bluuebunny/crossref_metadata_2025_split huggingface dataset:
Germinal center responses to SARS-CoV-2 mRNA vaccines in healthy and immunocompromised individuals
Authors: Lederer Katlyn , Parvathaneni Kalpana , Painter Mark M. , Bettini Emily , Agarwal Divyansh , Lundgreen Kendall A. , Weirick Madison , Goel Rishi R. , Xu Xiaoming , Drapeau Elizabeth M. , Gouma Sigrid , Greenplate Allison R. , Coz Carole Le , Romberg Neil , Jones Lisa , Rosen Mark , Besharatian Behdad , Kaminiski Mary , Weiskopf Daniela , Sette Alessandro , Hensley Scott E. , Bates Paul , Wherry E. John , Naji Ali , Bhoj Vijay , Locci Michela 
Published: September 2021

SUMMARYVaccine-mediated immunity often relies on the generation of protective antibodies and memory B cells, which commonly stem from germinal center (GC) reactions. An in-depth comparison of the GC responses elicited by SARS-CoV-2 mRNA vaccines in healthy and immunocompromised individuals has not yet been performed due to the challenge of directly probing human lymph nodes. In this study, through a fine-needle-aspiration-based approach, we profiled the immune responses to SARS-CoV-2 mRNA vaccines in lymph nodes of healthy individuals and kidney transplant (KTX) recipients. We found that, unlike healthy subjects, KTX recipients presented deeply blunted SARS-CoV-2-specific GC B cell responses coupled with severely hindered T follicular helper cells, SARS-CoV-2 receptor-binding-domain-specific memory B cells and neutralizing antibodies. KTX recipients also displayed reduced SARS-CoV-2-specific CD4 and CD8 T cell frequencies. Broadly, these data indicate impaired GC-derived immunity in immunocompromised individuals, and suggest a GC-origin for certain humoral and memory B cell responses following mRNA vaccination.
Optimized Post-Vaccination Strategies and Preventative Measures for SARS-CoV-2
Authors: Pettit Rowland , Peng Bo , Yu Patrick , Matos Peter G. , Greninger Alexander L. , McCashin Julie , Amos Christopher Ian 
Published: September 2021

AbstractIntroductionSince March of 2020, over 210 million SARS-CoV-2 cases have been reported and roughly five billion doses of a SARS-CoV-2 vaccine have been delivered. The rise of the more infectious delta variant has recently indicated the value of reinstating previously relaxed non-pharmacological and test-driven preventative measures. These efforts have been met with resistance, due, in part, to a lack of site-specific quantitative evidence which can justify their value. As vaccination rates continue to increase, a gap in knowledge exists regarding appropriate thresholds for escalation and de-escalation of COVID-19 preventative measures.MethodsWe conducted a series of simulation experiments, trialing the spread of SARS-CoV-2 virus in a hypothesized working environment that is subject to COVID-19 infections from the surrounding community. We established cohorts of individuals who would, in simulation, work together for a set period of time. With these cohorts, we tested the rates of workplace and community acquired infections based on applied isolation strategies, community infection rates (CIR), scales of testing, non-pharmaceutical interventions, variant predominance’s and testing strategies, vaccination coverages, and vaccination efficacies of the members included. Permuting through each combination of these variables, we estimated expected case counts for 33,462 unique workplace scenarios.ResultsWhen the CIR is 5 new confirmed cases per 100,000 or fewer, and at 50% of the workforce is vaccinated with a 95% efficacious vaccine, then testing daily with an antigen-based or PCR based test in only unvaccinated workers will result in less than one infection through 4,800 person weeks. When the community infection rate per 100,000 persons is less than or equal to 60, and the vaccination coverage of the workforce is 100% with 95% vaccine efficacy then no masking or routine testing + isolation strategies are needed to prevent workplace acquired infections regardless of variant predominance. Identifying and isolating workers with antigen-based SARS-CoV-2 testing methods results in the same or fewer workplace acquired infections than testing with polymerase chain reaction (PCR) methods.ConclusionsSpecific scenarios exist in which preventative measures taken to prevent SARS-CoV-2 spread, including masking, and testing plus isolation strategies can safely be relaxed. Further, efficacious testing with quarantine strategies exist for implementation in only unvaccinated cohorts in a workplace. Due to shorter turnaround time, antigen-based testing with lower sensitivity is more effective than PCR testing with higher sensitivities in comparable testing strategies. The general reference interactive heatmap we provide can be used for site specific, immediate, parameter-based case count predictions to inform appropriate institutional policy making.
Phenotypic Heterogeneity Facilitates Survival While Hindering the Evolution of Drug Resistance Due to Intraspecific Competition
Authors: Guthrie Joshua , Charlebois Daniel A. 
Published: September 2021

ABSTRACTRising rates of resistance to antimicrobial drugs threatens the effective treatment of infections across the globe. Drug resistance has been established to emerge from non-genetic mechanisms, such as “persistence” in quiescent microbes and fluctuations in gene expression in actively replicating cells, as well as from genetic mutations. However, it is still unclear how non-genetic drug resistance affects the evolution of genetic drug resistance. We develop deterministic and stochastic population models that incorporate resource competition to quantitatively investigate the transition from non-genetic to genetic resistance during the exposure to static and cidal drugs. We find that non-genetic resistance facilitates the survival of cell populations during drug treatment, but that it hinders the development of genetic resistance due to the competition between the non-genetically and genetically resistant subpopulations. Non-genetic drug resistance in the presence of subpopulation competition is found to increase the first-appearance and fixation times of drug resistance mutations, while increasing the probability of mutation before population extinction during cidal drug treatment. Intense intraspecific competition during drug treatment leads to extinction of the susceptible and non-genetically resistant subpopulations. These findings advance our fundamental understanding of the evolution of drug resistance and may guide novel treatment strategies for patients with drug-resistant infections.SIGNIFICANCEDrug resistance is predicted to kill as many as 10 million people per year and cost over 100 trillion USD in cumulative lost production globally by 2050. To mitigate these socio-economic costs, we need to fundamentally understand the drug resistance process. We investigate the effect that different forms of resistance have on the evolution of drug resistance using mathematical modeling and computer simulations. We find that the presence of non-genetically drug-resistant cells (whose resistance is temporary and not encoded in a genetic mutation) allows the population to survive drug treatment, while competition between these subpopoulations simultaneously slows down the evolution of permanent genetic drug resistance and in some cases drives them extinct. These findings have important implications for advancing evolutionary theory and for developing effective “resistance-proof” treatments.
Hydroxyl radical footprinting analysis of a human haptoglobin-hemoglobin complex
Authors: Loginov Dmitry S. , Fiala Jan , Brechlin Peter , Kruppa Gary , Novak Petr 
Published: September 2021

AbstractMethods of structural mass spectrometry have become more popular to study protein structure and dynamics. Among them, fast photochemical oxidation of proteins (FPOP) has several advantages such as irreversibility of modifications and more facile determination of the site of modification with single residue resolution. In the present study, FPOP analysis was applied to study the hemoglobin (Hb) – haptoglobin (Hp) complex allowing identification of respective regions altered upon the complex formation. Oxidative modifications were precisely localized on specific residues using a timsTOF Pro mass spectrometer. The data allowed determination of amino acids directly involved in Hb – Hp interactions and those located outside of the interaction interface yet affected by the complex formation. Data are available via ProteomeXchange with identifier PXD021621.
A novel R3H protein, OsDIP1, confers ABA-mediated adaptation to drought and salinity stress in rice
Authors: Huang Liping , Tanveer Mohsin , Ji E , Shabala Sergey , Jiang Mingyi 
Published: September 2021

AbstractAbscisic acid (ABA) is a key component of many signaling networks mediating plant adaptation to various stresses. In this context, ABA-induced antioxidant defence is considered to be a main mechanism to that enhances water stress tolerance in plants. The specific details of this activation remain, however, elusive. In this work, we show that DIP1, a protein from novel R3H family, played a central role in modulating water stress tolerance in rice. OsDIP1 transcripts were induced by hydrogen peroxide (H2O2), ABA, drought (polyethylene glycol treatment), and salt stress. Overexpression of OsDIP1 in rice enhanced drought and salinity tolerance while knocking out OsDIP1 by CRISPR-Cas9 editing resulted in drought and salt sensitive phenotype. The activity and gene expression of antioxidant defence enzymes, superoxide dismutase (SOD), catalase (CAT), increased in OsDIP1-overexpressed transgenic rice plants, while the content of malondialdehyde (MDA) decreased. In contrast, the content and gene expression of SOD and CAT, decreased, and the content of MDA increased in knockout of OsDIP1 rice plants, suggesting that overexpression of OsDIP1 enhances the antioxidant capacity of rice plants. The yeast two hybrid screening test revealed that OsDIP1 interacted with ZFP36, a key zinc finger transcription factor involved in ABA-induced antioxidant defence. Moreover, OsDIP1 could modulate some key ABA-responsive genes via interacting with ZFP36. Overall, our findings indicate an important role of OsDIP1 in ABA-induced antioxidant defence signaling and adaptation to salinity and drought in rice.
Loss ofFgfr1andFgfr2in Scleraxis-lineage cells leads to enlarged bone eminences and attachment cell death
Authors: Wernlé Kendra K. , Sonnenfelt Michael A. , Leek Connor C. , Ganji Elahe , Tata Zachary , Sullivan Anna Lia , Paparella Elijah , Offutt Claudia , Shuff Jordan , Ornitz David M. , Killian Megan L. 
Published: September 2021

AbstractTendons and ligaments are structural tissues that attach to bone and are essential for joint mobility and stability in vertebrates. Tendon and ligament attachments (i.e., entheses) are often found at bony protrusions (i.e., eminences), and the shape and size of these protrusions depends on both mechanical forces and cellular cues during growth and development. The formation of tendon eminences also contributes to mechanical leverage for skeletal muscle. Fibroblast growth factor receptor (FGFR) signaling plays a critical role in bone development, andFgfr1andFgfr2are highly expressed in the perichondrium and periosteum of bone where tendon and ligament attachments can be found. However, the role of FGFR signaling in attachment development and maintenance in the limb remains unknown. In this study, we used transgenic mouse models for combinatorial knockout ofFgfr1and/orFgfr2in tendon/ligament and attachment progenitors using ScxCre and measured eminence size and bone shape in the appendicular skeleton. Conditional deletion of both, but not individual,Fgfr1andFgfr2inScxprogenitors led to enlarged eminences in the postnatal appendicular skeleton and smaller secondary ossification centers in long bones. In addition,Fgfr1 Fgfr2double conditional knockout mice had more variation in the size of collagen fibrils in tendon, narrowed synovial joint spacing, and increased cell death at sites of ligament attachments, as well as decreased plasticity of mature bone compared to age-matched wildtype littermates. These findings identify a role for FGFR signaling in regulating growth and maintenance of tendon/ligament attachments and the size and shape of bony eminences.
Synergic Renoprotective Effects Of Combined ASC Therapy With RAAS Blockade In Experimental Advanced CKD
Authors: Maires Marina PC , Pereira Krislley R , Silva Everidiene KVB , Souza Victor HR , Teles Flavio , Barbosa Paulyana F , Garnica Margoth R , Ornellas Felipe M , Noronha Irene L , Fanelli Camilla 
Published: September 2021

ABSTRACTGlobal prevalence of chronic kidney disease (CKD) has increased considerably in the recent decades. Overactivity of the renin-angiotensin-aldosterone system (RAAS), associated to renal inflammation and fibrosis contribute to its evolution. The treatments currently employed to control CKD progression are limited and mainly based on the pharmacological inhibition of RAAS, associated with diuretics and immunosuppressive drugs. However, this conservative management promotes only partial deceleration of CKD evolution, and does not completely avoid the progression of the disease and the loss of renal function, which motivates the medical and scientific community to investigate new therapeutic approaches to detain renal inflammation / fibrosis and CKD progression. Recent studies have shown the application of mesenchymal stem cells (mSC) to exert beneficial effects on the renal tissue of animals submitted to experimental models of CKD. In this context, the aim of the present study was to evaluate the effects of subcapsular application of adipose tissue-derived mSC (ASC) in rats submitted to the 5/6 renal ablation model, 15 days after the establishment of CKD, when the nephropathy was already severe. We also verify whether ASC associated to Losartan, would promote greater renoprotection when compared to the respective monotherapies. Animals were followed until 30 days of CKD, when body weight, systolic blood pressure, biochemical, histological, immunohistochemical and gene expression analysis were performed. The combination of ASC and Losartan was more effective than Losartan monotherapy in reducing systolic blood pressure and glomerulosclerosis, and also promoted the complete normalization of proteinuria and albuminuria, a significant reduction in renal interstitial macrophage infiltration and downregulation of renal IL-6 gene expression. The beneficial effects of ACS are possibly due to the immunomodulatory and anti-inflammatory role of factors secreted by these cells, modulating the local immune response. Although studies are still required, our results demonstrated that a subcapsular inoculation of ASC, associated with the administration of Losartan, exerted additional renoprotective effect in rats submitted to a severe model of established CKD, when compared to Losartan monotherapy, thus suggesting ASC may be a potential adjuvant to RAAS-blockade therapy currently employed in the conservative management of CKD.
Efficient targeted transgenesis of large donor DNA into multiple mouse genetic backgrounds using bacteriophage Bxb1 integrase
Authors: Low Benjamin E. , Hosur Vishnu , Lesbirel Simon , Wiles Michael V. 
Published: September 2021

AbstractEfficient, targeted integration of large DNA constructs represent a significant hurdle in genetic engineering for the development of mouse models of human disease and synthetic biology research. To address this, we developed a system for efficient and precise, targeted single-copy integration of large transgenes directly into the zygote using multiple mouse genetic backgrounds. Conventional approaches, such as random transgenesis, CRISPR/Cas9-mediated homology-directed repair (HDR), lentivirus-based insertion, or DNA transposases all have significant limitations. Our strategy uses in vivo Bxb1 mediated recombinase-mediated cassette exchange (RMCE) to efficiently generate precise single-copy integrations of transgenes. This is achieved using a transgene “landing pad” composed of dual heterologous Bxb1 attachment (att) sites in cis, pre-positioned in the Gt(ROSA)26Sor safe harbor locus. Successful RMCE is achieved in att carrier zygotes using donor DNA carrying cognate attachment sites flanking the desired donor transgene microinjected along with Bxb1-integrase mRNA. This approach routinely achieves perfect vector-free integration of donor constructs at efficiencies as high as 43% and has generated transgenic animals containing inserts up to ∼43kb. Furthermore, when coupled with a nanopore-based Cas9-targeted sequencing (nCATS) approach, complete verification of the precise insertion sequence can be achieved. As a proof-of-concept we describe the creation and characterization of C57BL/6J and NSG Krt18-ACE2 transgenic mouse models for SARS-CoV2 research with verified heterozygous N1 animals available for experimental use in ∼4 months. In addition, we created a diverse series of mouse backgrounds carrying a single att site version of the landing pad allele in C57BL/6J, NSG, B6(Cg)-Tyrc-2J/J, FVB/NJ, PWK/PhJ, 129S1/SvImJ, A/J, NOD/ShiLtJ, NZO/HILtJ, CAST/EiJ, and DBA/2J for rapid transgene insertion. Combined, this system enables predictable, rapid creation of precisely targeted transgenic animals across multiple genetic backgrounds, simplifying characterization, speeding expansion and use.
HCN2 in cholinergic interneurons of the nucleus accumbens mediates reward response
Authors: Lee J , Weinberger M , Kawahara Y , Cheng J , Umschweif G , Medrihan L , Flajolet M , Nishi A , Sagi Y 
Published: September 2021

SummaryCholinergic interneurons (ChIs) of the nucleus accumbens (NAc) are important for mediating the behavioral response to rewarding stimuli. A major role for these cells is to regulate dopamine (DA) transmission by activating cholinergic receptors at local DAergic nerve terminals. However, the mechanisms that enable cholinergic neurons to enhance DA release in response to reward remain unknown. Here we report that the hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2) in NAc ChIs mediates an enhancement in DA signaling in response to rewarding stimuli. The HCN current in NAc ChIs and its modulation by DA, as well as the increase in cholinergic efflux by local cocaine infusion were impaired in mice with deletion of HCN2 in cholinergic cells. Enhancement in the DA efflux and signaling in the NAc in response to rewarding stimuli, as well as cocaine conditioning were also dependent on HCN2 in ChIs. These results provide a mechanistic link between the activity of NAc ChIs and reward encoding.
Experimental evidence for the gaze-signaling hypothesis: White sclera enhances the visibility of eye-gaze direction in humans and chimpanzees
Authors: Kano Fumihiro , Kawaguchi Yuri , Yeow Hanling 
Published: September 2021

AbstractHallmark social activities of humans, such as cooperation and cultural learning, involve eye-gaze signaling through joint attentional interaction and ostensive communication. The gaze-signaling and related cooperative-eye hypotheses posit that humans evolved unique external eye morphology, including exposed white sclera (the white of the eye), to enhance the visibility of eye-gaze for conspecifics. However, experimental evidence is still lacking. This study tested the ability of human and chimpanzee participants to detect the eye-gaze directions of human and chimpanzee images in computerized tasks. We varied the level of brightness and size in the stimulus images to examine the robustness of the eye-gaze directional signal against visually challenging conditions. We found that both humans and chimpanzees detected gaze directions of the human eye better than that of the chimpanzee eye, particularly when eye stimuli were darker and smaller. Also, participants of both species detected gaze direction of the chimpanzee eye better when its color was inverted compared to when its color was normal; namely, when the chimpanzee eye has artificial white sclera. White sclera thus enhances the visibility of eye-gaze direction even across species, particularly in visually challenging conditions. Our findings supported but also critically updated the central premises of the gaze-signaling hypothesis.
Self-organized emergence of hyaline cartilage in hiPSC-derived multi-tissue organoids
Authors: Li Manci , Abrahante Juan E. , Vegoe Amanda , Chai Yi Wen , Lindborg Beth , Toth Ferenc , Larsen Peter A. , O’Brien Timothy D. 
Published: September 2021

AbstractDespite holding great therapeutic potential, existing protocols for in vitro chondrogenesis and hyaline cartilage production from human induced pluripotent stem cells (hiPSC) are laborious and complex with unclear long-term consequences. Here, we developed a simple xeno- and feeder-free protocol for human hyaline cartilage production in vitro using hydrogel-cultured multi-tissue organoids (MTOs). We investigate gene regulatory networks during spontaneous hiPSC-MTO differentiation using RNA sequencing and bioinformatic analyses. We find the interplays between BMPs and neural FGF pathways are associated with the phenotype transition of MTOs. We recognize TGF-beta/BMP and Wnt signaling likely contribute to the long-term maintenance of MTO cartilage growth and further adoption of articular cartilage development. By comparing the MTO transcriptome with human lower limb chondrocytes, we observe that the expression of chondrocyte-specific genes in MTO shows a strong correlation with fetal lower limb chondrocytes. Collectively, our findings describe the self-organized emergence of hyaline cartilage in MTO, its associated molecular pathways, and its spontaneous adoption of articular cartilage development trajectory.
Ownership structure and real earnings management: evidence from an emerging market
Authors: AL-Duais Shaker Dahan , Malek Mazrah , Abdul Hamid Mohamad Ali , Almasawa Amal Mohammed 
Published: September 2021

PurposeThis study aims to investigate the monitoring role of ownership structure (OWS) on real earnings management (REM) practices; previous studies primarily examined the effect of OWS on accrual-based earnings management.Design/methodology/approachThe sample of this study is 490 companies listed on the Malaysian Stock Exchange during the period 2013–2016 (1,960 company-year observations). The regression of a feasible generalized least square was used for data analysis. The authors use three regression models ordinary least squares, panel-corrected standard errors and Driscoll–Kraay standard errors to corroborate the findings and also examine alternative REM measures.FindingsAnalysis of the data shows that family, foreign and institutional ownership has a positive link with the quality of financial reporting and, to a large extent, is capable of alleviating REM. The findings also indicate that some form of OWS significantly affects REM, corroborating existing theories on corporate governance (CG) and the perspectives of practitioners.Practical implicationsThe evidence concerns the significant role played by the OWS in reducing REM activities. The findings are useful in support of regulatory activities, particularly in the design of policies to regulate the OWS. The results may also provide useful insights to inform other policymakers, investors, shareholders and researchers about the active role of family, foreign and institutional investors in monitoring Malaysia's public listed companies (PLCs) to strengthen CG practices. This also leads to less REM and enhances the quality of financial reporting.Originality/valueTo the authors' knowledge, this work is pioneering research from a developing country, specifically from Malaysia, to investigate the manner in which all possible OWSs influence REM. More importantly, the study recommends that regulators and researchers do not envisage OWS as a holistic phenomenon.