bluuebunny/crossref_metadata_2025 huggingface dataset:
Acis-regulatory element regulatesERAP2expression through autoimmune disease risk SNPs
Authors: Venema Wouter J. , Hiddingh Sanne , van Loosdregt Jorg , Bowes John , Balliu Brunilda , de Boer Joke H. , Norel Jeanette Ossewaarde-van , Thompson Susan. D. , Langefeld Carl D. , van der Veken Lars T. , Sofiadis Konstantinos , Krijger Peter H.L. , de Laat Wouter , Kuiper Jonas J.W.
Published: March 2023

Single nucleotide polymorphisms (SNP) near theERAP2gene are associated with autoimmune conditions such asCrohn’s disease, andbirdshot chorioretinopathy, as well as protection against lethal infections, including theBlack Death. Due to high linkage disequilibrium (LD), a great number of trait-associated SNPs are correlated withERAP2expression, however their functional mechanisms remain unidentified. We used genome editing and functional genomics to identify causal variants that remain obscured by LD. We demonstrate by reciprocal allelic replacement thatERAP2expression is directly controlled by the genotype of splice region SNP rs2248374. However, we demonstrate that autoimmune disease-risk SNPs located near the downstreamLNPEPgene promoter are independently associated withERAP2expression. Allele-specific conformation capture assays revealed long-range chromatin contacts between theLNPEPpromoter region and theERAP2promoter and showed that interactions were stronger in patients carrying the alleles that increase susceptibility to autoimmune diseases. Replacing the disease-associated SNPs in theLNPEPpromoter by reference sequences loweredERAP2expression. These findings show that clustered GWAS signals associated with diverse autoimmune conditions and lethal infections act in concert to control ERAP2 expression and that disease-associated variants can convert a gene promoter region into a potent enhancer of a distal gene.
Amyloid fibril proteomics of AD brains reveals modifiers of aggregation and toxicity
Authors: Upadhyay Arun , Chhangani Deepak , Rao Nalini R. , Kofler Julia , Vassar Robert , Rincon-Limas Diego E. , Savas Jeffrey N.
Published: March 2023

Background

The accumulation of amyloid beta (Aβ) peptides in fibrils is prerequisite for Alzheimer’s disease (AD). Our understanding of the proteins that promote Aβ fibril formation and mediate neurotoxicity has been limited due to technical challenges in isolating pure amyloid fibrils from brain extracts.

Methods

To investigate how amyloid fibrils form and cause neurotoxicity in AD brain, we developed a robust biochemical strategy. We benchmarked the success of our purifications using electron microscopy, amyloid dyes, and a large panel of Aβ immunoassays. Tandem mass-spectrometry based proteomic analysis workflows provided quantitative measures of the amyloid fibril proteome. These methods allowed us to compare amyloid fibril composition from human AD brains, three amyloid mouse models, transgenic Aβ42 flies, and Aβ42 seeded cultured neurons.

Results

Amyloid fibrils are primarily composed by Aβ42 and unexpectedly harbor Aβ38 but generally lack Aβ40 peptides. Multidimensional quantitative proteomics allowed us to redefine the fibril proteome by identifying 17 new amyloid-associated proteins. Notably, we confirmed 126 previously reported plaque-associated proteins. We validated a panel of these proteins as bona fide amyloid-interacting proteins using antibodies and orthogonal proteomic analysis. One metal-binding chaperone metallothionein-3 is tightly associated with amyloid fibrils and modulates fibril formationin vitro.Lastly, we used a transgenic Aβ42 fly model to test if knock down or over-expression of fibril-interacting gene homologues modifies neurotoxicity. Eight RNAi lines suppressed and 11 enhanced Aβ42 toxicity.

Conclusions

These discoveries and subsequent confirmation indicate that fibril-associated proteins play a key role in amyloid formation and AD pathology.
PREMISE: A database of 20Macaca FascicularisPET/MRI brain imaging available for research
Authors: Chalet Lucie , Debatisse Justine , Wateau Oceane , Boutelier Timothe , Wiart Marlène , Costes Nicolas , Merida Ines , Redouté Jérôme , Langlois Jean-Baptiste , Lancelot Sophie , Léon Christelle , Cho Tae-Hee , Mechtouff Laura , Eker Omer Faruk , Nighoghossian Norbert , Canet-Soulas Emmanuelle , Becker Guillaume
Published: March 2023

Non-human primate (NHP) studies are unique in translational research, especially in neurosciences and neuroimaging approaches are a preferred method for scaling cross-species comparative neurosciences. In this regard, neuroimaging database development and sharing are encouraged to increase the number of subjects available to the community while limiting the number of animals used in research. We present here a simultaneous PET/MR dataset of 20 Macaca Fascicularis structured according to the Brain Imaging Data Structure (BIDS) standards. This database contains multiple MRI sequences (anatomical, diffusion and perfusion imaging notably), as well as PET perfusion and inflammation using respectively [15O]H2O and [11C]PK11195 radiotracers. We describe the pipeline method to assemble baseline data from various cohorts and qualitatively assessed all the data using signal-to-noise and contrast-to-noise ratios as well as the median of intensity. The database is stored and available through the PRIME-DE consortium repository.
Addition of adjuvant to DTaP modulates vaccine-induced immunological responses but is insufficient to improve protection in CD-1 mice
Authors: Weaver Kelly L. , Pyles Gage M. , Dublin Spencer R. , Huckaby Annalisa B. , Miller Sarah J. , Paz Gutierrez Maria De La , Sen-Kilic Emel , Witt William T. , Boehm Dylan T. , Damron F. Heath , Barbier Mariette
Published: March 2023

3.1

Pertussis is a vaccine-preventable respiratory disease caused by the Gram-negative bacteriumBordetella pertussis. While vaccination rates remain high in developed countries, incidence of pertussis has increased following the transition from wP vaccines to aP vaccines. The reemergence of pertussis is attributed, in part, to waning immunity induced by aP vaccination. Therefore, the objective of this work was to determine if addition of adjuvant to DTaP can modulate the immune response and improve protection compared to DTaP alone. In this study we immunized outbred, female CD-1 mice with 1/320ththe human dose of vehicle control, DTaP, and DTaP supplemented with adjuvant. Markers of early vaccine-induced memory were measured using a chemokine assay or by flow cytometry. Protection was assessed by measuring serological responses and quantifying bacterial burden in the respiratory tract at day 3 post-challenge. From this work we identified a partially protective aP vaccine dose to use for vaccination and challenge studies. We observed that MPLA and SWE promote robust anti-B. pertussisantibody responses and stimulate significant increases in early markers of vaccine-induced memory such as CXCL13, FDCs, and TFHcells. Quil-A induced Th1 responses compared to DTaP alone, but none of the adjuvants improved protection against challenge withB. pertussis. Overall, the data suggests that addition of adjuvant modulates the protective immune responses induced by aPs. Further studies are needed to evaluate the B cell compartment and longevity of protection.
Jedi-1/MEGF12-mediated phagocytosis controls the pro-neurogenic properties of microglia in the ventricular-subventricular zone
Authors: Morrison Vivianne E. , Houpert Matthew G. , Trapani Jonathan B. , Brockman Asa A. , Kingsley Philip J. , Katdare Ketaki A. , Layden Hillary M. , Nguena-Jones Gabriela , Trevisan Alexandra J. , Maguire-Zeiss Kathleen A. , Marnett Lawrence J. , Bixa Gregory J. , Ihrie Rebecca A. , Carter Bruce D.
Published: March 2023

Microglia are the primary phagocytes in the central nervous system and are responsible for clearing dead cells generated during development or disease. The phagocytic process shapes the phenotype of the microglia, which affects the local environment. A unique population of microglia reside in the ventricular-subventricular zone (V-SVZ) of neonatal mice, but how they influence this neurogenic niche is not well-understood. Here, we demonstrate that phagocytosis creates a pro-neurogenic microglial phenotype in the V-SVZ and that these microglia phagocytose apoptotic cells via the engulfment receptor Jedi-1. Deletion of Jedi-1 decreases apoptotic cell clearance, triggering the development of a neuroinflammatory phenotype, reminiscent of neurodegenerative and-age-associated microglia, that reduces neural precursor proliferation via elevated interleukin (IL)-1β signaling; inhibition of IL-1 receptor rescues precursor proliferation in vivo. Together, these results reveal a critical role for Jedi-1 in connecting microglial phagocytic activity to a phenotype that promotes neurogenesis in the developing V-SVZ.

Graphical Abstract. Jedi-1-dependent phagocytosis supports neurogenesis via suppression of microglial inflammatory pathway activation

Top: Wild-type Proliferative-zone-Associated Microglia (PAMs) (cyan) use the engulfment receptor Jedi-1 (‘Jedi’) to engulf apoptotic cells (yellow) in the neurogenic ventricular-subventricular zone (V-SVZ) of the early postnatal brain. Jedi activation supports neural precursor cell (NPC) proliferation and the generation of new neurons.

Bottom: Deletion of Jedi reduces microglial phagocytosis and transforms PAMs into Disease-associated Inflammatory Microglia (DIMs) characterized by the upregulation of canonical inflammatory genes and core DIM markers iden ified in the aging and neurodegenerative brain (Nlrp3, NLR family pyrin domain-containing 3; Tnf, tumor necrosis factor; Ccl4, C-C chemokine ligand 4 (also called macrophage inflammatory protein 1β); Ccr5, C-C chemokine receptor type 5). Increased interleukin-1β (IL-1β) synthesis, release, and signaling in the Jedi-null V-SVZ reduces NPC proliferation and newborn neuron number.

Highlights

The engulfment receptor Jedi-1 is expressed by microglia in the neonatal ventricular-subventricular zone (V-SVZ) neurogenic niche.

Jedi-1knockout microglia have decreased engulfment ability, resulting in accumulation of dead cells in the V-SVZ.

Loss ofJedi-1leads to a neuroinflammatory phenotype in microglia that is characteristic of neurodegenerative and age-associated microglia.

Microglial-specific loss ofJedi-1 reduces neurogenesis, which is rescuedin vivoby inhibition of interleukin-1β signaling.
Chiral flows in the separating wall during cell division
Authors: Ganguly Vijit , Chatterjee Mainak , Sain Anirban
Published: March 2023

Material flow in the acto-myosin cortex of a cell, during cell division, has been found to be chiral in nature. Here we look for possible signature of such chirality during the growth of the intra-cellular membrane partition which physically divides the cell into two compartments. Many groups have recorded this partition formation phenomenon in C. elegans embryo, in real time, using fluorescent microscopy. We analyze some of these movies using PIV technique in order to search for signatures of chirality in the acto-myosin flow field on this partition. Further, we use standard hydrodynamic theory of active gell to predict possible chiral flow structures in the growing partition. While the flows in the growing annular shaped membrane partition is mainly radially inward, it can also develop non zero azimuthal velocity components due to chirality.
State-dependent effectiveness of cathodal transcranial direct current stimulation on cortical excitability
Authors: Vergallito Alessandra , Varoli Erica , Pisoni Alberto , Mattavelli Giulia , Del Mauro Lilia , Feroldi Sarah , Vallar Giuseppe , Romero Lauro Leonor J.
Published: March 2023

The extensive use of transcranial direct current stimulation (tDCS) in experimental and clinical settings does not correspond to an in-depth understanding of its underlying neurophysiological mechanisms. In previous studies, we employed an integrated system of Transcranial Magnetic Stimulation and Electroencephalography (TMS-EEG) to track the effect of tDCS on cortical excitability. At rest, anodal tDCS (a-tDCS) over the right Posterior Parietal Cortex (rPPC) elicits a widespread increase in cortical excitability. In contrast, cathodal tDCS (c-tDCS) fails to modulate cortical excitability, being indistinguishable from sham stimulation.

Here we investigated whether an endogenous task-induced activation during stimulation might change this pattern, improving c-tDCS effectiveness in modulating cortical excitability.

In Study 1, we tested whether performance in a Visuospatial Working Memory Task (VWMT) and a modified Posner Cueing Task (mPCT), involving rPPC, could be modulated by c-tDCS. Thirty-eight participants were involved in a two-session experiment receiving either c-tDCS or sham during tasks execution. In Study 2, we recruited sixteen novel participants who performed the same paradigm but underwent TMS-EEG recordings pre- and 10 minutes post-sham and c-tDCS.

Behavioral results showed that c-tDCS significantly modulated mPCT performance compared to sham. At a neurophysiological level, c-tDCS significantly reduced cortical excitability in a frontoparietal network involved in task execution. Taken together, our results provide evidence of the state dependence of c-tDCS in modulating cortical excitability effectively. The conceptual and applicative implications are discussed.
Cell type-specific intracellular protein delivery with inactivated botulinum toxin
Authors: Roh Heegwang , Dorner Brigitte G. , Ting Alice Y.
Published: March 2023

The ability to deliver proteins and peptides across the plasma membrane into the cytosol of living mammalian cells would be highly impactful for both basic science and medicine. Natural cell-penetrating protein toxins have shown promise as protein delivery platforms but existing approaches are limited by immunogenicity, lack of cell type specificity, or their multicomponent nature. Here we explore inactivated botulinum toxin (BoNT) as a protein delivery platform. Using split luciferase reconstitution in the cytosol as a readout for endosomal escape and cytosolic delivery, we showed that BoNT chimeras with nanobodies replacing their natural receptor binding domain could be selectively targeted to cells expressing nanobody-matched surface markers. We used chimeric BoNTs to deliver a range of cargo from 1.3-55 kD, and demonstrated selective delivery of orthogonal cargoes to distinct cell populations within a heterogenous mixture. These explorations suggest that BoNT can be a versatile platform for targeted protein and peptide delivery into mammalian cells.
Alternative end-joining results in smaller deletions in heterochromatin relative to euchromatin
Authors: Miller Jacob M. , Prange Sydney , Ji Huanding , Rau Alesandra R. , Khodaverdian Varandt Y. , Li Xiao , Patel Avi , Butova Nadejda , Lutter Avery , Chung Helen , Merigliano Chiara , Rawal Chetan C. , Hanscom Terrence , McVey Mitch , Chiolo Irene
Published: March 2023

Pericentromeric heterochromatin is highly enriched for repetitive sequences prone to aberrant recombination. Previous studies showed that homologous recombination (HR) repair is uniquely regulated in this domain to enable ‘safe’ repair while preventing aberrant recombination. InDrosophilacells, DNA double-strand breaks (DSBs) relocalize to the nuclear periphery through nuclear actin-driven directed motions before recruiting the strand invasion protein Rad51 and completing HR repair. End-joining (EJ) repair also occurs with high frequency in heterochromatin of fly tissues, but how alternative EJ (alt-EJ) pathways operate in heterochromatin remains largely uncharacterized. Here, we induce DSBs in single euchromatic and heterochromatic sites using a new system that combines the DR-whitereporter and I-SceI expression in spermatogonia of flies. Using this approach, we detect higher frequency of HR repair in heterochromatin, relative to euchromatin. Further, sequencing of mutagenic repair junctions reveals the preferential use of different EJ pathways across distinct euchromatic and heterochromatic sites. Interestingly, synthesis-dependent microhomology-mediated end joining (SD-MMEJ) appears differentially regulated in the two domains, with a preferential use of motifs close to the cut site in heterochromatin relative to euchromatin, resulting in smaller deletions. Together, these studies establish a new approach to study repair outcomes in fly tissues, and support the conclusion that heterochromatin uses more HR and less mutagenic EJ repair relative to euchromatin.
Unsupervised decomposition of natural monkey behavior into a sequence of motion motifs
Authors: Mimura Koki , Matsumoto Jumpei , Mochihashi Daichi , Nakamura Tomoaki , Hirabayashi Toshiyuki , Higuchi Makoto , Minamimoto Takafumi
Published: March 2023

Nonhuman primates (NHPs) exhibit complex and diverse behavior that typifies advanced cognitive function and social communication, but quantitative and systematical measure of this natural nonverbal processing has been a technical challenge. Specifically, a method is required to automatically segment time series of behavior into elemental motion motifs, much like finding meaningful words in character strings. Here, we propose a solution called SyntacticMotionParser (SMP), a general-purpose unsupervised behavior parsing algorithm using a non-parametric Bayesian model. Using three-dimensional posture-tracking data from NHPs, SMP automatically outputs an optimized sequence of latent motion motifs classified into the most likely number of states. When applied to behavioral datasets from common marmosets and rhesus monkeys, SMP outperformed conventional posture-clustering models and detected a set of behavioral ethograms from publicly available data. SMP also quantified and visualized the behavioral effects of chemogenetic neural manipulations. SMP thus has the potential to dramatically improve our understanding of natural NHP behavior in a variety of contexts.
A redox-regulated, heterodimeric NADH:cinnamate reductase inVibrio ruber
Authors: Bertsova Yulia V. , Serebryakova Marina V. , Anashkin Victor A. , Baykov Alexander A. , Bogachev Alexander V.
Published: March 2023

Genes of putative reductases of α,β-unsaturated carboxylic acids are abundant among anaerobic and facultatively anaerobic microorganisms, yet substrate specificity has been experimentally verified for few encoded proteins. Here, we co-produced inEscherichia colione such protein of the marine bacteriumVibrio ruber(GenBank SJN56021; annotated as urocanate reductase) withVibrio choleraeflavin transferase. The isolated protein (named Crd) is a heterodimer of the SJN56021-encoded subunit CrdB (NADH:flavin, FAD binding 2, andFMN binddomains) and an additional subunit CrdA (SJN56019, a singleNADH:flavindomain) that interact via theirNADH:flavindomains (Alphafold2 prediction). Each domain contains a flavin group (three FMNs and one FAD in total), one of the FMN groups being linked covalently by the flavin transferase. Crd readily reduces cinnamate,p-coumarate, caffeate, and ferulate under anaerobic conditions with NADH or methyl viologen as the electron donor, is moderately active against acrylate and practically inactive against urocanate. The reduction reactions started by NADH demonstrated a time lag of several minutes, suggesting a redox regulation of Crd activity. The oxidized enzyme is inactive, which apparently prevents production of reactive oxygen species under aerobic conditions. Our findings identify Crd as a regulated NADH-dependent cinnamate reductase, apparently protectingV. ruberfrom cinnamate poisoning.

Abbreviated Summary

The genome of the marine bacteriumVibrio ruberencodes a heterodimeric NADH-dependent cinnamate reductase, apparently protectingV. ruberfrom poisoning by cinnamate and its derivatives. The reductase contains four flavin groups, one being linked covalently, and appears to be redox-regulated. Oxidized enzyme is inactive, which apparently prevents production of reactive oxygen species under aerobic conditions.
Brain areas for reversible symbolic reference, a potential singularity of the human brain
Authors: van Kerkoerle Timo , Pape Louise , Ekramnia Milad , Feng Xiaoxia , Tasserie Jordy , Dupont Morgan , Li Xiaolian , Jarraya Bechir , Vanduffel Wim , Dehaene Stanislas , Dehaene-Lambertz Ghislaine
Published: March 2023

The emergence of symbolic thinking has been proposed as a dominant cognitive criterion to distinguish humans from other primates during hominization. Although the proper definition of a symbol has been the subject of much debate, one of its simplest features is bidirectional attachment: the content is accessible from the symbol, and vice versa. Behavioural observations scattered over the past four decades suggest that this criterion might not be met in non-human primates, as they fail to generalise an association learned in one temporal order (A to B) to the reverse order (B to A). Here, we designed an implicit fMRI test to investigate the neural mechanisms of arbitrary audio-visual and visual-visual pairing in monkeys and humans and probe their spontaneous reversibility. After learning a unidirectional association, humans showed surprise signals when this learned association was violated. Crucially, this effect occurred spontaneously in both learned and reversed directions, within an extended network of high-level brain areas, including, but also going beyond, the language network. In monkeys, by contrast, violations of association effects occurred solely in the learned direction and were largely confined to sensory areas. We propose that a human-specific brain network may have evolved the capacity for reversible symbolic reference.
ProteinVAE: Variational AutoEncoder for Translational Protein Design
Authors: Lyu Suyue , Sowlati-Hashjin Shahin , Garton Michael
Published: March 2023

There have recently been rapid advances in deep learning models for protein design. To demonstrate proof-of-concept, these advancements have focused on small proteins with lots of data for training. This means that they are often not suitable for generating proteins with the most potential for high clinical impact –due to the additional challenges of sparse data and large size many therapeutically relevant proteins have. One major application that fits this category is gene therapy delivery. Viral vectors such as Adenoviruses and AAVs are a common delivery vehicle for gene therapy. However, environmental exposure means that most people exhibit potent pre-existing immune responses to many serotypes. This response, primarily driven by neutralizing antibodies, also precludes repeated administration with the same serotype. Rare serotypes, serotypes targeting other species, and capsid engineering, have all been deployed in the service of reducing neutralization by pre-existing antibodies. However, progress has been very limited using conventional methods and a new approach is urgently needed. To address this, we developed a variational autoencoder that can generate synthetic viral vector serotypes without epitopes for pre-existing neutralizing antibodies. A compact generative computational model was constructed, with only 12.4 million parameters that could be efficiently trained on the limited natural sequences (e.g., 711 natural Adenovirus hexon sequences with average length of 938 amino acids). In contrast to the current state-of-the-art, the model was able to generate high-quality Adenovirus hexon sequences that were folded with high confidence by Alphafold2 to produce structures essentially identical to natural hexon structures. Molecular dynamics simulations confirmed that the structures are stable and protein–protein interfaces are intact. Local secondary structure and local mobility is also comparable with natural serotype behavior. Our model could be used to generate a broad range of synthetic adenovirus serotype sequences without epitopes for pre-existing neutralizing antibodies in the human population. It could be used more broadly to generate different types of viral vector, and any large, therapeutically valuable proteins, where available data is sparse.
Chromatin binding by HORMAD proteins regulates meiotic recombination initiation
Authors: Milano Carolyn R. , Ur Sarah N. , Gu Yajie , Tromer Eelco C. , Zhang Jessie , Hochwagen Andreas , Corbett Kevin D.
Published: March 2023

The meiotic chromosome axis coordinates chromosome organization and interhomolog recombination in meiotic prophase and is essential for fertility. InS. cerevisiae, the HORMAD protein Hop1 mediates enrichment of axis proteins at nucleosome-rich genomic islands through a central chromatin-binding region (CBR). Here, we use cryoelectron microscopy to show that the Hop1 CBR directly recognizes bent nucleosomal DNA through a composite interface in its PHD and winged helix-turn-helix domains. Targeted disruption of the Hop1 CBR-nucleosome interface causes loss of axis proteins from nucleosome-rich islands, reduces meiotic DNA double-strand breaks (DSBs), and leads to defects in chromosome synapsis. Synthetic effects with the disassemblase Pch2 suggest that nucleosome binding delays a conformational switch in Hop1 from a DSB-promoting, Pch2-inaccessible state to a DSB-inactive, Pch2-accessible state to regulate the extent of meiotic DSB formation. Phylogenetic analyses of meiotic HORMADs reveal an ancient origin of this domain, suggesting that these mechanisms are broadly conserved.
Performance of ChatGPT on the MCAT: The Road to Personalized and Equitable Premedical Learning
Authors: Bommineni Vikas L , Bhagwagar Sanaea , Balcarcel Daniel , Davatzikos Christos , Boyer Donald
Published: March 2023

Despite an increasingly diverse population, an unmet demand for undergraduates from underrepresented racial and ethnic minority (URM) backgrounds exists in the field of medicine as a result of financial hurdles and insufficient educational support faced by URM students in the premedical journey. With the capacity to provide highly individualized and accessible no- or low-cost dynamic instruction, large language models (LLMs) and their chatbot derivatives are posed to change this dynamic and subsequently help shape a more diverse future physician workforce. While studies have established the passing performance and insightful explanations of one of the most accurate LLM-powered chatbots to date—Chat Generative Pre-trained Transformer (ChatGPT)—on standardized exams such as medical licensing exams, the role of ChatGPT in premedical education remains unknown. We evaluated the performance of ChatGPT on the Medical College Admission Test (MCAT), a standardized 230-question multiple choice exam that assesses a broad range of competencies in the natural, physical, social, and behavioral sciences as well as critical analysis and reasoning. Depending on its visual item response strategy, ChatGPT performed at or above the median performance of 276,779 student test takers on the MCAT. Additionally, ChatGPT-generated answers demonstrated both a high level of agreement with the official answer key as well as insight into its explanations. Based on these promising results, we anticipate two primary applications of ChatGPT and future LLM iterations in premedical education: firstly, such models could provide free or low-cost access to personalized and insightful explanations of MCAT competency-related questions to help students from all socioeconomic and URM backgrounds. Secondly, these models could be used to generate additional test questions by test-makers or for targeted preparation by pre-medical students. These applications of ChatGPT in premedical education could be an invaluable, innovative path forward to increase diversity and improve equity among premedical students.
Digitally Diagnosing Multiple Developmental Delays using Crowdsourcing fused with Machine Learning: A Research Protocol
Authors: Washington Peter
Published: March 2023

Background

Roughly 17% percent of minors in the United States aged 3 through 17 years have a diagnosis of one or more developmental or psychiatric conditions, with the true prevalence likely being higher due to underdiagnosis in rural areas and for minority populations. Unfortunately, timely diagnostic services are inaccessible to a large portion of the United States and global population due to cost, distance, and clinician availability. Digital phenotyping tools have the potential to shorten the time-to-diagnosis and to bring diagnostic services to more people by enabling accessible evaluations. While automated machine learning (ML) approaches for detection of pediatric psychiatry conditions have garnered increased research attention in recent years, existing approaches use a limited set of social features for the prediction task and focus on a single binary prediction.

Objective

I propose the development of a gamified web system for data collection followed by a fusion of novel crowdsourcing algorithms with machine learning behavioral feature extraction approaches to simultaneously predict diagnoses of Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD) in a precise and specific manner.

Methods

The proposed pipeline will consist of: (1) a gamified web applications to curate videos of social interactions adaptively based on needs of the diagnostic system, (2) behavioral feature extraction techniques consisting of automated ML methods and novel crowdsourcing algorithms, and (3) development of ML models which classify several conditions simultaneously and which adaptively request additional information based on uncertainties about the data.

Conclusions

The prospective for high reward stems from the possibility of creating the first AI-powered tool which can identify complex social behaviors well enough to distinguish conditions with nuanced differentiators such as ASD and ADHD.
Zfp106 binds to G-quadruplex RNAs and inhibits RAN translation and formation of RNA foci caused by G4C2 repeats
Authors: Celona Barbara , Wu Haifan , Dang Bobo , Kratochvil Huong T. , DeGrado William F. , Black Brian L.
Published: March 2023

Expansion of intronic GGGGCC repeats in theC9orf72gene causes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Transcription of the expanded repeats results in the formation of RNA-containing nuclear foci and altered RNA metabolism. In addition, repeat-associated non-AUG (RAN) translation of the expanded GGGGCC-repeat sequence results in the production of highly toxic dipeptide-repeat (DPR) proteins. GGGGCC-repeat-containing transcripts form G-quadruplexes, which are associated with formation of RNA foci and RAN translation. Zfp106, an RNA-binding protein essential for motor neuron survival in mice, suppresses neurotoxicity in aDrosophilamodel ofC9orf72ALS via a previously unknown mechanism. Here, we show that Zfp106 inhibits formation of RNA foci and significantly reduces RAN translation caused by GGGGCC-repeats in mammalian cells. Further, we show that Zfp106 binds to RNA G-quadruplexes and causes a conformational change in the G-quadruplex structure formed by GGGGCC-repeats. These data suggest that Zfp106 suppresses GGGGCC repeat-mediated cytotoxicity through alteration of the repeat’s G-quadruplex structure.
FBP1 is a nonenzymatic safety valve that curtails AKT activation to prevent insulin hyperresponsiveness
Authors: Gu Li , Zhu Yahui , Watari Kosuke , Lee Maiya , Liu Junlai , Perez Sofia , Thai Melinda , Mayfield Joshua , Zhang Bichen , Rocha Karina Cunha e , Li Fuming , Kim Laura C. , Jones Alexander C. , Wierzbicki Igor H , Liu Xiao , Newton Alexandra C. , Kisseleva Tatiana , Lee Jun Hee , Ying Wei , Gonzalez David J. , Saltiel Alan R. , Simon M. Celeste , Karin Michael
Published: March 2023

Insulin inhibits gluconeogenesis and stimulates glucose conversion to glycogen and lipids. How these activities are coordinated to prevent hypoglycemia and hepatosteatosis is not clear. Fructose-1,6 bisphosphatase (FBP1) is rate controlling for gluconeogenesis. However, inborn human FBP1 deficiency does not cause hypoglycemia unless accompanied by fasting or starvation, which also trigger paradoxical hepatomegaly, hepatosteatosis, and hyperlipidemia in affected individuals. Hepatocyte FBP1-ablated mice exhibit identical fasting-conditional pathologies along with AKT hyperactivation, whose inhibition reversed hepatomegaly, hepatosteatosis and hyperlipidemia but not hypoglycemia. Surprisingly, fasting-mediated AKT hyperactivation is insulin-dependent. FBP1 prevents insulin hyperresponsiveness, independently of its catalytic activity, by interacting with AKT, PP2A-C and Aldolase-B (ALDOB) to specifically accelerate AKT dephosphorylation. Enhanced by fasting and weakened by elevated insulin, FBP1:AKT:PP2A-C:ALDOB complex formation, which is disrupted by human FBP1 deficiency mutations or a C-terminal FBP1 truncation, prevents insulin-triggered liver pathologies and maintains lipid and glucose homeostasis. Conversely, a complex disrupting peptide reverses diet-induced insulin resistance.
Differential requirements for different subfamilies of the mammalian SWI/SNF chromatin remodeling enzymes in myoblast differentiation
Authors: Padilla-Benavides Teresita , Olea-Flores Monserrat , Sharma Tapan , Syed Sabriya A. , Witwicka Hanna , Zuñiga-Eulogio Miriam D. , Zhang Kexin , Navarro-Tito Napoleon , Imbalzano Anthony N.
Published: March 2023

Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodeling enzymes that are critical for normal cellular functions and that are mis-regulated in ∼20% of human cancers. These enzymes exhibit significant diversity in the composition of individual enzyme complexes. mSWI/SNF enzymes are classified into three general sub-families based on the presence or absence of specific subunit proteins. The three sub-families are called BAF (BRM or BRG1-associated factors), ncBAF (non-canonical BAF), and PBAF (Polybromo-associated BAF). The biological roles for the different subfamilies of mSWI/SNF enzymes are poorly described. We knocked down (KD) the expression of genes encoding subunit proteins unique to each of the three subfamilies,Baf250A, Brd9, andBaf180, which mark the BAF, ncBAF, and PBAF sub-families, respectively, and examined the requirement for each in myoblast differentiation. We found that BAF250A and the BAF complex was required to drive lineage-specific gene expression during myoblast differentiation. KD ofBaf250Areduced the expression of the lineage determinantMyogeninand other differentiation markers, due to decreased binding of BAF250A to myogenic gene promoters. KD ofBrd9delayed myoblast differentiation. However, RNA-seq analysis revealed that while theBaf250A-dependent gene expression profile included genes involved in myogenesis, theBrd9-dependent gene expression profile did not. Moreover, no-colocalization of Baf250A and Brd9 was observed in differentiating cells, suggesting independent mechanisms of action for BAF and ncBAF complexes in myogenesis. The PBAF complex was dispensable for myoblast differentiation. The results distinguish between the roles of the mSWI/SNF enzyme subfamilies during myoblast differentiation.
Transcription factor interactions explain the context-dependent activity of CRX binding sites
Authors: Loell Kaiser J. , Friedman Ryan Z. , Myers Connie A. , Corbo Joseph C. , Cohen Barak A. , White Michael A.
Published: March 2023

The effects of transcription factor binding sites (TFBSs) on the activity of acis-regulatory element (CRE) depend on the local sequence context. In rod photoreceptors, binding sites for the transcription factor (TF) Cone-rod homeobox (CRX) occur in both enhancers and silencers, but the sequence context that determines whether CRX binding sites contribute to activation or repression of transcription is not understood. To investigate the context-dependent activity of CRX sites, we fit neural network-based models to the activities of synthetic CREs composed of photoreceptor TFBSs. The models revealed that CRX binding sites consistently make positive, independent contributions to CRE activity, while negative homotypic interactions between sites cause CREs composed of multiple CRX sites to function as silencers. The effects of negative homotypic interactions can be overcome by the presence of other TFBSs that either interact cooperatively with CRX sites or make independent positive contributions to activity. The context-dependent activity of CRX sites is thus determined by the balance between positive heterotypic interactions, independent contributions of TFBSs, and negative homotypic interactions. Our findings explain observed patterns of activity among genomic CRX-bound enhancers and silencers, and suggest that enhancers may require diverse TFBSs to overcome negative homotypic interactions between TFBSs.
Rapid generation ofC. eleganssingle copy transgenes combining RMCE and drug selection
Authors: Nonet Michael L.
Published: March 2023

I outline a streamlined method to create single copy large genomic insert transgenes using Recombination-Mediated Cassette Exchange (RMCE) that relies solely on drug selection yielding a homozygous fluorescent protein (FP) marked transgene in 3 generations (8 days) at high efficiency (>1 insertion per 2 injected P0 animals). Landing sites for this approach are available on four chromosomes in several configurations which yield lines marked in distinct cell types. An array of vectors permit creating transgenes using a variety of selection methods (HygR, NeoR, PuroR, unc-119(+)) that yield lines expressing different colored FP tagged lines (BFP, GFP, mNG, andScarlet). Although these transgenes retain a plasmid backbone and a selection marker, the inclusion of these sequences typically does not alter the expression of several cell specific promoters tested. However, in certain orientations promoters exhibits crosstalk with adjacent transcription units. In cases where crosstalk is problematic, theloxP-flanked fluorescent marker, plasmid backbone andhygRgene can be excised by crossing through germline Cre expressing lines also created using this technique. Finally, genetic and molecular reagents designed to facilitate customization of both targeting vectors and landing sites are also described. Together, the rRMCE toolbox provides a platform for developing further innovative uses of RMCE to create complex genetically engineered tools.
Intra and interspecific diversity in a tropical plant clade alter herbivory and ecosystem resilience
Authors: Grele Ari J. , Massad Tara J. , Uckele Kathryn A. , Dyer Lee A. , Antonini Yasmine , Braga Laura , Forister Matthew L. , Sulca Lidia , Kato Massuo J. , Lopez Humberto G. , Nascimento Andre R. , Parchman Thomas L. , Simbaña Wilmer R. , Smilanich Angela M. , Stireman John O. , Tepe Eric J. , Walla Thomas R. , Richards Lora A.
Published: March 2023

Declines in biodiversity generated by anthropogenic stressors at both species and population levels can alter emergent processes instrumental to ecosystem function and resilience. As such, understanding the role of biodiversity in ecosystem function and its response to climate perturbation is increasingly important, especially in tropical systems where responses to changes in biodiversity are less predictable and more challenging to assess experimentally. Using large scale transplant experiments conducted at five neotropical sites, we documented the impacts of changes in intraspecific and interspecific plant richness in the genusPiperon insect herbivory, insect richness, and ecosystem resilience to perturbations in water availability. We found that reductions of both intraspecific and interspecificPiperdiversity had measurable and site specific effects on herbivory, herbivorous insect richness, and plant mortality. The responses of these ecosystem-relevant processes to reduced intraspecificPiperrichness were often similar in magnitude to the effects of reduced interspecific richness. Increased water availability reduced herbivory by 4.2% overall, and the response of herbivorous insect richness and herbivory to water availability were altered by both intra and interspecific richness in a site dependent manner. Our results underscore the role of intraspecific and interspecific richness as foundations of ecosystem function and the importance of community and location specific contingencies in controlling function in complex tropical systems.
Unravelling the anticancer and enzyme inhibition potential of different classes of compounds including a new steroid, isolated fromCassia mimosoïdes
Authors: Tchebou Robert Viani Kepdieu , Farooq Umar , Khan Sara , Rasool Azhar , Sarwar Rizwana , Khushal Aneela , Tapondjou Léon Azefack , Bukhari Syed Majid , Teponno Rémy Bertrand
Published: March 2023

The genusCassiais a significant source of secondary metabolites that are physiologically active and come from several chemical classes. The current research deals with the isolation, spectroscopic elucidation (1D and 2D NMR spectroscopy) and enzymatic activity of fifteen known compounds as well as a new unidentified avenasterol derivative namely 21-methylene-24-ethylidene lophenol. The urease andβ-glucosidase inhibitory effects of these compounds were studied for the first time, and molecular docking studies were also performed to verify the structure-activity relationships. All the compounds evaluated towards urease showed higher inhibitory activity (1.224±0.43 < IC50> 6.678±0.11μM) compared to standard thiourea (IC50= 18.61±0.11μM). Molecular docking results revealed that compound7strongly inhibits urease due to the formation of a stable ligand-urease complex via hydrogen bonding, van der Waal and hydrophobic interactions. Formation of a favourable complex of7with the target enzyme gave a more negative docking score (−6.95 kcal/mol) than that of thiourea (−3.13 kcal/mol). Regarding theβ-glucosidase enzyme, all the compounds evaluated did not show activity except compound1which inhibited the latter with a percentage of inhibition of 82.6. These findings imply that this plant may be a contender for developing novel treatments for infectious disorders brought on by urease-producing bacteria.
Diatom adhesive trail proteins acquired by horizontal gene transfer from bacteria serve as primers for marine biofilm formation
Authors: Zackova Suchanova Jirina , Bilcke Gust , Romanowska Beata , Fatlawi Ali , Pippel Martin , Skeffington Alastair , Schroeder Michael , Vyverman Wim , Vandepoele Klaas , Kröger Nils , Poulsen Nicole
Published: March 2023

Biofilm-forming benthic diatoms are key primary producers in coastal habitats, where they frequently dominate sunlit submerged and intertidal substrata. The development of a unique form of gliding motility in raphid diatoms was a key molecular adaptation that contributed to their evolutionary success. Gliding motility is hypothesized to be driven by an intracellular actin-myosin motor and requires the secretion of polysaccharide- and protein-based adhesive materials. To date, the structure-function correlation between diatom adhesives utilized for gliding and their relationship to the extracellular matrix that constitutes the diatom biofilm is unknown.

Proteomics analysis of the adhesive material fromCraspedostauros australisrevealed eight novel, diatom-specific proteins. Four of them constitute a new family of proteins, named Trailins, which contain an enigmatic domain termed Choice-of-Anchor-A (CAA). Immunostaining demonstrated that Trailins are only present in the adhesive trails required to generate traction on native substrata, but are absent from the extracellular matrix of biofilms. Phylogenetic analysis and Protein 3D structure prediction suggests that the CAA-domains in Trailins were obtained from bacteria by horizontal gene transfer, and exhibit a striking structural similarity to ice-binding proteins.

Our work advances the understanding of the molecular basis for diatom underwater adhesion and biofilm formation providing evidence that there is a molecular switch between proteins required for initial surface colonization and those required for 3D biofilm matrix formation.
GenoDrawing: An autoencoder framework for image prediction from SNP markers
Authors: Jurado-Ruiz Federico , Rousseau David , Botía Juan A. , Aranzana Maria José
Published: March 2023

Advancements in genome sequencing have facilitated whole genome characterization of numerous plant species, providing an abundance of genotypic data for genomic analysis. Genomic selection and neural networks, particularly deep learning, have been developed to predict complex traits from dense genotypic data. Autoencoders, a neural network model to extract features from images in an unsupervised manner, has proven to be useful for plant phenotyping. This study introduces an autoencoder framework, GenoDrawing, for predicting and retrieving apple images from a low-depth single nucleotide polymorphism (SNP) array, potentially useful in predicting traits that are difficult to define. GenoDrawing demonstrated proficiency in its task while using a small dataset of shape-related SNPs, and multiple experiments were conducted to evaluate the impact of SNP selection and shape relation. Results indicated that the correct relationship of SNPs with visual traits had a significant impact on the generated images, consistent with biological interpretation. While using significant SNPs is crucial, incorporating additional, unrelated SNPs results in performance degradation for simple NN architectures that cannot easily identify the most important inputs. The proposed GenoDrawing method is a practical framework for exploring genomic prediction in fruit tree phenotyping, particularly beneficial for small to medium breeding companies to predict economically significant heritable traits. Although GenoDrawing has limitations, it sets the groundwork for future research in image prediction from genomic markers. Future studies should focus on using stronger models for image reproduction, SNP information extraction, and improved dataset balance in terms of shape for more precise outcomes.
Re-engineering a lost trait:IPD3, a master regulator of arbuscular mycorrhizal symbiosis, affects genes for immunity and metabolism of non-host Arabidopsis when restored long after its evolutionary loss
Authors: Hornstein Eli D. , Charles Melodi , Franklin Megan , Edwards Brianne , Vintila Simina , Kleiner Manuel , Sederoff Heike
Published: March 2023

Arbuscular mycorrhizal symbiosis (AM) is a beneficial trait originating with the first land plants, which has subsequently been lost by species scattered throughout the radiation of plant diversity to the present day, including the modelArabidopsis thaliana. To explore why an apparently beneficial trait would be repeatedly lost, we generatedArabidopsisplants expressing a constitutively active form ofInteracting Protein of DMI3, a key transcription factor that enables AM within the Common Symbiosis Pathway, which was lost fromArabidopsisalong with the AM host trait. We characterize the transcriptomic effect of expressingIPD3inArabidopsiswith and without exposure to the AM fungus (AMF)Rhizophagus irregularis, and compare these results to the AM modelLotus japonicusand itsipd3knockout mutantcyclops-4. Despite its long history as a non-AM species, restoringIPD3in the form of its constitutively active DNA-binding domain toArabidopsisaltered expression of specific gene networks. Surprisingly, the effect of expressingIPD3inArabidopsisand knocking it out inLotuswas strongest in plants not exposed to AMF, which is revealed to be due to changes inIPD3genotype causing a transcriptional state which partially mimics AMF exposure in non-inoculated plants. Our results indicate that despite the long interval since loss of AM andIPD3inArabidopsis, molecular connections to symbiosis machinery remain in place in this nonAM species, with implications for both basic science and the prospect of engineering this trait for agriculture.