , Ward Michael , Todd Peter , Barmada Sami J.
Published: July 2024

The nuclear RNA-binding protein TDP43 is integrally involved in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Previous studies uncovered N-terminal TDP43 isoforms that are predominantly cytosolic in localization, highly prone to aggregation, and enriched in susceptible spinal motor neurons. In healthy cells, however, these shortened (s)TDP43 isoforms are difficult to detect in comparison to full-length (fl)TDP43, raising questions regarding their origin and selective regulation. Here, we show that sTDP43 is created as a byproduct of TDP43 autoregulation and cleared by nonsense mediated RNA decay (NMD). The sTDP43-encoding transcripts that escape NMD can lead to toxicity but are rapidly degraded post-translationally. Circumventing these regulatory mechanisms by overexpressing sTDP43 results in neurodegenerationin vitroandin vivovia N-terminal oligomerization and impairment of flTDP43 splicing activity, in addition to RNA binding-dependent gain-of-function toxicity. Collectively, these studies highlight endogenous mechanisms that tightly regulate sTDP43 expression and provide insight into the consequences of aberrant sTDP43 accumulation in disease.
Eight-Fold Increased COVID-19 Mortality in Autosomal Dominant Tubulointerstitial Kidney Disease due toMUC1Mutations: An Observational Study
Authors: Kidd Kendrah O. , Williams Adrienne H. , Taylor Abbigail , Martin Lauren , Robins Victoria , Sayer John A. , Olinger Eric , Mabillard Holly R. , Papagregoriou Gregory , Deltas Constantinos , Stavrou Christoforos , Conlon Peter J. , Hogan Richard Edmund , Elhassan Elhussein A.E. , Springer Drahomíra , Zima Tomáš , Izzi Claudia , Vrbacká Alena , Piherová Lenka , Pohludka Michal , Radina Martin , Vylet’al Petr , Hodanova Katerina , Zivna Martina , Kmoch Stanislav , Bleyer Anthony J.
Published: July 2024

Background

MUC1andUMODpathogenic variants cause autosomal dominant tubulointerstitial kidney disease (ADTKD).MUC1is expressed in kidney, nasal mucosa and respiratory tract, whileUMODis expressed only in kidney. Due to haplo-insufficiency ADTKD-MUC1patients produce approximately 50% of normal mucin-1.

Methods

To determine whether decreased mucin-1 production was associated with an increased COVID-19 risk, we sent a survey to members of an ADTKD registry in September 2021, after the initial, severe wave of COVID-19. We linked results to previously obtained ADTKD genotype and plasma CA15-3 (mucin-1) levels and created a longitudinal registry of COVID-19 related deaths.

Results

Surveys were emailed to 637 individuals, with responses from 89 ADTKD-MUC1and 132 ADTKD-UMODindividuals. 19/83 (23%) ADTKD-MUC1survey respondents reported a prior COVID-19 infection vs. 14/125 (11%) ADTKD-UMODrespondents (odds ratio (OR) 2.35 (95%CI 1.60-3.11,P= 0.0260). Including additional familial cases reported from survey respondents, 10/41 (24%) ADTKD-MUC1individuals died of COVID-19 vs. 1/30 (3%) with ADTKD-UMOD, with OR 9.21 (95%CI 1.22-69.32),P= 0.03. The mean plasma mucin-1 level prior to infection in 14 infected and 27 uninfected ADTKD-MUC1individuals was 7.06±4.12 vs. 10.21±4.02 U/mL (P= 0.035). Over three years duration, our longitudinal registry identified 19 COVID-19 deaths in 360 ADTKD-MUC1individuals (5%) vs. 3 deaths in 478 ADTKD-UMODindividuals (0.6%) (P= 0.0007). Multivariate logistic regression revealed the following odds ratios (95% confidence interval) for COVID-19 deaths: ADTKD-MUC18.4 (2.9-29.5), kidney transplant 5.5 (1.6-9.1), body mass index (kg/m2) 1.1 (1.0-1.2), age (y) 1.04 (1.0-1.1).

Conclusions

Individuals with ADTKD-MUC1are at an eight-fold increased risk of COVID-19 mortality vs. ADTKD-UMODindividuals. Haplo-insufficient production of mucin-1 may be responsible.
Effect of truffle extracts on growth ofChlorella vulgaris
Authors: Vlasova Anfisa A. , Lipatova Olga E. , Belyshenko Alexander Y. , Martynova Elena I. , Imidoeva Natalia A. , Telnova Tamara Y. , Malygina Ekaterina V. , Morgunova Maria M. , Dmitrieva Maria E. , Shelkovnikova Victoria N. , Shashkina Sophia S. , Vavilina Tatiana N. , Axenov-Gribanov Denis V.
Published: July 2024

Truffles are hypogeous ectomycorrhizal fungi with a complex system of chemical communications and biotic interactions. This study examines the influence of truffle extracts on the growth of the algaChlorella vulgarisas a model organism commonly employed in pharmacology, food industry and biomonitoring. The study involved sampling of fruiting bodies of black truffles in a number of regions across Russia, over a number of years. The observed differences in truffle condition were used to illustrate a potential correlation between the quality and biological activity of truffles. Methanolic extracts were prepared and added to the culture ofC. vulgaristo evaluate the growth of algae using the spectrophotometry methods. For the first time, we demonstrated that truffle extracts had biological activity in terms of the algaeC. vulgarisgrowth stimulation. We observed the effects of short-term and long-term growth stimulation. To date, it can be concluded that there is no direct correlation between the stimulating effects on algae and the state of truffles, place of their sampling, or their quality. Finally, it is crucial to examine biological regulations that operate in complex systems such as truffles. It is suggested that in the near future truffles may become a model system for the study of complex biotic and chemical communications.
Transcriptome-wide characterization of genetic perturbations
Authors: Nadig Ajay , Replogle Joseph M. , Pogson Angela N. , McCarroll Steven A , Weissman Jonathan S. , Robinson Elise B. , O’Connor Luke J.
Published: July 2024

Single cell CRISPR screens such as Perturb-seq enable transcriptomic profiling of genetic perturbations at scale. However, the data produced by these screens are often noisy due to cost and technical constraints, limiting power to detect true effects with conventional differential expression analyses. Here, we introduce TRanscriptome-wide Analysis of Differential Expression (TRADE), a statistical framework which estimates the transcriptome-wide distribution of true differential expression effects from noisy gene-level measurements. Within TRADE, we derive multiple novel, interpretable statistical metrics, including the “transcriptome-wide impact”, an estimator of the overall transcriptional effect of a perturbation which is stable across sampling depths. We analyze new and published large-scale Perturb-seq datasets to show that many true transcriptional effects are not statistically significant, but detectable in aggregate with TRADE. In a genome-scale Perturb-seq screen, we find that a typical gene perturbation affects an estimated 45 genes, whereas a typical essential gene perturbation affects over 500 genes. An advantage of our approach is its ability to compare the transcriptomic effects of genetic perturbations across contexts and dosages despite differences in power. We use this ability to identify perturbations with cell-type dependent effects and to find examples of perturbations where transcriptional responses are not only larger in magnitude, but also qualitatively different, as a function of dosage. Lastly, we expand our analysis to case/control comparison of gene expression for neuropsychiatric conditions, finding that transcriptomic effect correlations are greater than genetic correlations for these diagnoses. TRADE lays an analytic foundation for the systematic comparison of genetic perturbation atlases, as well as differential expression experiments more broadly.
Comparative Genomic Analysis of Metal-Tolerant Bacteria Reveals Significant Differences in Metal Adaptation Strategies
Authors: Chen Dai Di , Zhang Liu Lian , Zhang Jiu Hua , Ban Wen Ting , Li Qingxin , Wu Jin Chuan
Published: July 2024

Metal-tolerant bacteria have been commercially used in wastewater treatment, bio-fertilizer and soil remediation etc. However, their action mechanisms have not yet been well understood. We screened metal-tolerant bacteria isolated from the rhizosphere soil samples with metal-enriched media containing Cu, Fe or Mn, sequenced and compared the genomes, and analyzed their metal adaptation strategies at genomic levels to better understand their mechanisms of actions. Totally 32 metal-tolerant isolates were identified and classified into 12 genera based on phylogenetic analysis. The determination of MTC and effect of metal ions on the isolates indicated thatSerratia marcescensX1,Mammaliicoccus sciuriX26 andRummeliibacillus pycnusX33 showed the significant differences in metal tolerance to Cu, Fe and Mn with other isolates. They have quite different genomic features to adapt various metal ions.S. marcescensX1 possesses abundant genes required for Cu, Fe and Mn homeostasis.M. sciuriX26 has a number of genes involved in Mn and Zn homeostasis but with no genes responsible for Cu and Ca transport.R. pycnusX33 is rich in Fe, Zn and Mg transport systems but poor in Cu and Mn transport systems. It is thus inferred that the combined use of them would compensate their differences and enhance their ability in accumulating a wider range of heavy metals for promoting their applications in wastewater treatment, soil remediation and organic fertilizer etc.

IMPORTANCE

Metal-tolerant bacteria have wide applications in environment, agriculture and ecology, but their action strategies have not yet been well understood. We isolated 32 metal-tolerant bacteria from the rhizosphere soil samples. Among them,S. marcescensX1,M. sciuriX26 andR. pycnusX33 showed the significant differences in metal tolerance to Cu, Fe and Mn with other isolates. Comparative genomic analysis revealed that they have abundant and different genomic features to adapt various metal ions. It is thus inferred that the combined use of them would compensate their differences and enhance their ability in accumulating heavy metal ions widening their applications in industry, agriculture and ecology.