bluuebunny/crossref_metadata_2025_split huggingface dataset:
En1 and Lmx1b do not recapitulate embryonic dorsal-ventral limb patterning functions during mouse digit tip regeneration
Authors: Johnson Gemma L. , Glasser Morgan B. , Charles Julia F. , Duryea Jeffrey , Lehoczky Jessica A. 
Published: March 2022

ABSTRACTThe mouse digit tip is a complex tissue that is capable of regeneration after amputation. How the regenerated digit tip is patterned is unknown, but a long-standing hypothesis in the field of regeneration proposes that developmental patterning mechanisms are re-used during regeneration. The digit tip bone exhibits strong dorsal-ventral (DV) polarity, so we focus on Engrailed 1 (En1) and LIM homeobox transcription factor 1B (Lmx1b), two well-studied transcription factors necessary for DV patterning during limb development. We investigate if En1 and Lmx1b are re-expressed during regeneration in a developmental-like spatially restricted pattern, and if they direct DV morphology of the regenerated digit tip. We find that both En1 and Lmx1b are expressed in the regenerating mouse digit tip epithelium and mesenchyme, respectively, but without DV polarity. We use conditional genetics and quantitative analysis of digit tip bone morphology to determine that genetic deletion of En1 or Lmx1b in adult digit tip regeneration modestly reduces bone regeneration but does not affect DV patterning of the regenerate. Collectively, our data suggest that while En1 and Lmx1b are re-expressed during mouse digit tip regeneration, they do not define the DV axis during regeneration.
Integrated protein and transcriptome high-throughput spatial profiling
Authors: Ben-Chetrit Nir , Niu Xiang , Swett Ariel D. , Sotelo Jesus , Jiao Maria S. , Roelli Patrick , Stoeckius Marlon , Landau Dan A. 
Published: March 2022

AbstractSpatial transcriptomics and proteomics have independently transformed our understanding of complex biological processes; however, integration of these modalities is currently limited. To overcome this challenge, we developedSpatialPrOtein andTranscriptomeSequencing (SPOTS) for high-throughput integration of transcriptome and protein profiling within the spatial context. Applying SPOTS to spleen and breast cancer samples revealed that spatially-resolved multi-omic integration provides a comprehensive perspective on key biological processes in health and disease.
Multivalent, BispecificαB7-H3-αCD3 Chemically Self-Assembled Nanorings Direct Potent T-cell Responses Against Medulloblastoma
Authors: Mews Ellie A. , Beckmann Pauline J. , Patchava Mahathi , Wang Yiao , Largaespada David A. , Wagner Carston R. 
Published: March 2022

AbstractFew therapeutic options have been made available for treating central nervous system tumors, especially upon recurrence. Recurrent medulloblastoma is uniformly lethal with no approved therapies. Recent preclinical studies have shown promising results for eradicating various solid tumors by targeting the overexpressed immune checkpoint molecule, B7-H3. However, due to several therapy-related toxicities and reports of tumor escape, the full potential of targeting this pan-cancer antigen has yet to be realized. Here, we designed and characterized bispecific chemically self-assembling nanorings (CSANs) that target the T cell receptor, CD3ε, and tumor associated antigen, B7-H3, derived from the humanized 8H9 single chain variable fragment (scFv). We show that theαB7-H3-αCD3 CSANs increase T cell infiltration and facilitate selective cytotoxicity of B7-H3+medulloblastoma spheroids and that activity is independent of target cell MHC class I expression. Importantly, non-specific T cell activation against the ONS 2303 medulloblastoma cell line can be reduced by tuning the valency of theαCD3 targeted monomer in the oligomerized CSAN. Intraperitoneal injections ofαB7-H3-αCD3 bispecific CSANs were found to effectively cross the blood-tumor barrier into the brain and elicit significant anti-tumor T cell activity intracranially as well as systemically in an orthotopic medulloblastoma model. Moreover, following treatment withαB7-H3-αCD3 CSANs, intratumoral CD4+and CD8+T cells were found to primarily have a central memory phenotype that displayed significant levels of characteristic activation markers. Collectively, these results demonstrate the ability of our multi-valent, bispecific CSANs to direct potent anti-tumor T cell responses and indicate its potential utility as an alternative or complementary therapy for immune cell targeting of B7-H3+brain tumors.SignificanceThis study presentsαB7-H3-αCD3 bispecific CSANs as a promising, new immunotherapeutic option for patients with established B7-H3+medulloblastomas.
Cavitation Induced Fracture of Intact Brain Tissue
Authors: Dougan Carey E. , Song Zhaoqiang , Fu Hongbo , Crosby Alfred J. , Cai Shengqiang , Peyton Shelly R. 
Published: March 2022

AbstractNonpenetrating traumatic brain injuries (TBI) are linked to cavitation. The structural organization of the brain makes it particularly susceptible to tears and fractures from these cavitation events, but limitations in existing characterization methods make it difficult to understand the relationship between fracture and cavitation in this tissue. More broadly, fracture energy is an important, yet often overlooked, mechanical property of all soft tissues. We combined needle-induced cavitation (NIC) with hydraulic fracture models to induce and quantify fracture in intact brains at precise locations. We report here the first measurements of the fracture energy of intact brain tissue that range from 1.5 to 8.9 J/m2, depending on the location in the brain and the model applied. We observed that fracture consistently occurs along interfaces between regions of brain tissue. These fractures along interfaces allow cavitation-related damage to propagate several millimeters away from the initial injury site. Quantifying the forces necessary to fracture brain and other soft tissues is critical for understanding how impact and blast waves damage tissue in vivo and has implications for the design of protective gear and tissue engineering.SignificanceMild injuries associated with concussion and blast waves cause tearing of brain tissue, which leads to traumatic brain injury (TBI). TBI is a leading cause of death and disability among children and young adults in the U.S., with 1.5 million Americans reporting a TBI each year. We introduce a novel approach to visualize these tears in intact brain tissue, and report the energies associated with brain fracture. Quantifying the fracture energy of brain, as we have done here, is critical to understand the forces from injury that lead to TBI.
Automation of plate inoculation and reading reduces process time in the clinical microbiology laboratory, compared to a manual workflow
Authors: Peisach Nicole , Krotkov Natalia , Shaye Rachel , Cárdenas Ana María , Powers Richard L. 
Published: March 2022

ABSTRACTWe evaluated the benefits of automation for clinical microbiology laboratory workflow and compared the time required for culture inoculation and plate reading between manual processes and BD Kiestra (but Kiestra) automation. Kiestra automation consists of different modules, each of which facilitate different tasks and work together from specimen inoculation to results reporting. We tracked the steps and measured the associated times-to-completion for both manual and automated workflows, including number of plate touches, hands-on-time (HOT), total technologist time (TTT), and walk-away time (WAT). Manual and automated processes both included 90 samples, and a total of 180 agar plates. There were three media quantity protocols used to mimic common laboratory samples: 1) 30 ‘urine’ specimens on one biplate; 2) 30 ‘urine’ specimens divided across two plates; and 3) 30 ‘blood’ or ‘wound’ specimens divided across three plates; all cultures incubated for a minimum of 18 hours prior to reading or imaging. Automation reduced HOT by 85% and overall plate touches by 88%. Automated inoculation (through implementation of the BD InoqulA module) resulted in a 100% reduction in plate touches and created 81.5-minutes of WAT. Automation of culture reading (through implementation of the BD ReadA incubation/plate imaging module and BD Synapsys Informatics) reduced HOT by 53%. Overall, laboratory automation resulted in shorter TTT and created WAT when compared to manual processes. Automation can facilitate increased processing capacity, more efficient use of the labor force, and reduced time to results in the clinical microbiology laboratory.
Epidemic Model with Direct and Indirect Transmission modes and Two Delays
Authors: Najm F. , Yafia R. , Alaoui M. A. Aziz , Aghriche A. 
Published: March 2022

AbstractWe propose an epidemic model in which all diseases are transmitted by direct transmission (infectives to susceptibles) and indirect transmission which occurs through shedding of virus by infectives and acquisition by susceptibles. The model takes into account the effect of latency period and time needed for a susceptible to become infective by indirect contact. Under the certain assumptions, the basic reproduction number of the model is identified from the direct and indirect basic reproduction numbers. The main goal is to analyse the asymptotic behaviours, global stability, bifurcation and to detecte the most sensitive parameters. Numerical simulations are carried out to illustrate the theoretical part.
The decay of coronavirus in sewage pipes and the development of a predictive model for the estimation of SARS-CoV-2 infection cases based on wastewater surveillance
Authors: Fu Songzhe , Wang Qingyao , He Fenglan , Zhou Can , Zhang Jin , Xia Wen 
Published: March 2022

AbstractWastewater surveillance serves as a promising approach to elucidate the silent transmission of SARS-CoV-2 in a given community by detecting the virus in wastewater treatment facilities. This study monitored the viral RNA abundance at one WWTP and three communities during the COVID-19 outbreak in the Yanta district of Xi’an city from December 2021 to January 2022. To further understand the decay of the coronavirus in sewage pipes, avian infectious bronchitis virus (IBV) was seeded in two recirculating water systems and operated for 90 days. Based on the viral abundance in the wastewater of Xi’an and the above data regarding the decay of coronavirus in sewage pipes, Monte Carol simulations were performed to estimate the infectious cases in Xi’an. The results suggested that the delta variant was first detected on Dec-10, five days earlier than the reported date of clinical samples. SARS-CoV-2 was detected on December 18 in the monitored community two days earlier than the first case and was consecutively detected in the following two sampling times. In pipelines without biofilms, the results showed that high temperature significantly reduced the viral RNA abundance by 2.18 log10 GC/L after experiencing 20 km travel distance, while only a 1.68 log10 GC/L reduction was observed in the pipeline with a low water temperature. After 90 days of operation, the biofilm matured in the pipeline in both systems. Reductions of viral RNA abundance of 2.14 and 4.79 log10 GC/L were observed in low- and high-temperature systems with mature biofilms, respectively. Based on the above results, we adjusted the input parameters for Monte Carol simulation and estimated 23.3, 50.1, 127.3 and 524.2 infected persons in December 14, 18, 22 and 26, respectively, which is largely consistent with the clinical reports. This work highlights the viability of wastewater surveillance for the early warning of COVID-19 at both the community and city levels, which represents a valuable complement to clinical approaches.
[18F]-Labeled PARP-1 PET Imaging of PSMA Targeted Alpha Particle Radiotherapy Response
Authors: Zhang Hanwen , Abou Diane , Villmer Alexandria , Benabdallah Nadia , Jiang Wen , Ulmert David , Carlin Sean , Rogers Buck E. , Turtle Norman F. , McDevitt Michael R. , Baumann Brian , Simons Brian W. , Zhou Dong , Thorek Daniel L. J. 
Published: March 2022

ABSTRACTMotivationThe growing interest and clinical translation of alpha particle (α) therapies brings with it new challenges to assess target cell engagement and to monitor therapeutic effect. Noninvasive imaging has great potential to guide α-treatment and to harness the potential of these agents in the complex environment of disseminated disease. Poly(ADP) ribose polymerase 1 (PARP-1) is among the most abundantly expressed DNA repair enzymes with key roles in multiple repair pathways - such as those induced by irradiation.Materials and MethodsHere, we used a third-generation PARP1-specific radiotracer, [18F]-PARPZ, to delineate castrate resistant prostate cancer xenografts. Following treatment with the clinically applied [225Ac]-PSMA-617, positron emission tomography was performed and analyzed, along with and correlative autoradiography and histology acquired.Results[18F]-PARPZ was able to distinguish treated from control (saline) xenografts by uptake. Kinetic analysis of tracer accumulation also suggests that the localization of the agent to sites of increased PARP-1 expression is a consequence of DNA damage response.ConclusionsTogether, these data support expanded investigation of [18F]-PARPZ to facilitate clinical translation in the α-therapy space.
A naturally arising broad and potent CD4-binding site antibody with low somatic mutation
Authors: Barnes Christopher O. , Schoofs Till , Gnanapragasam Priyanthi N.P. , Golijanin Jovana , Huey-Tubman Kathryn E. , Gruell Henning , Schommers Philipp , Suh-Toma Nina , Lee Yu Erica , Cetrulo Lorenzi Julio C. , Piechocka-Trocha Alicja , Scheid Johannes F. , West Anthony P. , Walker Bruce D. , Seaman Michael S. , Klein Florian , Nussenzweig Michel C. , Bjorkman Pamela J. 
Published: March 2022

AbstractThe induction of broadly neutralizing antibodies (bNAbs) is a potential strategy for a vaccine against HIV-1. However, most bNAbs exhibit features such as unusually high somatic hypermutation, including insertions and deletions, which make their induction challenging. VRC01-class bNAbs exhibit extraordinary breadth and potency, but also rank among the most highly somatically-mutated bNAbs. Here we describe a VRC01-class antibody isolated from a viremic controller, BG24, that has less than half the mutations of most other relatives of its class, while achieving comparable breadth and potency. A 3.8 Å X-ray crystal structure of a BG24-BG505 Env trimer complex revealed conserved contacts at the gp120 interface characteristic of the VRC01-class Abs, despite lacking common CDR3 sequence motifs. The existence of moderately-mutated CD4-binding site (CD4bs) bNAbs such as BG24 provides a simpler blueprint for CD4bs antibody induction by a vaccine, raising the prospect that such an induction might be feasible with a germline-targeting approach.TeaserAn anti-HIV-1 antibody with comparable neutralization breadth and potency to similarly-classed antibodies, with half as many mutations.
The Arabidopsis Hop1 homolog ASY1 mediates cross-over assurance and interference
Authors: Pochon Gaetan , Henry Isabelle M , Yang Chao , Lory Niels , Jiménez Nadia Fernández- , Böwer Franziska , Hu Bingyan , Carstens Lena , Tsai Helen T. , Pradillo Monica , Comai Luca , Schnittger Arp 
Published: March 2022

AbstractThe chromosome axis plays a crucial role in meiotic recombination. Here, we study the function of ASY1, the Arabidopsis homolog of the yeast chromosome axis associated component Hop1. Specifically, we characterized cross-over (CO) distribution in female and male meiosis by deep sequencing of the progeny of an allelic series ofasy1mutants. Combining data from nearly 1000 individual plants, we find that reduced ASY1 activity leads to genomic instability and sometimes drastic genomic rearrangements. We further observed that COs are less frequent and appear in more distal chromosomal regions in plants with no or reduced ASY1 activity, consistent with previous analyses. However, our sequencing approach revealed that the reduction in CO number is not as dramatic as suggested by cytological analyses. Analysis of double mutants ofasy1with mutants with three other CO factors, MUS81, MSH4 and MSH5 as well as the determination of foci number of the CO regulator MLH1 demonstrates that the majority of the COs inasy1, similar to the situation in the wildtype, largely belong to the class I, which are subject to interference. However, these COs are redistributed inasy1mutants and typically appear much closer than in the wildtype. Hence, ASY1 plays a key role in CO interference that spaces COs along a chromosome. Conversely, since a large proportion of chromosomes do not receive any CO, we conclude that CO assurance, the process that ensures the obligatory assignment of one CO per chromosome, is also affected inasy1mutants.Significant statementThe regulation of the number and placement of cross-overs (COs) during meiosis is critical to ensure meiotic fidelity and promote new genetic combinations. Here, we investigated the function of one of the proteins of the chromosome axis, which plays a key role in CO formation: ASY1. Our results show that COs inasy1mutants are positioned closer to each other than in the wildtype and that, despite a roughly similar number of COs, not every chromosome receives a CO. With this, our results shed light on the mechanisms regulating two important but still poorly understood aspects of meiosis: CO assurance, which safeguards at least one CO per chromosome pair, and CO interference, which prevents two COs from occurring close to each other.
Proteome reallocation enables the selective de novo biosynthesis of non-linear, branched-chain acetate esters
Authors: Seo Hyeongmin , Giannone Richard J. , Yang Yung-Hun , Trinh Cong T. 
Published: March 2022

ABSTRACTThe one-carbon recursive ketoacid elongation pathway is responsible for making various branched-chain amino acids, aldehydes, alcohols, and acetate esters in living cells. Controlling selective microbial biosynthesis of these target molecules at high efficiency is challenging due to enzyme promiscuity, regulation, and metabolic burden. In this study, we present a systematic modular design approach to control proteome reallocation for selective microbial biosynthesis of branched-chain acetate esters. Through pathway modularization, we partitioned the branched-chain ester pathways into four submodules including keto-isovalerate submodule for converting pyruvate to keto-isovalerate, ketoacid elongation submodule for producing longer carbon-chain keto-acids, ketoacid decarboxylase submodule for converting ketoacids to alcohols, and alcohol acyltransferase submodule for producing branched-chain acetate esters by condensing alcohols and acetyl-CoA. By systematic manipulation of pathway gene replication and transcription, enzyme specificity of the first committed steps of these submodules, and downstream competing pathways, we demonstrated selective microbial production of isoamyl acetate over isobutyl acetate. We found that the optimized isoamyl acetate pathway globally redistributed the amino acid fractions in the proteomes and required up to 23-31% proteome reallocation at the expense of other cellular resources, such as those required to generate precursor metabolites and energy for growth and amino acid biosynthesis. The engineered strains produced isoamyl acetate at a titer of 8.8 g/L (> 0.25 g/L toxicity limit), a yield of 0.17 g/g (47% of maximal theoretical value), and 86% selectivity, achieving the highest titers, yields and selectivity of isoamyl acetate reported to date.
Resilience of S309 and AZD7442 monoclonal antibody treatments against infection by SARS-CoV-2 Omicron lineage strains
Authors: Case James Brett , Mackin Samantha , Errico John , Chong Zhenlu , Madden Emily A. , Guarino Barbara , Schmid Michael A. , Rosenthal Kim , Ren Kuishu , Jung Ana , Droit Lindsay , Handley Scott A. , Halfmann Peter J. , Kawaoka Yoshihiro , Crowe James E. , Fremont Daved H. , Virgin Herbert W. , Loo Yueh-Ming , Esser Mark T. , Purcell Lisa A. , Corti Davide , Diamond Michael S. 
Published: March 2022

ABSTRACTOmicron variant strains encode large numbers of changes in the spike protein compared to historical SARS-CoV-2 isolates. Although in vitro studies have suggested that several monoclonal antibody therapies lose neutralizing activity against Omicron variants1-4, the effects in vivo remain largely unknown. Here, we report on the protective efficacy against three SARS-CoV-2 Omicron lineage strains (BA.1, BA.1.1, and BA.2) of two monoclonal antibody therapeutics (S309 [Vir Biotechnology] monotherapy and AZD7442 [AstraZeneca] combination), which correspond to ones used to treat or prevent SARS-CoV-2 infections in humans. Despite losses in neutralization potency in cell culture, S309 or AZD7442 treatments reduced BA.1, BA.1.1, and BA.2 lung infection in susceptible mice that express human ACE2 (K18-hACE2). Correlation analyses between in vitro neutralizing activity and reductions in viral burden in K18-hACE2 or human Fcγ R transgenic mice suggest that S309 and AZD7442 have different mechanisms of protection against Omicron variants, with S309 utilizing Fc effector function interactions and AZD7442 acting principally by direct neutralization. Our data in mice demonstrate the resilience of S309 and AZD7442 mAbs against emerging SARS-CoV-2 variant strains and provide insight into the relationship between loss of antibody neutralization potency and retained protection in vivo.
The role of social entrepreneurial leadership and benchmarking in women empowerment
Authors: Dixit Abha R. , Malik Nishtha , Seth Manisha , Sethi Deepa 
Published: March 2022

PurposeWomen are the change agents in today's society. They are not only the harbingers of growth and development but also act as a major catalyst in the economic advancement and prosperity of the nation. India has been witnessing an expansion in women entrepreneurs given the conducive startup ecosystem we have created over the years. It has inspired women to break the shackles and switch to being a game changer for themselves and many others over the years. The study aims to explore the impact of social entrepreneurial leadership on women empowerment and how does benchmarking help in this process.Design/methodology/approachUsing a semi-structured questionnaire, the study conducted one-to-one in-depth and focused group interviews with the five women social entrepreneurs and their team. NVivo was used for content and thematic analysis.FindingsMajor themes identified from the study include financial independence, women empowerment, social identity, autonomy, mobility, attaining self-confidence, creativity and innovation, fulfillment of motives, action and social learning, and setting standards (benchmarks). The findings revealed that social entrepreneurial leadership has a significant impact on women empowerment through benchmarking.Originality/valueSocial entrepreneurial leadership has the potential to revolutionize the very concept of women empowerment. The research tries to study specific cases of social entrepreneurial leadership and how they have been instrumental in shaping up the life of others through their efforts and determination.