bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multi-population dissolution in confined active fluids
Authors: Fylling Cayce , Tamayo Joshua , Gopinath Arvind , Theillard Maxime 
Published: September 2023

AbstractAutonomous out-of-equilibrium agents or cells in suspension are ubiquitous in biology and engineering. Turning chemical energy into mechanical stress, they generate activity in their environment, which may trigger spontaneous large-scale dynamics. Often, these systems are composed of multiple populations that may reflect the coexistence of multiple species, differing phenotypes, or chemically varying agents in engineered settings. Here, we present a new method for modeling such multi-population active fluids subject to confinement. We use a continuum multi-scale mean-field approach to represent each phase by its first three orientational moments and couple their evolution with those of the suspending fluid. The resulting coupled system is solved using a parallel adaptive level-set-based solver for high computational efficiency and maximal flexibility in the confinement geometry. Motivated by recent experimental work, we employ our method to study the spatiotemporal dynamics of confined bacterial suspensions and swarms dominated by fluid hydrodynamic effects. Our computational explorations reproduce observed emergent collective patterns, including features of active dissolution in two-population active-passive swarms, with results clearly suggesting that hydrodynamic effects dominate dissolution dynamics. Our work lays the foundation for a systematic characterization of natural and synthetic multi-population systems such as bacterial colonies, bird flocks, fish schools, colloidal swimmers, or programmable active matter.
UCLA’s Competitive Edge Program Provides an Advantage to STEM Doctoral Students from Historically Excluded and Underrepresented Groups
Authors: Del Carpio Christina A. , Azurdia Diana E. 
Published: September 2023

AbstractUniversities benefit from recruiting and retaining diverse students, as it leads to more creative and rigorous problem solving. Efforts to improve the diversity, equity, and inclusion of graduate education have historically been focused on recruitment but are now shifting to retaining enrolled students. A low percentage of doctoral students, particularly those from historically underrepresented groups (URGs), complete their PhD within 10 years. To increase support of incoming doctoral students from URGs, UCLA established the Competitive Edge (CE) bridge program. CE provides six weeks of professional development and research training at the start of the PhD program. We surveyed 55+ first-year doctoral students (14 CE students, eight non-CE students from URGs, and 34 well-represented (WR) students) in STEM fields to understand CE’s effectiveness. We found that the CE program aided students in four areas that influence graduate student attrition: mentor/mentee relationship, socialization, finances, and preparedness. At the end of their first academic year, CE students reported that the program helped them in multiple areas relating to student success, such as mental wellbeing and sense of belonging. CE students reported a larger mean growth in seven of eight skills needed in graduate school compared to NonCE URG and WR students. Short answer responses revealed that NonCE students wished for more support in areas covered by the CE program, such as managing advising relationships and protecting mental health. Additionally, CE students received significant funding during the program. The CE program’s successful model at UCLA can be adapted to improve support for underrepresented doctoral students at other institutions.
ZZZ3 protects human embryonic stem cells from nucleolar stress by boosting mTOR/ribosome pathway
Authors: Conte Michela Lo , Lucchino Valeria , Scalise Stefania , Zannino Clara , Murfuni Maria Stella , Cicconetti Chiara , Scaramuzzino Luana , Matassa Danilo Swann , Procopio Anna , Cuda Giovanni , Parrotta Elvira Immacolata 
Published: September 2023

AbstractEmbryonic stem cells (ESCs) are defined as stem cells with self-renewing and differentiation capabilities. These unique properties are tightly regulated and controlled by complex genetic and molecular mechanisms whose understanding is essential for both basic and translational research. A large number of studies have mostly focused on understanding the molecular mechanisms governing pluripotency and differentiation of ESCs, while the regulation of proliferation has received comparably less attention. In mouse ESCs, pluripotency and proliferation can be independent processes meaning that it is possible for mouse ESCs to maintain their pluripotent state without actively proliferating. Here, we investigate the role of ZZZ3 (Zinc Finger ZZ-Type Containing 3) function in human ESCs homeostasis. We found that knockdown of ZZZ3 strongly decreases ribosome biogenesis, translation, and mTOR signaling leading to nucleolar stress and significant reduction of cell proliferation. This process occurs without affecting pluripotency, suggesting that ZZZ3-depleted ESCs enter a dormant-like state and that proliferation and pluripotency can be uncoupled also in human ESCs.
Spatial and temporal control of lysis by the lambda holin
Authors: Cahill Jesse , Holt Ashley , Theodore Matthew , Moreland Russell , O’Leary Chandler , Martin Cody , Bettridge Kelsey , Xiao Jie , Young Ry 
Published: September 2023

ABSTRACTThe infection cycle of phage λ terminates in lysis mediated by three types of lysis proteins, each disrupting a layer in the bacterial envelope: the S105 holin, the R endolysin, and the Rz/Rz1 spanin complex targeting the inner membrane (IM), cell wall or peptidoglycan (PG), and the outer membrane (OM), respectively. Video microscopy has shown that in most infections lysis occurs as a sudden, explosive event at a cell pole, such that the initial product is a less refractile ghost that retains rod-shaped morphology. Here, we investigate the molecular basis of polar lysis using time lapse fluorescence microscopy. The results indicate that the holin determines the morphology of lysis by suddenly forming two-dimensional rafts at the poles about 100 seconds prior to lysis. Given the physiological and biochemical similarities between the lambda holin and other class I holins, dynamic redistribution and sudden concentration may be common features of holins, probably reflecting the fitness advantage of all-or-nothing lysis regulation.
C4 induces pathological synaptic loss by impairing AMPAR trafficking
Authors: Phadke Rhushikesh A. , Kruzich Ezra , Fournier Luke A. , Brack Alison , Sha Mingqi , Picard Ines , Johnson Connor , Stroumbakis Dimitri , Salgado Maria , Yeung Charlotte , Escude Velasco Berta , Liu Yen Yu , Cruz-Martín Alberto 
Published: September 2023

ABSTRACTDuring development, activation of the complement pathway, an extracellular proteolytic cascade, results in microglia-dependent synaptic elimination via complement receptor 3 (CR3). Here, we report that decreased connectivity caused by overexpression ofC4(C4-OE), a schizophrenia-associated gene, is CR3 independent. Instead, C4-OE triggers GluR1 degradation through an intracellular mechanism involving endosomal trafficking protein SNX27, resulting in pathological synaptic loss. Moreover, the connectivity deficits associated with C4-OE were rescued by increasing levels of SNX27, linking excessive complement activity to an intracellular endolysosomal recycling pathway affecting synapses.
Cellular gibberellin dynamics govern indeterminate nodule development, morphology and function
Authors: Drapek Colleen , Radzman-Mohd Nadiatul , Rizza Annalisa , Schiessl Katharina , Barbosa Fabio Dos Santos , Wen Jiangqi , Oldroyd Giles E.D. , Jones Alexander M. 
Published: September 2023

SUMMARYDuring nutrient scarcity, plants can adapt their developmental strategy to maximize their chance of survival. Such plasticity in development is underpinned by hormonal regulation, which mediates the relationship between environmental cues and developmental outputs. In legumes, endosymbiosis with nitrogen fixing bacteria (rhizobia) is a key adaptation for supplying the plant with nitrogen in the form of ammonium. Rhizobia are housed in lateral root-derived organs termed nodules that maintain an environment conducive to Nitrogenase in these bacteria. Several phytohormones are important for regulating the formation of nodules, with both positive and negative roles proposed for gibberellin (GA). In this study, we determined the cellular location and function of bioactive GA during nodule organogenesis using a genetically-encoded second generation GA biosensor, GPS2. We found endogenous bioactive GA accumulates locally at the site of nodule primordia, increasing dramatically in the cortical cell layers, persisting through cell divisions and maintaining accumulation in the mature nodule meristem. We show, through mis-expression of GA catabolic enzymes that suppress GA accumulation, that GA acts as a positive regulator of nodule growth and development. Furthermore, increasing or decreasing GA through perturbation of biosynthesis gene expression can increase or decrease the size of nodules, respectively. This is unique from lateral root formation, a developmental program that shares common organogenesis regulators. We link GA to a wider gene regulatory program by showing that cytokinin as well as nodule-identity genes induce and sustain GA accumulation necessary for nodule function.
A minimum threshold for myelination of pyramidal cells in human and mouse neocortex
Authors: Pascual-García M. , Unkel M. , Slotman J. A. , Bolleboom A. , Bouwen B. , Houtsmuller A. B. , Dirven C. , Gao Z. , Hijazi S. , Kushner S.A. 
Published: September 2023

AbstractNeocortical pyramidal neurons are frequently myelinated. Diversity in the topography of axonal myelination in the cerebral cortex has been attributed to a combination of electrophysiological activity, axonal morphology, and neuronal-glial interactions. Previously, we showed that axonal segment length and calibre are critical determinants of fast-spiking interneuron myelination (Stedehouder, J. etal(2019). However, the factors that determine the myelination of individual axonal segments along neocortical pyramidal neurons remain largely unexplored. Here, we used structured illumination microscopy and cell type-specific manipulations to examine the extent to which axonal morphology determines the topography of axonal myelination in mouse neocortical pyramidal neurons. We found that, unlike what was determined for fast-spiking interneurons, the joint combination of axonal calibre and interbranch distance does not predict axonal myelination in pyramidal neurons, rather it provides a minimum threshold for myelination; pyramidal neurons with an axon calibre and interbranch distance lower than 0.24 µm and 19 µm, respectively, are almost never myelinated. Moreover, we further confirmed that these findings in mice also extend to human neocortical pyramidal cell myelination, suggesting that this mechanism is evolutionarily conserved. Taken together, our findings suggest that axonal morphology is highly deterministic of the topography and cell-type specificity of neocortical myelination.
Polymorphic Structure Determination of the Macrocyclic Drug Paritaprevir by MicroED
Authors: Bu G , Danelius E , Wieske L.H , Gonen T 
Published: September 2023

AbstractParitaprevir is an orally bioavailable, macrocyclic drug used for treating chronic Hepatitis C virus infection. Its structures had been elusive to the public until recently when one of the crystal forms was solved by MicroED. In this work, we report the MicroED structures of two distinct polymorphic crystal forms of paritaprevir from the same experiment. The different polymorphs show conformational changes in the macrocyclic core, as well as the cyclopropylsulfonamide and methylpyrazinamide substituents. Molecular docking shows that one of the conformations fits well into the active site pocket of the NS3/4A serine protease target, and can interact with the pocket and catalytic triad via hydrophobic interactions and hydrogen bonds. These results can provide further insight for optimization of the binding of acylsulfonamide inhibitors to the NS3/4A serine protease. In addition, this also demonstrate the opportunity of deriving different polymorphs and distinct macrocycle conformations from the same experiments using MicroED.
Malaria trends in districts that were targeted and not-targeted for seasonal malaria chemoprevention in children under five years of age in Guinea, 2014–2021
Authors: Bisanzio D , Keita MS , Camara A , Guilavogui T , Diallo T , Barry H , Preston A , Bangoura L , Mbounga E , Florey L , Taton JL , Fofana A , Reithinger R 
Published: September 2023

ABSTRACTBackgroundSeasonal malaria chemoprevention (SMC) is one of the main interventions recommended by WHO to prevent and reduce childhood malaria. Since 2015, Guinea has implemented SMC targeting children aged 3–59 months (CU5) in districts with high and seasonal malaria transmission.ObjectiveWe assessed the programmatic impact of SMC in Guinea’s context of scaled-up malaria intervention programming by comparing malaria-related outcomes in 14 districts that had (n = 8) or had not (n = 6) been targeted for SMC.MethodUsing routine health management information system data, we calculated the district-level monthly test positivity rate (TPR) and monthly uncomplicated and severe malaria incidence for the whole population and disaggregated age groups (<5yrs and ≥5yrs of age). Changes in malaria indicators through time were analyzed by calculating the district-level compound annual growth rate (CAGR) from 2014 to 2021; we used statistical analyses to describe the time trend of the number of tested clinical cases, TPR, uncomplicated malaria incidence, and severe malaria incidence.ResultThe CAGR of TPR of all age groups was statistically lower in SMC (median = −7.8%, range [IQR] = −9.7%, −5.5%) compared to non-SMC (median = −3.0%, IQR = −3.0%, −1.2%) districts. Similarly, the CAGR in uncomplicated malaria incidence was significantly lower in SMC (median = 1.8%, IQR = −0.9%, 3.5%) compared to non-SMC (median = 11.5%, IQR = 8.8%, 14.0%) districts. For both TPR and uncomplicated malaria incidence the observed difference was also significant age disaggregated. The CAGR of severe malaria incidence showed that all age groups experienced a decline in severe malaria in both SMC and non-SMC districts. However, this decline was significantly higher in SMC (median = −22.3%, IQR= −27.6%, −18.2%) than in non-SMC (median = −5.1%, IQR= - 7.7; −3.6) districts for the entire population, as well as both CU5 and people over 5 years of age.ConclusionOur results provide evidence to support that—even in an operational programming context—adding SMC to the comprehensive package of malaria interventions yields a positive epidemiological impact and results in greater reduction in TPR, as well as the incidence of uncomplicated and severe malaria in CU5.
Genomic Insights into the Population History and Adaptive Traits of Latin American Criollo Cattle
Authors: Ward James A. , Ng’ang’a Said I. , Randhawa Imtiaz A. S. , McHugo Gillian P. , O’Grady John F. , Flórez Julio M. , Browne John A. , Pérez O’Brien Ana M. , Landaeta-Hernández Antonio J. , Garcia José F. , Sonstegard Tad S. , Frantz Laurent A. F. , Salter-Townshend Michael , MacHugh David E. 
Published: September 2023

ABSTRACTCriollo cattle, descendants of animals brought by Iberian colonists to the Americas, have been subject to centuries of natural and human-mediated selection in novel tropical agroecological zones. Consequently, these breeds have evolved distinct characteristics such as resistance to disease and exceptional heat tolerance. In addition to European taurine (Bos taurus) ancestry, it has been proposed that gene flow from African taurine and Asian indicine (Bos indicus) cattle has shaped the ancestry of Criollo cattle. In this study, we analysed Criollo breeds from Colombia and Venezuela using whole-genome sequencing (WGS) and single-nucleotide polymorphism (SNP) array data to examine population structure and admixture at high resolution. Analysis of genetic structure and ancestry components provided evidence for African taurine and Asian indicine admixture in Criollo cattle. In addition, using WGS data, we detected selection signatures associated with a myriad of adaptive traits, revealing genes linked to thermotolerance, reproduction, fertility, immunity, and distinct coat and skin coloration traits. This study underscores the remarkable adaptability of Criollo cattle and highlights the genetic richness and potential of these breeds in the face of climate change, habitat flux, and disease challenges. Further research is warranted to leverage these findings for more effective and sustainable cattle breeding programmes.
Intracellular Tau Fragment Droplets Serve as Seeds for Tau Fibrils
Authors: Soeda Yoshiyuki , Yoshimura Hideaki , Bannai Hiroko , Koike Riki , Shiiba Isshin , Takashima Akihiko 
Published: September 2023

SummaryIntracellular tau aggregation requires a local protein concentration increase, referred to as "droplets". However, the cellular mechanism for droplet formation is poorly understood. Here, we expressed OptoTau, a P301L mutant tau fused with CRY2olig, a light-sensitive protein that can form homo-oligomers. Under blue light exposure, OptoTau increased tau phosphorylation and was sequestered in aggresomes. Suppressing aggresome formation by nocodazole formed tau granular clusters in the cytoplasm. The granular clusters disappeared by discontinuing blue light exposure or 1,6-hexanediol treatment suggesting that intracellular tau droplet formation requires microtubule collapse. Expressing OptoTau-ΔN, a species of N-terminal cleaved tau observed in the Alzheimer’s disease brain, formed 1,6-hexanediol and detergent-resistant tau clusters in the cytoplasm with blue light stimulation. This intracellular stable tau clusters acted as a seed for tau fibrils in vitro. These results suggest that tau droplet formation and N-terminal cleavage are necessary for neurofibrillary tangles formation in neurodegenerative diseases.
Dysfunctional parvalbumin interneurons in a genetic mouse model of schizophrenia
Authors: Hijazi S. , Pascual-García M. , Tolido A. , Pham A. , Kushner S.A. 
Published: September 2023

AbstractThe 22q11 deletion syndrome (22q11DS) is an interstitial microdeletion associated to an increased risk of developing schizophrenia. In this disorder, there is a dysfunction in the overall connectivity of the brain. Parvalbumin-expressing (PV+) interneurons have been associated with multiple pre- and post-synaptic impairments that affect various brain regions. Specifically, previous results have suggested that alterations in hippocampal networks may be related to PV+interneurons dysfunction. In this study, we used the Df1 mouse model that carries the 22q11 deletion to examine the excitability of PV+cells in the dorsal CA1 region of the hippocampus, due to its importance in memory and cognition. We found that PV+interneurons were hyperexcitable in this region. To understand the source of the altered excitability, we measured potassium currents, highly involved in the intrinsic firing properties of neurons. We observed that voltage-gated potassium channel subfamily A member 1 (Kv1.1) was impaired in PV+cells. Specific activation of this channel recovered some of the excitability disturbances observed in Df1 mice. Furthermore, blockade of synaptic inputs also restored PV+interneuron’s excitability. Taken together, these results suggest that PV excitability is increased in the CA1 region of the hippocampus and it is partially mediated by Kv1.1 in a mouse model of 22q11DS.
Collaborative and privacy-preserving workflows on a clinical data warehouse: an example developing natural language processing pipelines to detect medical conditions
Authors: Petit-Jean Thomas , Gérardin Christel , Berthelot Emmanuelle , Chatellier Gilles , Frank Marie , Tannier Xavier , Kempf Emmanuelle , Bey Romain 
Published: September 2023

AbstractObjectiveTo develop and validate advanced natural language processing pipelines that detect 18 conditions in clinical notes written in French, among which 16 comorbidities of the Charlson index, while exploring a collaborative and privacy-preserving workflow.Materials and methodsThe detection pipelines relied both on rule-based and machine learning algorithms for named entity recognition and entity qualification, respectively. We used a large language model pre-trained on millions of clinical notes along with clinical notes annotated in the context of three cohort studies related to oncology, cardiology and rheumatology, respectively. The overall workflow was conceived to foster collaboration between studies while complying to the privacy constraints of the data warehouse. We estimated the added values of both the advanced technologies and the collaborative setting.ResultsThe 18 pipelines reached macro-averaged F1-score positive predictive value, sensitivity and specificity of 95.7 (95%CI 94.5 - 96.3), 95.4 (95%CI 94.0 - 96.3), 96.0 (95%CI 94.0 - 96.7) and 99.2 (95%CI 99.0 - 99.4), respectively. F1-scores were superior to those observed using either alternative technologies or non-collaborative settings. The models were shared through a secured registry.ConclusionsWe demonstrated that a community of investigators working on a common clinical data warehouse could efficiently and securely collaborate to develop, validate and use sensitive artificial intelligence models. In particular, we provided efficient and robust natural language processing pipelines that detect conditions mentioned in clinical notes.