bluuebunny/crossref_metadata_2025 huggingface dataset:
Loss of mitochondrial pyruvate transport initiates cardiac glycogen accumulation and heart failure
Authors: Weiss Rachel C. , Pyles Kelly D. , Cho Kevin , Brennan Michelle , Fisher Jonathan S. , Patti Gary J. , McCommis Kyle S.
Published: June 2024

Background

Heart failure involves metabolic alterations including increased glycolysis despite unchanged or decreased glucose oxidation. The mitochondrial pyruvate carrier (MPC) regulates pyruvate entry into the mitochondrial matrix, and cardiac deletion of the MPC in mice causes heart failure. How MPC deletion results in heart failure is unknown.

Methods

We performed targeted metabolomics and isotope tracing in wildtype (fl/fl) and cardiac-specific Mpc2-/- (CS-Mpc2-/-) hearts after in vivo injection of U-13C-glucose. Cardiac glycogen was assessed biochemically and by transmission electron microscopy. Cardiac uptake of 2-deoxyglucose was measured and western blotting performed to analyze insulin signaling and enzymatic regulators of glycogen synthesis and degradation. Isotope tracing and glycogen analysis was also performed in hearts from mice fed either low-fat diet or a ketogenic diet previously shown to reverse the CS-Mpc2-/- heart failure. Cardiac glycogen was also assessed in mice infused with angiotensin-II that were fed low-fat or ketogenic diet.

Results

Failing CS-Mpc2-/- hearts contained normal levels of ATP and phosphocreatine, yet these hearts displayed increased enrichment from U-13C-glucose and increased glycolytic metabolite pool sizes.13C enrichment and pool size was also increased for the glycogen intermediate UDP-glucose, as well as increased enrichment of the glycogen pool. Glycogen levels were increased ∼6-fold in the failing CS-Mpc2-/- hearts, and glycogen granules were easily detected by electron microscopy. This increased glycogen synthesis occurred despite enhanced inhibitory phosphorylation of glycogen synthase and reduced expression of glycogenin-1. In young, non-failing CS-Mpc2-/- hearts, increased glycolytic13C enrichment occurred, but glycogen levels remained low and unchanged compared to fl/fl hearts. Feeding a ketogenic diet to CS-Mpc2-/- mice reversed the heart failure and normalized the cardiac glycogen and glycolytic metabolite accumulation. Cardiac glycogen levels were also elevated in mice infused with angiotensin-II, and both the cardiac hypertrophy and glycogen levels were improved by ketogenic diet.

Conclusions

Our results indicate that loss of MPC in the heart causes glycogen accumulation and heart failure, while a ketogenic diet can reverse both the glycogen accumulation and heart failure. We conclude that maintaining mitochondrial pyruvate import and metabolism is critical for the heart, unless cardiac pyruvate metabolism is reduced by consumption of a ketogenic diet.
Background compensation revisited: Conserved phase response curves in frequency controlled homeostats with coherent feedback
Authors: Ruoff Peter
Published: June 2024

Background compensation is the ability of a controlled variable to respond to an applied perturbation in an unchanged manner and independent of different but constant background signals which act in parallel to the perturbation. We found that background compensation occurs by ‘coherent feedback’ mechanisms where additional control variables feed directly back to the controlled variable. This paper extends a previous study on background compensation to include phase responses in frequency controlled coherent feedback oscillators. While the frequency resetting amplitude in coherent feedback oscillators is found to be dependent on the inflow/outflow perturbation of the controlled variable and thereby become phase dependent, the frequency resetting itself and the corresponding phase response curves are found to be background compensated. It is speculated that this type of background compensation may be an additional way how ambient noise can be ‘ignored’ by organisms.
Efficient positioning of QTL and Secondary Limit thresholds in a clinical trial risk-based monitoring
Authors: Shnaydman Vladimir
Published: June 2024

In the high-stakes world of clinical trials, where a company’s multimillion-dollar drug development investment is at risk, the increasing complexity of these trials only compounds the challenges. Therefore, the development of a robust risk mitigation strategy, as a crucial component of comprehensive risk planning, is not just important but essential for effective drug development, particularly in the RBQM ecosystem. This emphasis on the urgency and significance of risk mitigation strategy can help the audience understand the gravity of the topic.

The paper introduces a novel framework for deriving an efficient risk mitigation strategy at the planning stage of a clinical trial and establishing operational rules (thresholds). This approach combines optimization and simulation models, offering a fresh perspective on risk management in clinical trials. The optimization model aims to derive an efficient contingency budget and allocate limited mitigation resources across mitigated risks. The simulation model aims to efficiently position the QTL/KRI and Secondary Limit thresholds for each risk to be aligned with risk assessment and contingency resources.

A compelling case study vividly illustrates the practical application and effectiveness of the proposed technique. This real-world example not only demonstrates the framework’s potential but also instills confidence in its successful implementation, reassuring the audience of its practicality and effectiveness.
In Silico-Driven Engineering ofHalomonas elongataL-Asparaginase: Towards Enhanced Proteolytic Resistance in Lymphoblastic Leukemia
Authors: Ghadikolaei Maryam Samadaei , Asad Sedigheh , Hassan-Zadeh Vahideh
Published: June 2024

The shortened L-asparaginase’s half-life in leukemia patients due to elevated serum proteases, poses a challenge. This study aimed to enhance the stability ofHalomonas elongataL-asparaginase against trypsin. Employing the trRosetta server, we modeled the enzyme’s 3D structure with a quality score of 96.5, revealing predominant secondary structure of random coils (42%), alpha helices (33%), and extended strands (20%) organized in two domains. Molecular docking unveiled a triad alignment among residues Thr16, Ser65, and Asp97 with L-asparagine. Site selection for mutation considered secondary structure prediction, dimerization analysis, trypsin cleavage site determination and epitope mapping. A library of enzyme variants was constructed through site saturation mutagenesis which led to the identification of the Arg206 to Thr, resulting in a 1.7-fold increased enzyme-specific activity (2400 U/mg) and heightened trypsin resistance. The mutant displayed a half-life of 3.47 hin human serum, approximately 50% longer than the wild type.In silicoanalyses confirmed structural stability, reduced flexibility, and enhanced substrate binding, contributing to increased proteolysis resistance and enzymatic activity. The Arg206Thr mutant exhibited anti-proliferative activity (IC50of 1.45 U/ml) on leukemia cell line K562, suggesting potential therapeutic implications.
Plasma proteomics in the UK Biobank reveals youthful brains and immune systems promote healthspan and longevity
Authors: Oh Hamilton Se-Hwee , Le Guen Yann , Rappoport Nimrod , Urey Deniz Yagmur , Rutledge Jarod , Brunet Anne , Greicius Michael D. , Wyss-Coray Tony
Published: June 2024

Organ-derived plasma protein signatures derived from aptamer protein arrays track organ-specific aging, disease, and mortality in humans, but the robustness and clinical utility of these models and their biological underpinnings remain unknown. Here, we estimate biological age of 11 organs from 44,526 individuals in the UK Biobank using an antibody-based proteomics platform to model disease and mortality risk. Organ age estimates are associated with future onset of heart failure (heart age HR=1.83), chronic obstructive pulmonary disease (lung age HR=1.39), type II diabetes (kidney age HR=1.58), and Alzheimer’s disease (brain age HR=1.81) and sensitive to lifestyle factors such as smoking and exercise, hormone replacement therapy, or supplements. Remarkably, the accrual of aged organs progressively increases mortality risk while a youthful brain and immune system are uniquely associated with disease-free longevity. These findings support the use of plasma proteins for monitoring organ health and the efficacy of drugs targeting organ aging disease.
Transposable Element (TE) insertion predictions from RNAseq inputs and TE impact on RNA splicing and gene expression inDrosophilabrain transcriptomes
Authors: Azad Md Fakhrul , Tong Tong , Lau Nelson C.
Published: June 2024

Recent studies have suggested that Transposable Elements (TEs) residing in introns frequently splice into and alter primary gene coding transcripts. To re-examine the exonization of TEs into protein-coding gene transcripts, we re-analyzed aDrosophilaneuron circadian rhythm RNAseq dataset and a deep long RNA fly midbrain RNAseq dataset using our Transposon Insertion and Depletion Analyzer (TIDAL) program. Our TIDAL results were able to predict several TE insertions from RNAseq data that were consistent with previous published studies. However, we also uncovered many discrepancies in TE-exonization calls, such as reads that mainly support intron retention of the TE and little support for chimeric mRNA spliced to the TE. We then deployed rigorous gDNA-PCR and RT-PCR procedures on TE-mRNA fusion candidates to see how many of bioinformatics predictions could be validated. By testing aw1118strain from which the deeper long RNAseq data was derived from and comparing to anOreRstrain, only 9 of 23 TIDAL candidates (<40%) could be validated as a novel TE insertion by gDNA-PCR, indicating that deeper study is needed on using RNAseq as inputs into current TE-insertion prediction programs. Of these validated calls, the RT-PCR results only supported TE-intron retention. Lastly, in theDscam2andBxgenes of thew1118strain that contained intronic TEs, gene expression was 2-3 times higher than theOreRgenes lacking the TEs. This study’s validation approach indicates that chimeric TE-mRNAs are infrequent and cautions that more optimization is required in bioinformatics programs to call TE insertions using RNAseq datasets.
Bola-amphiphilic dendrimer empowers imatinib to target metastatic ovarian cancer stem cellsviaβ-catenin-HRP2 signaling axis
Authors: Shi Zeyu , Artemenko Margarita , Zhang Ming , Yi Canhui , Chen Peng , Lin Shuting , Bian Zhancun , Lian Baoping , Meng Fanzhen , Chen Jiaxuan , Roussel Tom , Li Ying , Chan Karen K. L. , Ip Philip P. C. , Lai Hung-Cheng , Liu Xiaoxuan , Peng Ling , Wong Alice S. T.
Published: June 2024

Ovarian cancer is the leading cause of death among all gynecological malignancies, and drug resistance renders the current chemotherapy agents ineffective for patients with advanced metastatic tumors. We report an effective treatment strategy for targeting metastatic ovarian cancer involving a nanoformulation (Bola/IM) – bola-amphiphilic dendrimer (Bola)-encapsulated imatinib (IM) – to target the critical mediator of ovarian cancer stem cells (CSCs) CD117 (c-Kit). Bola/IM offered significantly more effective targeting of CSCs compared to IM alone, through a novel and tumor-specific β-catenin/HRP2 axis, allowing potent inhibition of cancer cell survival, stemness and metastasis in metastatic and drug-resistant ovarian cancer cells. Promising results were also obtained in clinically relevant patient-derived ascites and organoids, alongside high tumor-oriented accumulation and favorable pharmacokinetic properties in mouse models. Furthermore, Bola/IM displayed synergistic anticancer activity when combined with the first-line chemotherapeutic drug cisplatin in patient-derived xenograft mouse models, without any adverse effects. Our findings support the use of Bola/IM as a nanoformulation to empower IM, providing targeted and potent treatment of metastatic ovarian cancer. Our study thus represents a significant advancement towards addressing the unmet medical need for improved therapies targeting this challenging disease.
In vivorat-brain mapping of multiple gray matter water populations using nonparametric D(ω)-R1-R2 distributions MRI
Authors: Yon Maxime , Narvaez Omar , Topgaard Daniel , Sierra Alejandra
Published: June 2024

Massively Multidimensional Diffusion MRI combines tensor-valued encoding, oscillating gradients, and diffusion-relaxation correlation to provide multicomponent sub-voxel parameters depicting the tissue microstructure. This method was successfully implementedex vivoin micro-imaging systems and in clinical conditions but with a reduced diffusion frequency (ω) range due to the use of classical tensor-valued encoding. We demonstrate here its preclinicalin vivoimplementation with a protocol of 389 contrast images probing a wide diffusion frequency range of 18 to 92 Hz atb-values up to 2.1 ms/µm2enabled by the use of modulated gradient waveforms and combined with multislice high-resolution and low-distortion EPI acquisition with segmented and full reversed phase-encode acquisition. This framework allows the identification of diffusionω-dependence in the rat cerebellum and olfactory bulb gray matter (GM) and the parameter distributions are shown to resolve two water pools in GM with different diffusion coefficients, shapes,ω-dependence, relaxation rates, and spatial repartition whose attribution to specific microstructure could modify the current understanding of the origin of restriction in GM.
A 20+ Ma old enamel proteome from Canada’s High Arctic reveals diversification of Rhinocerotidae in the middle Eocene-Oligocene
Authors: Paterson Ryan S. , Mackie Meaghan , Capobianco Alessio , Heckeberg Nicola S. , Fraser Danielle , Munir Fazeelah , Patramanis Ioannis , Ramos-Madrigal Jazmín , Liu Shanlin , Ramsøe Abigail D. , Dickinson Marc R. , Baldreki Chloë , Gilbert Marisa , Sardella Raffaele , Bellucci Luca , Scorrano Gabriele , Racimo Fernando , Willerslev Eske , Penkman Kirsty E.H. , Olsen Jesper V. , MacPhee Ross D.E. , Rybczynski Natalia , Höhna Sebastian , Cappellini Enrico
Published: June 2024

In the past decade, ancient protein sequences have emerged as a valuable source of data for deep-time phylogenetic inference. Still, the recovery of protein sequences providing novel phylogenetic insights does not exceed 3.7 Ma (Pliocene). Here, we push this boundary back to 21-24 Ma (early Miocene), by retrieving enamel protein sequences of an early-diverging rhinocerotid (Epiaceratheriumsp. - CMNF-59632) from the Canadian High Arctic. We recover partial sequences of seven enamel proteins (AHSG, ALB, AMBN, AMELX, AMTN, ENAM, MMP20) and over 1000 peptide-spectrum matches, spanning over at least 251 amino acids. Authentic endogeneity of these sequences is supported by indicators of protein damage, including several spontaneous and irreversible post-translational modifications accumulated during prolonged diagenesis and reaching near-complete occupancy at many sites. Bayesian tip-dating, across 15 extant and extinct perissodactyl taxa, places the divergence time of CMNF-59632 in the middle Eocene-Oligocene, and identifies a later divergence time for Elasmotheriinae in the Oligocene. The finding weakens alternative models suggesting a deep basal split between Elasmotheriinae and Rhinocerotinae. This divergence time of CMNF-59632 coincides with a phase of high diversification of rhinocerotids, and supports a Eurasian origin of this clade in the late Eocene or Oligocene. The findings are consistent with previous hypotheses on the origin of the enigmatic fauna of the Haughton crater, which, in spite of their considerable degree of endemism, also display similarity to distant Eurasian faunas. Our findings demonstrate the potential of palaeoproteomics in obtaining phylogenetic information from a specimen that is ten times older than any sample from which endogenous DNA has been obtained.
Maternal Immune Activation imprints translational dysregulation and differential MAP2 phosphorylation in descendant neural stem cells
Authors: Martín-Guerrero Sandra M. , Martín-Estebané María , Lara Ordóñez Antonio J. , Cánovas Miguel , Martín-Oliva David , González-Maeso Javier , Cutillas Pedro R. , López-Giménez Juan F.
Published: June 2024

Alterations induced by maternal immune activation (MIA) during gestation impact the subsequent neurodevelopment of progeny, a process that in humans, has been linked to the development of several neuropsychiatric conditions. To undertake a comprehensive examination of the molecular mechanisms governing MIA, we have devised an in vitro model based on neural stem cells (NSCs) sourced from fetuses carried by animals subjected to Poly I:C treatment. These neural progenitors demonstrate proliferative capacity and can be effectively differentiated into both neurons and glial cells. Transcriptomic, proteomic, and phosphoproteomic analyses conducted on these cellular models, in conjunction with counterparts from control treatments, revealed discernible shifts in the expression levels of a specific subset of proteins implicated in neuronal function. Noteworthy, we found an absence of congruence between these alterations at the transcriptomic level, suggesting that differences in protein translation contribute to the observed dysregulation. Furthermore, the phosphoproteomic data highlighted a discernible discrepancy in the basal phosphorylation of proteins between differentiated cells from both experimental groups, particularly within proteins associated with cytoskeletal architecture and synaptic functionality, notably those belonging to the MAP family. Observed alterations in MAP phosphorylation were found to potentially have functional consequences as they correlate with changes in neuronal plasticity and the establishment of neuronal synapses. Our data agrees with previous published observations and further underscore the importance of MAP2 phosphorylation state on its function and the impact that this protein has in neuronal structure and function.
Opportunities to improve the recommendation of plant varieties under the Recommended List (RL) system
Authors: Yang Chin Jian , Russell Joanne , Mackay Ian , Powell Wayne
Published: June 2024

Recommended List (RL) is the UK plant variety recommendation system introduced in 1944 for supporting growers in making decisions on variety choices. The current analysis for RL is largely based on published works on trial designs and statistical analyses in the 1980s. Given the statistical advances that have been developed and adopted elsewhere, it is timely to review and update the methods for data analysis in RL. In addition, threats from climate change challenge the prediction of variety performance in future environments. Better variety recommendations, particularly for matching varieties to specific environments can be achieved through improved modeling of effects from genetics, environments and genetic by environment interactions. Here, we evaluated grain yield data from 153 spring barley varieties that were trialed for RL from 2002 to 2019. Our results show that the available methods for predicting variety performance are poor and inconsistent across environments without any clearly superior method. However, these shortcomings can be easily overcome by switching the statistical model for analyzing RL data to one that fits variety effects as random and accounts for genetic relationships among varieties. Lastly, we also discuss other possible approaches for analyzing RL data and highlight the relevance of genomics in both variety registration and recommendation.
The Association between the JAK-STAT Pathway and Hypertension among Kenyan Women Diagnosed with Breast Cancer
Authors: Gitau John , Kinyori Godfrey , Sayed Shahin , Saleem Mohammad , Makokha Francis W , Kirabo Annet
Published: June 2024

Background

Breast cancer is the most common malignant tumor in women worldwide, and disproportionately affects Sub-Saharan Africa compared to high income countries. The global disease burden is growing, with Sub-Saharan Africa reporting majority of the cases. In Kenya, breast cancer is the most commonly diagnosed cancer, with an annual incidence of 7,243 new cases in 2022, representing 25.5% of all reported cancers in women. Evidence suggests that women receiving breast cancer treatment are at a greater risk of developing hypertension than women without breast cancer. Hypertension prevalence has been on the rise in SSA, with poor detection, treatment and control. The JAK-STAT signaling is activated in hormone receptor-positive breast tumors, leading to inflammation, cell proliferation, and treatment resistance in cancer cells. We sought to understand the association between the expression of JAK-STAT Pathway genes and hypertension among Kenyan women diagnosed with breast cancer.

Methods

Breast tumor and non-tumor tissues were acquired from patients with a pathologic diagnosis of invasive breast carcinoma. RNA was extracted from fresh frozen tumor and adjacent normal tissue samples of 23 participants who had at least 50% tumor after pathological examination, as well as their corresponding adjacent normal samples. Differentially expressed JAK-STAT genes between tumor and normal breast tissues were assessed using the DESEq2 R package. Pearson correlation was used to assess the correlation between differentially expressed JAK-STAT genes and participants’ blood pressure, heart rate, and body mass index (BMI).

Results

11,868 genes were differentially expressed between breast tumor and non-tumor tissues. Eight JAK-STAT genes were significantly dysregulated (Log2FC ≥ 1.0 and an Padj ≤ 0.05), with two genes (CISH and SCNN1A) being upregulated. Six genes (TGFBR2, STAT5A, STAT5B, TGFRB3, SMAD9, and SOCS2) were downregulated. We identified STAT5A and SOCS2 genes to be significantly correlated with elevated systolic pressure and heart rate, respectively.

Conclusions

Our study provides insights underlying the molecular mechanisms of hypertension among Kenyan women diagnosed with breast cancer. Understanding these mechanisms may help develop targeted treatments that may improve health outcomes of Kenyan women diagnosed with breast cancer. Longitudinal studies with larger cohorts will be needed to validate our results.
Optimization of systemic AAV9 gene therapy in Niemann-Pick disease type C1 mice
Authors: Mylvara Avani V. , Gibson Alana L. , Gu Tansy , Davidson Cristin D. , Incao Art A. , Melnyk Katerina , Pierre-Jacques Dominick , Cologna Stephanie M. , Venditti Charles P. , Porter Forbes D. , Pavan William J.
Published: June 2024

Niemann-Pick disease, type C1 (NPC1) is a rare, fatal neurodegenerative disorder caused by pathological variants inNPC1, which encodes a lysosomal cholesterol transport protein. There are no FDA approved treatments for this disorder. Both systemic and central nervous system delivery of AAV9-hNPC1have shown significant disease amelioration in NPC1 murine models. To assess the impact of dose and window of therapeutic efficacy inNpc1m1Nmice, we systemically administered three different doses of AAV9-hNPC1at 4 weeks old and the medium dose at pre-, early, and post-symptomatic timepoints. Higher vector doses and treatment earlier in life were associated with enhanced transduction in the nervous system and resulted in significantly increased lifespan. Similar beneficial effects were noted after gene therapy inNpc1I1061Tmice, a model that recapitulates a common human hypomorphic variant. Our findings help define dose ranges, treatment ages, and efficacy in severe and hypomorphic models of NPC1 deficiency and suggest that earlier delivery of AAV9-hNPC1in a pre-symptomatic disease state is likely to yield optimal outcomes in individuals with NPC1.

Summary Blurb

Systemic AAV9-hNPC1gene therapy in nullNpc1m1Nmice at higher doses or with earlier administration and treatment of hypomorphicNpc1I1061Tmice delays disease progression and increases lifespan.
Multimodal framework to resolve variants of uncertain significance inTSC2
Authors: Biar Carina G , Pfeifer Cole , Carvill Gemma L , Calhoun Jeffrey D
Published: June 2024

Efforts to resolve the functional impact of variants of uncertain significance (VUS) have lagged behind the identification of new VUS; as such, there is a critical need for scalable VUS resolution technologies. Computational variant effect predictors (VEPs), once trained, can predict pathogenicity for all missense variants in a gene, set of genes, or the exome. Existing tools have employed information on known pathogenic and benign variants throughout the genome to predict pathogenicity of VUS. We hypothesize that taking a gene-specific approach will improve pathogenicity prediction over globally-trained VEPs. We tested this hypothesis using the geneTSC2, whose loss of function results in tuberous sclerosis, a multisystem mTORopathy affecting about 1 in 6,000 individuals born in the United States.TSC2has been identified as a high-priority target for VUS resolution, with (1) well-characterized molecular and patient phenotypes associated with loss-of-function variants, and (2) more than 2,700 VUS already documented in ClinVar. We developedTuberous sclerosis classifier toResolve variants ofUncertainSignificance inTSC2(TRUST), a machine learning model to predict pathogenicity ofTSC2missense VUS. To test whether these predictions are accurate, we further introduce curated loci prime editing (cliPE) as an accessible strategy for performing scalable multiplexed assays of variant effect (MAVEs). Using cliPE, we tested the effects of more than 200TSC2variants, including 106 VUS. It is highly likely this functional data alone would be sufficient to reclassify 92 VUS with most being reclassified as likely benign. We found that TRUST’s classifications were correlated with the functional data, providing additional validation for thein silicopredictions. We provide our pathogenicity predictions and MAVE data to aid with VUS resolution. In the near future, we plan to host these data on a public website and deposit into relevant databases such as MAVEdb as a community resource. Ultimately, this study provides a framework to complete variant effect maps ofTSC1andTSC2and adapt this approach to other mTORopathy genes.
Combining supervised and unsupervised analyses to quantify behavioral phenotypes and validate therapeutic efficacy in a triple transgenic mouse model of Alzheimer’s disease
Authors: Del Rosario Hernandez Thais , Joshi Narendra R. , Gore Sayali V. , Kreiling Jill A. , Creton Robbert
Published: June 2024

Behavioral testing is an essential tool for evaluating cognitive function and dysfunction in preclinical research models. This is of special importance in the study of neurological disorders such as Alzheimer’s disease. However, the reproducibility of classic behavioral assays is frequently compromised by interstudy variation, leading to ambiguous conclusions about the behavioral markers characterizing the disease. Here, we identify age- and genotype-driven differences between 3xTg-AD and non-transgenic control mice using a low-cost, highly customizable behavioral assay that requires little human intervention. Through behavioral phenotyping combining both supervised and unsupervised behavioral classification methods, we are able to validate the preventative effects of the immunosuppressant cyclosporine A in a rodent model of Alzheimer’s disease, as well as the partially ameliorating effects of candidate drugs nebivolol and cabozantinib.

Abstract Figure
The transient and dynamic nature of splitter cells derive from behavior
Authors: Chaix-Eichel Naomi , Dagar Snigdha , Alexandre Fréderic , Boraud Thomas , Rougier Nicolas P.
Published: June 2024

Over the past decades, the hippocampal formation has undergone extensive studies leading researchers to identify a vast collection of cells with functional properties. The origin of such cells has been the topic of several investigations complemented with carefully crafted models whose latest hypothesized the role of temporal sequences to be the probable cause of observed spatial properties. We aim at investigating whether a random recurrent structure is sufficient to allow for such latent sequence to appear. To do so, we simulated an agent with egocentric sensory inputs that must navigate and alternate choices at intersections. We were subsequently able to identify several splitter cells inside the model. Lesioning those cells induce the incapacity for the agent to solve the task unless some hyper-parameters are tuned. In such case, new splitter cells appear even though the initial structure of the networks has been conserved. These results tend to show that splitter cells activity may appear spontaneously inside a random reccurrent network as long as the agent is performing the alternating task. These results may also modify our view regarding the origin on splitter cells. They are not the cause nor the consequence of learning and behavior.
Activation of three targets by a TAL effector confers susceptibility to bacterial blight of cotton
Authors: Mormile Brendan , Bauer Taran , Wang Li , Rivero Rachel , Carpenter Sara C.D. , Danmaigona-Clement Catherine , Cox Kevin , Zhang Lin , Ma Xiyu , Wheeler Terry A. , Dever Jane K. , He Ping , Bogdanove Adam J. , Shan Libo
Published: June 2024

Xanthomonasspp. employ transcription activator-like effectors (TALEs) to promote pathogenicity by activating host susceptibility (S) genes. CottonGhSWEET10is anSgene targeted by a TALE in an early isolate ofXanthomonas citripv.malvacearum(Xcm), but not by recent fieldXcmisolates. To understand the pathogenicity shift inXcmand its adaptation to cotton, we assembled the whole genome and the TALE repertoire of three recentXcmTexas field isolates. A newly evolved TALE, Tal7b, activated differentGhSWEETgenes,GhSWEET14aandGhSWEET14b. Simultaneous activation ofGhSWEET14aandGhSWEET14bresulted in pronounced water-soaked lesions. Transcriptome profiling coupled with TALE-binding element prediction identified a pectin lyase as an additional Tal7b target, quantitatively contributing toXcmvirulence alongsideGhSWEET14a/b. CRISPR-Cas9-based gene editing supported the function ofGhSWEETsasSgenes in cotton bacterial blight and the promise of disrupting the TALE-binding site in these genes to control the disease. Collectively, our findings elucidate the rapid evolution of TALEs inXanthomonasfield isolates and highlight the virulence mechanism wherein TALEs induce multipleSgenes simultaneously to promote pathogenicity.
A cognitive process model captures near-optimal confidence-guided waiting in rats
Authors: Boyd-Meredith J Tyler , Piet Alex T , Kopec Chuck D , Brody Carlos D
Published: June 2024

Rational decision-makers invest more time pursuing rewards they are more confident they will eventually receive. A series of studies have therefore used willingness to wait for delayed rewards as a proxy for decision confidence. However, interpretation of waiting behavior is limited because it is unclear how environmental statistics influence optimal waiting, and how sources of internal variability influence subjects’ behavior. We trained rats to perform a confidence-guided waiting task, and derived expressions for optimal waiting that make relevant environmental statistics explicit, including travel time incurred traveling from one reward opportunity to another. We found that rats waited longer than fully optimal agents, but that their behavior was closely matched by optimal agents with travel times constrained to match their own. We developed a process model describing the decision to stop waiting as an accumulation to bound process, which allowed us to compare the effects of multiple sources of internal variability on waiting. Surprisingly, although mean wait times grew with confidence, variability did not, inconsistent with scalar invariant timing, and best explained by variability in the stopping bound. Our results describe a tractable process model that can capture the influence of environmental statistics and internal sources of variability on subjects’ decision process during confidence-guided waiting.
Novel Behavioral Assays Reveal Sex Specific Behavioral Syndromes in Anemonefish
Authors: Graham Gabriel J. , Wilton Isabella M. , Panczyk Emily K. , Rhodes Justin S.
Published: June 2024

Sexually dimorphic behaviors are common across taxa, particularly in the contexts of parental care and territorial aggression. The false clown anemonefishAmphiprion ocellarisis unique among animals for its combination of female behavioral dominance and territoriality, protandrous sex change, and mutualistic symbiosis with sea anemones. Several laboratory studies have begun characterizing sex differences in parental care and aggression in this species, but aggression assays have mostly focused on intra-specific aggression where individual differences are large. The goals of this study were to expand the repertoire of behavioral assays available forA. ocellaris, establish repeatability of individual differences, identify assays that produce the most robust sex differences, and explore whether individual differences in correlated behaviors can be detected consistently across experimental contexts (i.e., whether behavioral syndromes can be detected). To this end, we measured 39 behaviors across 7 behavioral assays (parental care, large intruder aggression, small intruder aggression, male-oriented aggression, female-oriented aggression, immediate reaction to a threat, and nest maintenance) in 9 reproductively activeA. ocellarispairs under 3 different contexts (without eggs in the nest, with their own eggs, and with surrogate eggs). Behaviors were repeatedly measured three separate times (rounds) over repeated spawning cycles. We found 34 out of 39 behaviors were significantly individually repeatable across egg contexts and rounds, with an average intra-class correlation of 0.33. We found parental care, large intruder aggression, and female-oriented aggression assays produced the largest sex differences. Males performed 7-fold more egg care behaviors than females, while females performed 3.5-fold more aggressive behaviors toward a large interspecific intruder. Further, females bit, chased and struck the female intruder 6.5, 4.1, and 3.2 times as many times as males did. Five different behavioral syndromes were observed in males but only one was observed in females. These results expand our understanding of sex differences in behavior and the division of labor in the iconic anemonefish. Future studies can use these assays to measure the behavioral sex of fish in the middle of sex change, in the study of behavioral plasticity, or in the study of the neuroendocrine bases of aggression and parental care in this unique species.
Ribosome-Associated Vesicles promote activity-dependent local translation
Authors: Martin-Solana Eva , Carter Stephen D. , Donahue Eric K.F. , Ning Jiying , Glausier Jill R. , Preisegger Matias A. , Eisenman Leanna , Joseph Paul N. , Bouchet-Marquis Cedric , Wu Ken , Mobini Catherina L. , Frantz Amber N. , Puig Stephanie , Hampton Cheri M. , Kabbani Nadine , Jensen Grant J. , Watkins Simon C. , Deisseroth Karl , Fenno Lief E. , Gold Michael S. , Wills Zachary P. , Burkewitz Kristopher , Das Sulagna , Freyberg Zachary
Published: June 2024

Local protein synthesis in axons and dendrites underpins synaptic plasticity. However, the composition of the protein synthesis machinery in distal neuronal processes and the mechanisms for its activity-driven deployment to local translation sites remain unclear. Here, we employed cryo-electron tomography, volume electron microscopy, and live-cell imaging to identify Ribosome-Associated Vesicles (RAVs) as a dynamic platform for moving ribosomes to distal processes. Stimulation via chemically-induced long-term potentiation causes RAV accumulation in distal sites to drive local translation. We also demonstrate activity-driven changes in RAV generation and dynamicsin vivo, identifying tubular ER shaping proteins in RAV biogenesis. Together, our work identifies a mechanism for ribosomal delivery to distal sites in neurons to promote activity-dependent local translation.
The Pangenome ofEscherichia coli
Authors: Chauhan Siddharth M. , Ardalani Omid , Hyun Jason C. , Monk Jonathan M. , Phaneuf Patrick V. , Palsson Bernhard O.
Published: June 2024

Thousands of complete genome sequences for strains of a species that are now available enable the advancement of pangenome analytics to a new level of sophistication. We collected 2,377 publicly-available complete genomes ofEscherichia colifor detailed pangenome analysis. The core genome and accessory genomes consisted of 2,398 and 5,182 genes, respectively. We developed a machine learning approach to define the accessory genes characterizing the major phylogroups ofE. coliplus Shigella: A, B1, B2, C, D, E, F, G, and Shigella. The analysis resulted in a detailed structure of the genetic basis of the phylogroups’ differential traits. This pangenome structure was largely consistent with a housekeeping-gene-based MLST distribution, sequence-based Mash distance, and the Clermont quadruplex classification. The rare genome consisted of 163,619 genes, about 79% of which represented variations of 315 underlying transposon elements. This analysis generated a mathematical definition of the genetic basis for a species.
Menstrual cycle phase modulates causal connectivity in the resting-state brain of healthy females
Authors: Mcleod J. , Sattari S. , Chavan A. , Galea L. A.M. , Babul S. , Virji-Babul N.
Published: June 2024

Background

Ovarian hormones exert direct and indirect influences on the brain; however, little is known about how these hormones impact causal brain connectivity. Studying the female brain at a single time point may be confounded by distinct hormone phases. Despite this, the menstrual cycle is often overlooked. The primary objective of this pilot study was to evaluate resting-state causal connectivity during the early follicular and mid-luteal menstrual phases corresponding to lowvshigh estradiol and progesterone, respectively.

Methods

Fourteen healthy control females (M= 20.36 years,SD =2.02) participated in this study. Participants were scheduled for two resting-state electroencephalography (EEG) scans during their monthly menstrual cycle. A saliva sample was also collected at each EEG session for hormone analyses. Causal connectivity was quantified using information flow rate of EEG source data. Demographic information, emotional empathy, and sleep quality were obtained from self-report questionnaires.

Results

Progesterone levels were significantly higher in the mid-luteal phase compared to the early follicular phase (p= .041). We observed distinct patterns of causal connectivity along the menstrual cycle. Connectivity in the early follicular phase was centralized and shifted posteriorly during the mid-luteal phase. During the early follicular phase, the primary regions driving activity were the right central and left/right parietal regions, with the left central region being the predominant receiver of activity. During the mid-luteal phase, connections were primarily transmitted from the right side and the main receiver region was the left occipital region. Network topology during the mid-luteal phase was found to be significantly more assortative compared to the early follicular phase.

Conclusions

The observed difference in causal connectivity demonstrates how network dynamics reorganize as a function of menstrual phase and level of progesterone. In the mid-luteal phase, there was a strong shift for information flow to be directed at visual spatial processing and visual attention areas, whereas in the follicular phase, there was strong information flow primarily within the sensory-motor regions. The mid-luteal phase was significantly more assortative, suggesting greater network efficiency and resilience. These results contribute to the emerging literature on brain-hormone interactions.
MITOCHONDRIAL ANTIVIRAL PATHWAYS CONTROL ANTI-HIV RESPONSES AND ISCHEMIC STROKE OUTCOMES VIA THE RIG-1 SIGNALING AND INNATE IMMUNITY MECHANISMS
Authors: Torices Silvia , Moreno Thaidy , Ramaswamy Sita , Naranjo Oandy , Teglas Timea , Osborne Olivia M. , Park Minseon , Sun Enze , Toborek Michal
Published: June 2024

Occludin (ocln) is one of the main regulatory cells of the blood-brain barrier (BBB). Ocln silencing resulted in alterations of the gene expression signatures of a variety of genes of the innate immunity system, including IFN-stimulated genes (ISGs) and the antiviral retinoic acid-inducible gene-1 (RIG-1) signaling pathway, which functions as a regulator of the cytoplasmic sensors upstream of the mitochondrial antiviral signaling protein (MAVS). Indeed, we observed dysfunctional mitochondrial bioenergetics, dynamics, and autophagy in our system. Alterations of mitochondrial bioenergetics and innate immune protection translated into worsened ischemic stroke outcomes in EcoHIV-infected ocln deficient mice. Overall, these results allow for a better understanding of the molecular mechanisms of viral infection in the brain and describe a previously unrecognized role of ocln as a key factor in the control of innate immune responses and mitochondrial dynamics, which affect cerebral vascular diseases such as ischemic stroke.
Social valence dictates sex differences in identity recognition
Authors: Larosa Amanda , Xu Qi Wei , Wong Alice S. , Lee J. Quinn , Brandon Mark P. , Wong Tak Pan
Published: June 2024

Social valence is the directional emotional significance affiliated with social experiences. Maladaptive processing of negative social valence (NSV) has been linked to mood disorder susceptibility, which is more prevalent in women. To determine whether there are sex differences in NSV processing, we developed social valence tasks where the identity recognition of conspecifics with distinct valences served as the readout. Male mice demonstrated identity recognition regardless of social valence. Conversely, female mice did not show identity recognition following the NSV task.In vivocalcium imaging of the dorsal CA1 further revealed sex differences in NSV processing with reduced hippocampal representation of social information in female mice. These results suggest the imprecise encoding of NSV may contribute to the heightened vulnerability to social stress-related mood disorders in women.
KidneyChain: Leveraging Blockchain & Artificial Intelligence for a Streamlined Organ Donation Solution
Authors: Panda Kapil , Mazumder Anirudh
Published: June 2024

Currently the kidney organ transplantation process is a manual and cumbersome process, resulting in organ wastage and reoccurring issues in patients due to a lack of organ health screening prior to transplantation. To solve these issues in the industry, we utilize blockchain technology and artificial intelligence to create a streamlined kidney transplantation process. Utilizing blockchain technology, we automated the organ matching process, and matched donors and patients based on the same metrics that UNOS clinicians use, resulting in efficient and faster matching. Furthermore, using artificial intelligence, we created a model with perfect accuracy that screens organs pre-transplantation to predict possible risk for common kidney diseases such as chronic kidney disease(CKD), acute kidney injury(AKI), and polycystic kidney disease(PKD), to prevent recurring issues in patients, post-transplantation. Furthermore, a tapped delay line convolutional neural network provides cybersecurity by identifying valid blockchain transactions from fake patterns with 100% accuracy, ensuring full data privacy. By synergizing blockchain, AI, and cybersecurity, this research creates an efficient, secure platform that could expand patient access to life-saving transplants, prevent transplant failures, and save thousands of lives currently lost due to inefficiencies and wait times.
Pou4F2/Brn3B Overexpression Promotes the Genesis of Retinal Ganglion Cell-Like Projection Neurons from Late Progenitors
Authors: Oliveira-Valença V.M. , Roberts J.M , Fernandes-Cerqueira V.M. , Colmerauer C.H. , Toledo B.C. , Santos-França P.L. , Linden R. , Martins R.A.P. , Rocha-Martins M , Bosco A. , Vetter M.L. , Silveira M.S.
Published: June 2024

Retinal ganglion cells (RGCs) are the projection neurons of the retina. In early retinal progenitor cells (RPCs),Atoh7orchestrates the developmental RGC program and regulates the expression of critical downstream targets, includingPou4ffactors. The absence ofPou4f2or more POU4F family genes results in defects in RGC differentiation, aberrant axonal elaboration and ultimately RGC death, confirming the requirement of POU4F factors for RGC development and survival, with a critical role in regulating RGC axon outgrowth and pathfinding. Here, we investigatedin vivowhether ectopicPou4f2expression in late retinal progenitor cells (late RPCs) is sufficient to induce the generation of cells with RGC properties, including projecting axons to the brain. Using a strong ubiquitous promoter to inducePou4f2overexpression in neonates, we observed a change in targeted cell distribution in the retinal tissue, including the presence of cells in the ganglion cell layer and inner plexiform layer with high density of GFP+processes along the retina. Similar results on the induction of neuron processes were obtained when we overexpressedPou4f2inAtoh7knockout mice, suggesting that POU4F2 is sufficient to induce them. Single-cell RNA sequencing (scRNA-seq) analysis shows that several RGC-genes (such asRbpms,Gap-43,Hs6st3, andFoxp2) are upregulated afterPou4f2overexpression. Additionally, gene ontology analysis indicates the induction of genes related to axonogenesis and neuronal differentiation. Imaging throughout the visual pathway revealed high density of axons projecting toward the optic nerve head and extending to brain regions, such as the superior colliculus and geniculate nucleus. Thus,Pou4f2induced neurons with specific RGC characteristics that share similarities with resident RGCs and notably project axons that reach brain targets. In conclusion, these results showed that POU4F2 alone was sufficient to promote critical properties of projection neurons from retinal progenitors outside their developmental window.
Concurrent emergence of view invariance, sensitivity to critical features, and identity face classification through visual experience: Insights from deep learning algorithms
Authors: Rosemblaum Mandy , Guy Nitzan , Grosbard Idan , Kliger Libi , Abudarham Naphtali , Yovel Galit
Published: June 2024

Visual experience is known to play a critical role in face recognition. This experience is believed to enable the formation of a view-invariant representation, by learning which features are critical for face identification across views. Discovering these critical features and the type of experience that is needed to uncover them is challenging. We have recently revealed a subset of facial features that are critical for human face recognition. We further revealed that deep convolutional neural networks (DCNNs) that are trained on face classification, but not on object categorization, are sensitive to these facial features, highlighting the importance of experience with faces for the system to reveal these critical features. These findings enable us now to ask what type of experience with faces is required for the network to become sensitive to these human-like critical features and whether it is associated with the formation of a view-invariant representation and face classification performance. To that end, we systematically manipulated the number of within-identity and between-identity face images and examined its effect on the network performance on face classification, view-invariant representation, and sensitivity to human-like critical facial features. Results show that increasing the number of images per identity as well as the number of identities were both required for the simultaneous development of a view-invariant representation, sensitivity to human-like critical features, and successful identity classification. The concurrent emergence of sensitivity to critical features, view invariance and classification performance through experience implies that they depend on similar features. Overall, we show how systematic manipulation of the training diet of DCNNs can shed light on the role of experience on the generation of human-like representations.