bluuebunny/crossref_metadata_2025_split huggingface dataset:
Therapeutic suppression ofTubb4arescues H-ABC leukodystrophy
Authors: Sase Sunetra , Hacker Julia L , Napit Prabhat R. , Woidill Sarah , Bhagavatula Anjali , D’Alessandro Annemarie , Almad Akshata , Takanohashi Asako , Padiath Quasar , Marsh Eric D. , Vanderver Adeline 
Published: August 2024

AbstractHypomyelination and atrophy of basal ganglia and cerebellum (H-ABC) is a rare leukodystrophy associated with causal variants in β-tubulin 4A (TUBB4A). The recurring variant p.Asp249Asn (D249N) presents in infancy with dystonia, communication deficits, and loss of ambulation during the first decade of life. In this study, we characterized a genetic murine series (Tubb4aKO/KO,Tubb4aD249N/+,Tubb4aD249N/KO,andTubb4aD249N/D249N) to demonstrate that disease severity correlates with the expression of mutant Tubb4a and relative preservation of WT tubulin. To further evaluate the translational potential ofTubb4asuppression as a therapy in H-ABC, we identified a well-toleratedTubb4a-targeted antisense oligonucleotide (ASO) candidate that selectively reduces Tubb4ain vitroandin vivo. Notably, single intracerebroventricular (i.c.v.) administration of ASO in postnatalTubb4aD249N/KOmice drastically extends its lifespan, improves motor phenotypes, and reduces seizures. Neuropathologically, ASO treatment inTubb4aD249N/KOmice restores myelin and oligodendrocyte survival. Furthermore,in vivovisual evoked potential latencies recover in ASO-treatedTubb4aD249N/KOmice. This is the first preclinical proof-of-concept forTubb4asuppression via ASO as a disease-modifying therapy for H-ABC.
The role of β-defensin 103 (DEFB103) copy number variation in bull fertility
Authors: Sidekli Ozge , Hollox Edward J. , Fair Sean , Meade Kieran G. 
Published: August 2024

AbstractPregnancy rates for elite bulls used in artificial insemination (AI) can vary significantly and therefore the identification of molecular markers for fertility and targets to improve bull selection is important. β-defensins are peptides which have diverse regulatory roles in sperm function across multiple species. In this study, Holstein-Friesian bulls were screened based on field fertility data to identify two groups (High and Low fertility (HF and LF, respectively)) of n=10 bulls per group which were genotyped for copy number variation (CNV) in theDEFB103gene. Overall, lowDEFB103copy number (CN) was associated with increased sperm motility across all bulls (n=20, p<0.05). As genetic diversity ofDEFB103CN was only apparent in the LF group, three bulls per CNV class (low, intermediate and high CN) were chosen for functional analysis. Sperm from LF bulls with low CN exhibited higher binding to the oviduct epitheliumin vitro, while high CN affected sperm membrane fluidity in non-capacitating conditionsin vitro(p<0.05). To investigate the functional effect ofDEFB103CNV on the uterine responsein vivo, 18 heifers were inseminated with sperm from bulls with low, intermediate and high CN. Transcriptomic analysis on uterine tissue harvested 12 h post-insemination showed significant differential expression of 58 genes (FDR<0.1) involved in sperm migration, immune signalling and chemotaxis. These novel results confirm an important role forDEFB103CN in both sperm function and the uterine response to bull sperm, thereby potentially influencing pregnancy outcomes in cattle.Summary SentenceDEFB103copy number (CN) is associated with sperm motility and binding to the oviduct epithelium and uterine gene expression, thereby potentially influencing fertility outcomes.
Dimensionality reduction simplifies synaptic partner matching in an olfactory circuit
Authors: Lyu Cheng , Li Zhuoran , Xu Chuanyun , Lam Wong Kenneth Kin , Luginbuhl David J. , McLaughlin Colleen N. , Xie Qijing , Li Tongchao , Li Hongjie , Luo Liqun 
Published: August 2024

AbstractThe distribution of postsynaptic partners in three-dimensional (3D) space presents complex choices for a navigating axon. Here, we discovered a dimensionality reduction principle in establishing the 3D glomerular map in the fly antennal lobe. Olfactory receptor neuron (ORN) axons first contact partner projection neuron (PN) dendrites at the 2D spherical surface of the antennal lobe during development, regardless of whether the adult glomeruli are at the surface or interior of the antennal lobe. Along the antennal lobe surface, axons of each ORN type take a specific 1D arc-shaped trajectory that precisely intersects with their partner PN dendrites. Altering axon trajectories compromises synaptic partner matching. Thus, a 3D search problem is reduced to 1D, which simplifies synaptic partner matching and may generalize to the wiring process of more complex brains.
Mice colonized with the defined microbial community OMM19.1 are susceptible toC. difficileinfection without prior antibiotic treatment
Authors: Chua Michelle , Collins James 
Published: August 2024

ABSTRACTDiverse gut microorganisms present in humans and mice are essential for the prevention of microbial pathogen colonization. However, antibiotic-induced dysbiosis of the gut microbiome reduces microbial diversity and allowsC. difficileto colonize the intestine. The Oligo Mouse Microbiota 19.1 (OMM19.1) is a synthetic community that consists of bacteria that are taxonomically and functionally designed to mimic the specific pathogen-free (SPF) mouse gut microbiota. Here, we examined the susceptibility of OMM19.1 colonized mice toC. difficileinfection at a range of infectious doses (103, 105, and 107spores) without prior antibiotic treatment. We found that mice colonized with OMM19.1 were susceptible toC. difficileinfection regardless of the dose. The clinical scores increased with increasingC. difficiledosage. Infection withC. difficilewas correlated with a significant increase inLigilactobacillus murinusandEscherichia coli, while the abundance ofBacteroides caecimuris, Akkermansia muciniphila, Extibacter muris, and Turicimonas murissignificantly decreased followingC. difficileinfection. Our results demonstrate that the OMM19.1 community requires additional bacteria to enable colonization resistance.
Reusing excess staple oligonucleotides for economical production of DNA origami
Authors: Isinelli Giorgia , Wintersinger Christopher M. , Lill Pascal , Young Olivia J. , Deng Jie , Shih William M. , Zeng Yang C. 
Published: August 2024

ABSTRACTDNA origami has enabled the development of responsive drug-delivery vehicles with precision features that were previously not attainable in bionanotechnology. To reduce the costs of creating therapeutics-scale amounts of DNA origami that need to bear costly modifications with high occupancy, we reused the excess staple oligonucleotides that are leftover from the folding process to fold additional origami. We determined that a DNA origami can be successfully folded with up to 80% cost savings by cyclic recovery and reuse of excess staple strands. We found evidence that higher quality staple strands are preferentially incorporated into origami, consistent with past reports, and therefore are preferentially depleted from the free-strand pool. The folding of DNA origami with staple strands that were reused up to eleven times was indistinguishable by our panel of assays versus a control folded with new strands, so long as the reused oligonucleotides were replenished each cycle with a small excess of fresh strands. We also observed a high degree of incorporation of guests on the DNA origami. By recovering, reusing, and replenishing excess staple oligonucleotides, it is possible to significantly lessen production costs to create well-formed origami, which is useful to allow more therapeutic designs to be tested.
Hemodynamics Affects Factor XI/XII Anticoagulation Efficacy in Patient-Specific Left Atrial Models
Authors: Guerrero-Hurtado M. , Garcia-Villalba M. , Gonzalo A. , Durán E. , Martinez-Legazpi P. , Kahn A. M. , Chen M. Y. , McVeigh E. , Bermejo J. , del Álamo J. C. , Flores O. 
Published: August 2024

AbstractAtrial fibrillation (AF) disrupts the circulation of blood through the left atrium (LA), and may result in relative stasis in the left atrial appendage (LAA), increasing thromboembolic risk. Anticoagulant agents can lower this risk, but currently used agents target the common pathway central to the coagulation cascade, increasing bleeding risk. Anticoagulants such as factor XI/XII inhibitors target the initial phase of the intrinsic pathway, with a significantly lower associated bleeding risk. However, these agents’ efficacy in preventing thrombosis in patient-specific flow conditions is not fully understood. We hypothesized that patient-specific flow patterns in the LA and LAA not only influence the risk of thrombosis but also the effectiveness of anticoagulation agents. We simulated blood flow and the intrinsic coagulation pathway in patient-specific LA anatomies with and without factor XI/XII inhibition to test this hypothesis. We considered thirteen patients in sinus rhythm and AF, several of whom had an LAA clot or a history of transient ischemic attacks. We used computational fluid dynamics based on 4D CT imaging and a detailed 32-species coagulation system to run 247 simulations for 13 patients, systematically sweeping over a wide range of factor XI/XII inhibition levels. Implementing a novel multi-fidelity coagulation modeling approach accelerated computations by two orders of magnitude, enabling the large number of simulations performed. Our simulations provide spatiotemporally resolved maps of thrombin concentration throughout the LA, showing it peaks inside the LAA. Coagulation metrics based on peak LAA thrombin dynamics suggested patients could be classified asnon-coagulating, moderatelyandseverely coagulatingcases.Severely coagulatingcases had significantly slower flow and higher residence time thanmoderately coagulatingpatients inside the LAA, requiring stronger factor XI/XII inhibition to blunt thrombin growth. The methodology outlined in this study has the potential to enable personalized assessments of coagulation risk and tailor anticoagulation therapy based on medical imaging.
Improving N-Glycosylation and Biopharmaceutical Production Predictions Using AutoML-Built Residual Hybrid Models
Authors: Seber Pedro , Braatz Richard D. 
Published: August 2024

AbstractN-glycosylation has many essential biological roles, and is important for biotherapeutics as it can affect drug efficacy, duration of effect, and toxicity. Its importance has motivated the development of mechanistic models for quantitatively predicting the distribution of N-glycans during therapeutic protein production. Here we present a residual hybrid modeling approach that integrates mechanistic modeling with machine learning to produce significantly more accurate predictions for production of monoclonal antibodies in batch, fed-batch, and perfusion cell culture. For the largest dataset, the residual hybrid models have an average 736-fold reduction in testing prediction error. Furthermore, the residual hybrid models have lower prediction errors than the mechanistic models for all of the predicted variables in the datasets. We provide the automatic machine learning software used in this work, allowing other researchers to reproduce this work and use our software for other tasks and datasets.
Membrane potential modulates ERK activity and cell proliferation
Authors: Sasaki Mari , Nakahara Masanobu , Hashiguchi Takuya , Ono Fumihito 
Published: August 2024

SummaryThe plasma membrane potential has been linked to cell proliferation for more than 40 years. Here we experimentally showed that membrane depolarization upregulates cell mitosis, and that this process is dependent on voltage-dependent activation of ERK. ERK activity exhibits a membrane potential-dependency that is independent from the growth factor. This membrane potential dependence was observed even close to the resting membrane potential, indicating that small changes in resting membrane potential can alter cell proliferative activity. The voltage-dependent ERK activity is derived from changed dynamics of phosphatidylserine which is present in the plasma membrane and not by extracellular calcium entry. The data suggests that crucial biological processes such as cell proliferation are regulated by the physicochemical properties of the lipid. This study suggests that membrane potential may have diverse physiological functions beyond the action potential, which is well-established in the neural system.
Wound-initiated hair regeneration by adhesive and shrinkable materials
Authors: Kokabu Shoichiro , Tsuji Kunikazu , Washio Ayako , Murata Kazumasa , Nakatomi Mitsushiro , Ono Yusuke , Kaminuma Osamu , Matsubara Takuma 
Published: August 2024

AbstractAlthough there is a global demand for hair regrowth, particularly among middle-aged and older individuals, an effective hair growth technology has not yet been established1. Hair follicle neogenesis is restricted to the embryonic period, but hair regeneration accompanied by wound healing has been observed under some conditions2–4; however, the underlying mechanisms are unclear. Herein, we demonstrated that creating a wound without dermal defects effectively induced postneonatal hair follicle neogenesis. Separating the epidermis from the dermis by topical application of adhesive and shrinkable materials to mouse skin promoted epidermal regeneration, followed by new hair follicle formation. Hair follicle regeneration, accompanied by the upregulation of related genes, can be induced in mice, including middle-aged and aged mice, regardless of species, sex, skin location, or age. The cycle of the regenerated hair eventually synchronized with that of the surrounding physiological hairs. Our new hair regeneration technique based on reproduction of epidermis–dermis interactions provides a novel means to treat hair loss, including androgenetic alopecia.
Single-molecule analysis of protein targeting from the endoplasmic reticulum to lipid droplets
Authors: Mizrak Arda , Kæstel-Hansen Jacob , Matthias Jessica , Harper J. Wade , Hatzakis Nikos S. , Walther Tobias C. , Farese Robert V. 
Published: August 2024

SUMMARYNumerous proteins migrate from the bilayer membrane of the endoplasmic reticulum (ER) to the monolayer surface of lipid droplets (LD) to perform critical metabolic functions. How cargoes move between these organelles and accumulate on LDs is unclear, particularly for mammalian cells. Here, we developed a synchronized ER-to-LD protein-trafficking assay and combined it with MINFLUX- and HILO-based single-molecule tracking and machine-learning analysis. Trafficking of a model proteinLiveDropbetween the ER and LDs occurs by diffusion through seipin- associated ER-LD membrane bridges that allow bidirectional protein movement. Unexpectedly,LiveDropmoves with the same apparent diffusion coefficient in the ER and LDs, but becomes molecularly confined at LD surfaces through a mechanism requiring its tryptophan residues. These data show how a specific LD-targeting membrane sequence leads to confined motion and LD protein accumulation, and directly demonstrate intra-organellar protein trafficking through membrane contact sites.HighlightsSingle-molecule tracking reveals the path of ER-to-LD traffickingCargo diffuses with similar speeds in both organellesProtein accumulating on LDs exhibits more confined motion on the LD surfaceCargo moves bidirectionally between ER and LDs via seipin-mediated membrane bridges
Changes in affect variability after starting gender-affirming hormone therapy
Authors: Morssinkhof Margot W. L. , Schipper Marijn , Kreukels Baudewijntje P. C. , van der Tuuk Karin , den Heijer Martin , van den Heuvel Odile A. , Doyle David Matthew , Broekman Birit F. P. 
Published: August 2024

AbstractAffect variability is determined by how often and how strongly negative affect changes over time. Cisgender women report greater variability in affect than cisgender men. It has been suggested that sex hormone changes may influence affect variability. Transgender people frequently opt to use sex hormones in the form of gender-affirming hormone therapy (GAHT), but the extent to which GAHT can change negative affect variability is not yet clear. Therefore, this study aims to study changes in negative affect variability after starting GAHT.We have included data from 94 participants from the RESTED study: 49 transmasculine (TM) participants (assigned female at birth, starting testosterone) and 45 transfeminine (TF) participants (assigned male at birth, starting estrogens and anti-androgens). Participants completed up to 7 consecutive daily diaries at each of three time points: before starting GAHT, and after 3 and 12 months of GAHT. The daily diaries collected participants’ reports on symptoms related to negative affect: experienced low mood, less interest, tense feelings and restless feelings. We have used linear mixed models to compare negative affect variability during one week, corrected for mean negative affect, between gender groups (TM versus TF) and measurement time points.Results show that in the TM group, variability in low mood, tense feelings and restless feelings decreases after 12 months of GAHT. In the TF group, variability in low mood increases after 3 months and 12 months of GAHT, as does variability in restless feelings after 3 months of GAHT. Group comparisons indicate significant group differences in changes in variability in low mood and restless feelings, with stronger increases in variability of negative affect in the TF group compared to TM group after 3 and 12 months of GAHT.Our findings indicate that variability patterns in negative affect in transgender persons tend to cross- over from being consistent with sex assigned at birth before GAHT to being more in line with gender identity after 12 months of GAHT. Future studies should focus on measuring both negative and positive affect variability during GAHT, preferably through multiple measurements per day, taking into account diverse social and daily contextual factors during GAHT.Graphical abstractHighlights◦Cisgender women report greater affect variability than cisgender men.◦The impact of GAHT on affect variability in transgender people is unclear.◦We examined affect variability in transmasculine (TM) and transfeminine (TF) people.◦We find decreased variability in negative affect after starting masculinizing GAHT.◦We find increased variability in negative affect after starting feminizing GAHT.
Reconstitution of BNIP3/NIX-mediated autophagy reveals two pathways and hierarchical flexibility of the initiation machinery
Authors: Adriaenssens Elias , Schaar Stefan , Cook Annan S.I. , Stuke Jan F. M. , Sawa-Makarska Justyna , Nguyen Thanh Ngoc , Ren Xuefeng , Schuschnig Martina , Romanov Julia , Khuu Grace , Lazarou Michael , Hummer Gerhard , Hurley James H. , Martens Sascha 
Published: August 2024

SUMMARYSelective autophagy is a lysosomal degradation pathway that is critical for maintaining cellular homeostasis by disposing of harmful cellular material. While the mechanisms by which soluble cargo receptors recruit the autophagy machinery are becoming increasingly clear, the principles governing how organelle-localized transmembrane cargo receptors initiate selective autophagy remain poorly understood. Here, we demonstrate that transmembrane cargo receptors can initiate autophagosome biogenesis not only by recruiting the upstream FIP200/ULK1 complex but also via a WIPI-ATG13 complex. This latter pathway is employed by the BNIP3/NIX receptors to trigger mitophagy. Additionally, other transmembrane mitophagy receptors, including FUNDC1 and BCL2L13, exclusively use the FIP200/ULK1 complex, while FKBP8 and the ER-phagy receptor TEX264 are capable of utilizing both pathways to initiate autophagy. Our study defines the molecular rules for initiation by transmembrane cargo receptors, revealing remarkable flexibility in the assembly and activation of the autophagy machinery, with significant implications for therapeutic interventions.
Horizontal gene transfer can reshape bacterial warfare
Authors: Granato Elisa T. , Palmer Jacob D. , Kirk Christian , Sharp Connor , Shillcock George , Foster Kevin R. 
Published: August 2024

ABSTRACTBacteria commonly use molecular weaponry to kill or inhibit competitors. Genes encoding many of these weapons can be transmitted horizontally, but the impact on bacterial warfare is not understood. Here, we develop an ecological model of bacterial warfare where there is potential for horizontal gene transfer. Our model predicts that weapon gene transfer from an attacker to a target strain is possible, but at a low rate such that transfer has a negligible impact on competition outcomes. We tested the model empirically using a transmissible plasmid encoding colicin E2, a potent antibacterial toxin produced byEscherichia coli. As predicted by the model, we find that toxin plasmid transfer is feasible during warfare, but the resulting transconjugants remain rare. However, exploring the model further reveals realistic conditions where transfer has major impacts. Specifically, the model predicts that whenever competing strains have access to some unique nutrients, transconjugants can proliferate and reach high abundances. In support of these predictions, short- and long-term experiments show that transconjugants can thrive when nutrient competition is relaxed. Our work shows how horizontal gene transfer can reshape bacterial warfare in a way that can benefit a weapon gene but not the bacteria that carries it.
Asymmetric self-interacting dark matter with a canonical seesaw model
Authors: Borah Debasish , Mahapatra Satyabrata , Paul Partha Kumar , Sahu Narendra , Shukla Prashant 
Published: August 2024

We study the possibility of generating dark matter (DM) and baryon asymmetry of the Universe (BAU) simultaneously in an asymmetric DM framework, which also alleviates the small-scale structure issues of cold DM. While the thermal relic of such self-interacting DM remains underabundant due to efficient annihilation into light mediators, a nonzero asymmetry in the dark sector can lead to the survival of the required DM in the Universe. The existence of a light mediator leads to the required self-interactions of DM at small scales while keeping DM properties similar to cold DM at large scales. It also ensures that the symmetric DM component annihilates away, leaving the asymmetric part in the spirit of cogenesis. The particle physics implementation is done in canonical seesaw models of light neutrino mass, connecting it to the origin of DM and BAU. In particular, we consider type-I and type-III seesaw origin of neutrino mass for simplicity and minimality of the field content. We show that the desired self-interactions and relic of DM together with BAU while satisfying relevant constraints lead to strict limits on DM mass O(GeV)≲MDM≲460  GeV. In spite of being a high-scale seesaw, the models remain verifiable in different experiments, including direct and indirect DM searches as well as colliders.

Published by the American Physical Society
2024