bluuebunny/crossref_metadata_2025_split huggingface dataset:
A prefrontal motor circuit initiates persistent movement
Authors: Wang Yihan , Sun Qian-Quan 
Published: July 2023

AbstractPersistence reinforces continuous action, which benefits animals in many aspects. Diverse information may trigger animals to start a persistent movement. However, it is unclear how the brain decides to persist with current actions by selecting specific information. Using single-unit extracellular recordings and opto-tagging in awake mice, we demonstrated that a group of dorsal mPFC (dmPFC) motor cortex projecting (MP) neurons initiate a persistent movement selectively encoding contextual information rather than natural valence. Inactivation of dmPFC MP neurons impairs the initiation and reduces neuronal activity in the insular and motor cortex. Finally, a computational model suggests that a successive sensory stimulus acts as an input signal for the dmPFC MP neurons to initiate a persistent movement. These results reveal a neural initiation mechanism on the persistent movement.
Neutrophils culturedex vivofrom CD34+stem cells are immature and genetically tractable
Authors: Naveh Claire A. , Roberts Kiran , Rice Christopher M. , Fleming Kathryn , Thompson Megan , Panyapiean Nawamin , Diezmann Stephanie , Moura Pedro L. , Toye Ashley M. , Amulic Borko 
Published: July 2023

AbstractNeutrophils are essential antimicrobial effector cells with short lifespans. During infection or sterile inflammation, accelerated production and release of immature neutrophils from the bone marrow serves to boost circulating neutrophil counts. To facilitate the study of neutrophil development and function, we optimised a method forex vivoproduction of human neutrophils from CD34+haematopoietic progenitors. We obtain high yields of neutrophils, which phenotypically resemble immature neutrophils released into the circulation upon administration of GCSF to healthy donors. We show thatex vivodifferentiated immature neutrophils have similar rates of ROS production but altered degranulation, cytokine release and antifungal activity compared to mature neutrophils isolated from peripheral blood. We demonstrate thatex vivocultured neutrophils are genetically tractable via genome editing of precursors and thus provide a powerful model system for investigating the properties and behaviour of immature neutrophils.
Quantifying the impact of hospital catchment area definitions on hospital admissions forecasts: COVID-19 in England, September 2020 - April 2021
Authors: Meakin Sophie , Funk Sebastian 
Published: July 2023

AbstractBackgroundDefining healthcare facility catchment areas is a key step in predicting future healthcare demand in epidemic settings. Forecasts of hospitalisations can be informed by leading indicators measured at the community level. However, this relies on the definition of so-called catchment areas, or the geographies whose populations make up the patients admitted to a given hospital, and which are often not well-defined. Little work has been done to quantify the impact of hospital catchment area definitions on healthcare demand forecasting.MethodsWe made forecasts of Trust-level hospital admissions using a scaled convolution of local cases (as defined by the hospital catchment area) and a delay distribution. Hospital catchment area definitions were derived from either simple heuristics (in which people are admitted to their nearest hospital or any nearby hospital) or historical admissions data (all emergency or elective admissions in 2019, or COVID-19 admissions), plus a marginal baseline definition based on the distribution of all hospital admissions. We evaluated predictive performance using each hospital catchment area definition using the Weighted Interval Score (WIS) and considered how this changed by the length of the predictive horizon, the date on which the forecast was made, and by location. We also considered the change, if any, on the relative performance of each definition in retrospective vs. real-time settings, or at different spatial scales.ResultsThe choice of hospital catchment area definition affected the accuracy of hospital admission forecasts. The definition based on COVID-19 admissions data resulted in the most accurate forecasts at both a 7- and 14-day horizon, and was one of the top two best-performing definitions across forecast dates and locations. The “nearby” heuristic also performed well, but less consistently than the COVID-19 data definition. The marginal distribution baseline, which did not include any spatial information, was the lowest-ranked definition. The relative performance of the definitions was larger when using case forecasts compared to future observed cases. All results were consistent across spatial scales of the catchment area definitions.ConclusionsUsing catchment area definitions derived from context-specific data can improve local-level hospital admissions forecasts. Where context-specific data is not available, using catchment areas defined by carefully-chosen heuristics are a sufficiently-good substitute. There is clear value in understanding what drives local admissions patterns, and further research is needed to understand the impact of different catchment area definitions on forecast performance where case trends are more heterogeneous.
Epidemiological and health economic implications of symptom propagation in respiratory pathogens: A mathematical modelling investigation
Authors: Asplin Phoebe , Keeling Matt J. , Mancy Rebecca , Hill Edward M. 
Published: July 2023

AbstractBackgroundRespiratory pathogens inflict a substantial burden on public health and the economy. Although the severity of symptoms caused by these pathogens can vary from asymptomatic to fatal, the factors that determine symptom severity are not fully understood. Correlations in symptoms between infector-infectee pairs, for which evidence is accumulating, can generate large-scale clusters of severe infections that could be devastating to those most at risk, whilst also conceivably leading to chains of mild or asymptomatic infections that generate widespread immunity with minimal cost to public health. Although this effect could be harnessed to amplify the impact of interventions that reduce symptom severity, the mechanistic representation of symptom propagation within mathematical and health economic modelling of respiratory diseases is understudied.Methods and FindingsWe propose a novel framework for incorporating different levels of symptom propagation into models of infectious disease transmission via a single parameter,α. Varyingαtunes the model from having no symptom propagation (α= 0, as typically assumed) to one where symptoms always propagate (α= 1). For parameters corresponding to three respiratory pathogens — seasonal influenza, pandemic influenza and SARS-CoV-2 — we explored how symptom propagation impacted the relative epidemiological and health-economic performance of three interventions, conceptualised as vaccines with different actions: symptom-attenuating (labelled SA), infection-blocking (IB) and infection-blocking admitting only mild breakthrough infections (IB MB).In the absence of interventions, with fixed underlying epidemiological parameters, stronger symptom propagation increased the proportion of cases that were severe. For SA and IB MB, interventions were more effective at reducing prevalence (all infections and severe cases) for higher strengths of symptom propagation. For IB, symptom propagation had no impact on effectiveness, and for seasonal influenza this intervention type was more effective than SA at reducing severe infections for all strengths of symptom propagation. For pandemic influenza and SARS-CoV-2, at low intervention uptake, SA was more effective than IB for all levels of symptom propagation; for high uptake, SA only became more effective under strong symptom propagation. Health economic assessments found that for SA-type interventions, the amount one could spend on control whilst maintaining a cost-effective intervention (termed threshold unit intervention cost) was very sensitive to the strength of symptom propagation.ConclusionsOverall, the preferred intervention type depended on the combination of the strength of symptom propagation and uptake. Given the importance of determining robust public health responses, we highlight the need to gather further data on symptom propagation, with our modelling framework acting as a template for future analysis.
Comparative Effectiveness of the Bivalent (Original/Omicron BA.4/BA.5) mRNA COVID-19 Vaccines mRNA-1273.222 and BNT162b2 Bivalent in Adults in the United States
Authors: Kopel Hagit , Nguyen Van Hung , Boileau Catherine , Bogdanov Alina , Winer Isabelle , Ducruet Thierry , Zeng Ni , Bonafede Mac , Esposito Daina B. , Martin David , Rosen Andrew , Van de Velde Nicolas , Vermund Sten H , Gravenstein Stefan , Mansi James A. 
Published: July 2023

AbstractBackgroundThe emergence of Omicron variants coincided with declining vaccine-induced protection against SARS-CoV-2 infection and other COVID-19-related outcomes. Two bivalent mRNA vaccines, mRNA-1273.222 (Moderna) and BNT162b2 Bivalent (Pfizer-BioNTech) were developed to provide greater protection against the predominate circulating variants by including the mRNA that encodes both the ancestral (original) strain and BA.4/BA.5. We estimated their relative vaccine effectiveness (rVE) in preventing COVID-19-related outcomes in the US.MethodsWe conducted a retrospective cohort study using a US nationwide dataset linking primary care electronic health records (EHR) and pharmacy/medical claims data. The adult study population (aged ≥18 years) received either mRNA-1273.222 or BNT162b2 Bivalent vaccination between August 31, 2022, and February 28, 2023. We used a propensity score weighting based on the inverse probability of treatment to adjust for the baseline differences in age, sex, race, ethnicity, geographic region, vaccination week, and health status between groups. Outcomes evaluated were rVE of the two bivalent mRNA vaccines against COVID-19-related hospitalizations (primary outcome) and outpatient visits (secondary). We weighted the vaccine groups prior to analysis and estimated adjusted hazard ratios (HR) using multivariable Cox regression models. We calculated rVE as (1−HR) × 100.ResultsWe evaluated outcomes for 1,034,538 mRNA-1273.222 and 1,670,666 BNT162b2 Bivalent vaccine recipients. The adjusted rVE of mRNA-1273.222 versus BNT162b2 Bivalent vaccines against COVID-19-related hospitalization was 9.8% (95% confidence interval: 2.6%–16.4%). The adjusted rVE against COVID-19-related outpatient visits was 5.1% (95% CI: 3.2%–6.9%). When evaluated by age group, the incremental relative effectiveness was greater. Among adults ≥ 65, rVE against COVID-19-related hospitalizations and outpatient visits was 13.5% (95% CI: 5.5%–20.8%) and 10.7% (8.2%–13.1%), respectively.ConclusionWe found greater effectiveness of mRNA-1273.222 compared with the BNT162b2 Bivalent vaccine in preventing COVID-19-related hospitalizations and outpatient visits, with increased benefits in older adults.
Breeding of a near-isogenic wheat line resistant to wheat blast at both seedling and heading stages through incorporation ofRmg8
Authors: Yoshioka Motohiro , Shibata Mai , Morita Kohei , Fujita Masaya , Hatta Koichi , Tougou Makoto , Tosa Yukio , Asuke Soichiro 
Published: July 2023

AbstractWheat blast caused byPyricularia oryzae Triticumpathotype (MoT) has been transmitted from South America to Bangladesh and Zambia and is now spreading in these countries. To prepare against its further spread to Asian countries, we introducedRmg8, a gene for resistance to wheat blast, into a Japanese elite cultivar, Chikugoizumi (ChI), through recurrent backcrosses, and established ChI near-isogenic lines, #2-1-10 with theRmg8/Rmg8genotype and #4-2-10 with thermg8/rmg8genotype. A molecular analysis suggested that at least 96.6% of the #2-1-10 genome was derived from the recurrent parent ChI. The #2-1-10 line was resistant to MoT not only in primary leaves at the seedling stage but also in spikes and flag leaves at the heading stage. The strength of the resistance in spikes of thisRmg8carrier was comparable to that of a carrier of the 2NS segment which has been the only one genetic resource released to farmer’s field for wheat blast resistance. On the other hand, the 2NS resistance was not expressed on leaves at the seedling stage nor flag leaves at the heading stage. Considering that leaf blast has been increasingly reported and regarded as an important inoculum source for spike blast,Rmg8expressed at both the seedling and heading stages, or more strictly in both leaves and spikes, is suggested to be useful to prevent the spread of MoT in Asia and Africa.
Multidimensional super-resolution microscopy unveils nanoscale surface aggregates in the aging of FUS condensates
Authors: He Changdong , Wu Chun Ying , Li Wan , Xu Ke 
Published: July 2023

AbstractThe intracellular liquid-liquid phase separation (LLPS) of biomolecules gives rise to condensates that act as membrane-less organelles with vital functions. FUS, an RNA-binding protein, natively forms condensates through LLPS and further provides a model system for the often disease-linked liquid-to-solid transition of biomolecular condensates during aging. However, the mechanism of such maturation processes, as well as the structural and physical properties of the system, remain unclear, partly attributable to difficulties in resolving the internal structures of the micrometer-sized condensates with diffraction-limited optical microscopy. Harnessing a set of multidimensional super-resolution microscopy tools that uniquely map out local physicochemical parameters through single-molecule spectroscopy, here we uncover nanoscale heterogeneities in the aging process of FUS condensates. Through spectrally resolved single-molecule localization microscopy (SR-SMLM) with a solvatochromic dye, we unveil distinct hydrophobic nanodomains at the condensate surface. Through SMLM with a fluorogenic amyloid probe, we identify these nanodomains as amyloid aggregates. Through single-molecule displacement/diffusivity mapping (SMdM), we show that such nanoaggregates drastically impede local diffusion. Notably, upon aging or mechanical shears, these nanoaggregates progressively expand on the condensate surface, thus leading to a growing low-diffusivity shell while leaving the condensate interior diffusion-permitting. Together, beyond uncovering fascinating nanoscale structural arrangements and aging mechanisms in the single-component FUS condensates, the demonstrated synergy of multidimensional super-resolution approaches in this study opens new paths for understanding LLPS systems.
AI2BMD: efficient characterization of protein dynamics withab initioaccuracy
Authors: Wang Tong , He Xinheng , Li Mingyu , Wang Yusong , Wang Zun , Li Shaoning , Shao Bin , Liu Tie-Yan 
Published: July 2023

SUMMARYBiomolecular dynamics simulation is a fundamental technology for life sciences research, and its usefulness depends on its accuracy and efficiency. Classical molecular dynamics simulation is fast but lacks chemical accuracy. Quantum chemistry methods like density functional theory (DFT) can reach chemical accuracy but cannot scale to support large biomolecules. We introduce anAI-basedab initiobiomoleculardynamics system (AI2BMD) that can efficiently simulate large biomolecules withab initioaccuracy. AI2BMD uses a protein fragmentation scheme and machine learning force field to achieve generalizableab initioaccuracy for energy and force calculations for various proteins comprising over 10,000 atoms. Compared to DFT, it reduces computational time by several orders of magnitude. With several hundred nanoseconds of dynamics simulations, AI2BMD demonstrated its capability of efficiently exploring the conformational space of peptides and proteins, deriving accurate3J-couplingsthat match NMR experiments, and showing protein folding and unfolding tendencies. Furthermore, AI2BMD enables precise free energy calculations for protein folding, and the estimated melting temperatures are well aligned with experiments. AI2BMD could potentially complement wet-lab experiments, detect the dynamic processes of bioactivities, and enable biomedical research that is currently impossible to conduct.
EMDiffuse: a diffusion-based deep learning method augmenting ultrastructural imaging and volume electron microscopy
Authors: Lu Chixiang , Chen Kai , Qiu Heng , Chen Xiaojun , Chen Gu , Qi Xiaojuan , Jiang Haibo 
Published: July 2023

AbstractElectron microscopy (EM) revolutionized the way to visualize cellular ultrastructure. Volume EM (vEM) has further broadened its three-dimensional nanoscale imaging capacity. However, intrinsic trade-offs between imaging speed and quality of EM restrict the attainable imaging area and volume. Isotropic imaging with vEM for large biological volumes remains unachievable. Here we developed EMDiffuse, a suite of algorithms designed to enhance EM and vEM capabilities, leveraging the cutting-edge image generation diffusion model. EMDiffuse demonstrates outstanding denoising and super-resolution performance, generates realistic predictions without unwarranted smoothness, improves predictions’ resolution by ∼30%, and exhibits excellent transferability by taking only one pair of images to fine-tune. EMDiffuse also pioneers the isotropic vEM reconstruction task, generating isotropic volume similar to that obtained using advanced FIB-SEM even in the absence of isotropic training data. We demonstrated the robustness of EMDiffuse by generating isotropic volumes from six public datasets obtained from different vEM techniques and instruments. The generated isotropic volume enables accurate organelle reconstruction, making 3D nanoscale ultrastructure analysis faster and more accessible and extending such capability to larger volumes. More importantly, EMDiffuse features self-assessment functionalities and guarantees reliable predictions for all tasks. We envision EMDiffuse to pave the way for more in-depth investigations into the intricate subcellular nanoscale structures within large areas and volumes of biological systems.
The anti-tubercular callyaerins target theMycobacterium tuberculosis-specific non-essential membrane protein Rv2113
Authors: Podlesainski David , Adeniyi Emmanuel T. , Gröner Yvonne , Schulz Florian , Krisilia Violetta , Rehberg Nidja , Richter Tim , Sehr Daria , Xie Huzhuyue , Simons Viktor E. , Kiffe-Delf Anna-Lene , Kaschani Farnusch , Ioerger Thomas R. , Kaiser Markus , Kalscheuer Rainer 
Published: July 2023

ABSTRACTSpread of antimicrobial resistances in the pathogenMycobacterium tuberculosisremains a public health challenge. Thus, there is a continuous need for new therapeutic options with modes-of-action differing from current antibiotics. Previously, bioactivity-guided isolation identified the callyaerins, a class of hydrophobic cyclopeptides with an unusual (Z)-2,3-di-aminoacrylamide unit, as promising antitubercular agents. In this study, we investigated the molecular mechanisms underlying their antimycobacterial properties. Structure-activity relationship studies enabled the identification of the structural determinants relevant for their antibacterial activity. The antitubercular callyaerins are bacteriostatics selectively active againstM. tuberculosis, including extensively drug-resistant (XDR) strains, with minimal cytotoxicity against human cells and a promising intracellular activity in a macrophage infection model. Via spontaneous resistance mutant screens and various chemical proteomics approaches, we showed that they act by direct targeting of the non-essential,M. tuberculosis-specific putative membrane protein Rv2113, thereby triggering a complex stress response inM. tuberculosischaracterized by global downregulation of lipid biosynthesis, cell division, DNA repair and replication. Our study thus not only identifies Rv2113 as a newM. tuberculosis-specific target for antitubercular drugs, which should result in less harm of the microbiome and weaker resistance development in off-target pathogens. It furthermore demonstrates that also non-essential proteins may represent efficacious targets for antimycobacterial drugs.
Interchromosomal Colocalization with Parental Genes Is Linked to the Function and Evolution of Mammalian Retrocopies
Authors: Yan Yubin , Tian Yuhan , Wu Zefeng , Zhang Kunling , Yang Ruolin 
Published: July 2023

AbstractRetrocopies are gene duplicates arising from reverse transcription of mature mRNA transcripts and their insertion back into the genome. While long being regarded as processed pseudogenes, more and more functional retrocopies have been discovered. How the stripped- down retrocopies recover expression capability and become functional paralogs continually intrigues evolutionary biologists. Here, we investigated the function and evolution of retrocopies in the context of three-dimensional (3D) genome organization. By mapping retrocopy-parent pairs onto sequencing-based and imaging-based chromatin contact maps in human and mouse cell lines and onto Hi-C interaction maps in five other mammals, we found that retrocopies and their parental genes show a higher-than-expected interchromosomal colocalization frequency. The spatial interactions between retrocopies and parental genes occur frequently at loci in active subcompartments and near nuclear speckles. Accordingly, colocalized retrocopies are more actively transcribed and translated, and are more evolutionarily conserved than noncolocalized ones. The active transcription of colocalized retrocopies may result from their permissive epigenetic environment and shared regulatory elements with parental genes. Population genetic analysis of retroposed gene copy number variants (retroCNVs) in human populations revealed that retrocopy insertions are not entirely random in regard to interchromosomal interactions and that colocalized retroCNVs are more likely to reach high frequencies, suggesting that both insertion bias and natural selection contribute to the colocalization of retrocopy-parent pairs. Further dissection implies that reduced selection efficacy, rather than positive selection, contributes to the elevated allele frequency of colocalized retroCNVs. Overall, our results hint a role of interchromosomal colocalization in the “resurrection” of initially neutral retrocopies.
Novel role for peptidoglycan carboxypeptidases in maintaining the balance between bacterial cell wall synthesis and degradation
Authors: Obando Manuela Alvarado , Dörr Tobias 
Published: July 2023

AbstractPeptidoglycan (PG) is the main component of the bacterial cell wall; it maintains cell shape while protecting the cell from internal osmotic pressure and external environmental challenges. PG synthesis is essential for bacterial growth and survival, and a series of PG modifications are required to allow expansion of the sacculus. Endopeptidases (EPs), for example, cleave the crosslinks between adjacent PG strands to allow the incorporation of newly synthesized PG. EPs are collectively essential for bacterial growth and must likely be carefully regulated to prevent sacculus degradation and cell death. However, EP regulation mechanisms are poorly understood. Here, we used TnSeq to uncover novel EP regulation factors inVibrio cholerae. This screen revealed that the carboxypeptidase DacA1 (PBP5) alleviates EP toxicity.dacA1is essential for viability on LB medium, and this essentiality was suppressed by EP overexpression, revealing that EP toxicity both mitigates, and is mitigated by, a defect indacA1. A subsequent suppressor screen to restore viability ofΔdacA1in LB medium was answered by hypomorphic mutants in the PG synthesis pathway, as well as mutations that promote PG degradation. Our data thus reveal a key role of DacA1 in maintaining the balance between PG synthesis and degradation.