bluuebunny/crossref_metadata_2025_split huggingface dataset:
Redefining typhoid diagnosis: what would an improved test need to look like?
Authors: Mather Richard , Hopkins Heidi , Parry Christopher M. , Dittrich Sabine 
Published: July 2019

IntroductionTyphoid fever is one of the most common bacterial causes of acute febrile illness in the developing world, with an estimated 10.9 million new cases and 116.8 thousand deaths in 2017. Typhoid point-of-care (POC) diagnostic tests are widely used but have poor sensitivity and specificity, resulting in antibiotic overuse that has led to the emergence and spread of multidrug resistant strains. With recent advances in typhoid surveillance and detection, this is the ideal time to produce a target product profile (TPP) that guides product development and ensure that a next-generation test meets the needs of users in the resource-limited settings where typhoid is endemic.MethodsA structured literature review was conducted to develop a draft TPP for a next-generation typhoid diagnostic test with minimal and optimal desired characteristics for 36 test parameters. The TPP was refined using feedback collected from a Delphi survey of key stakeholders in clinical medicine, microbiology, diagnostics and public and global health.ResultsA next-generation typhoid diagnostic test should improve patient management through the diagnosis and treatment of infection with acute Salmonella enterica serovars Typhi or Paratyphi with a sensitivity ≥90% and specificity ≥95%. The test would ideally be used at the lowest level of the healthcare system in settings without a reliable power or water supply and provide results in less than 15 minutes at a cost of <$1.00 USD.ConclusionThis report outlines the first comprehensive TPP for typhoid fever and is intended to guide the development of a next-generation typhoid diagnostic test. An accurate POC test will reduce the morbidity and mortality of typhoid fever through rapid diagnosis and treatment and will have the greatest impact in reducing antimicrobial resistance if it is combined with diagnostics for other causes of acute febrile illness in a treatment algorithm.
Ethnicity and acculturation: Asian American substance use from early adolescence to mature adulthood
Authors: Ahmmad Zobayer , Adkins Daniel E. 
Published: July 2019

AbstractResearch on Asian American substance use has, to date, been limited by monolithic conceptions of Asian identity, inadequate attention to acculturative process, and a dearth of longitudinal analyses spanning developmental periods. Using five waves of the National Longitudinal Study of Adolescent to Adult Health, this study addresses these limitations by longitudinally investigating disparities in substance use from early adolescence into mature adulthood among Asian American ethnic groups, including subjects identifying as multiple Asian ethnicities and multiracial Asians. The conditional effects of acculturation indicators (e.g., nativity generation, co-ethnic peer networks, co-ethnic neighborhood concentration) on the substance use outcomes were also examined. Results indicate significant variation across Asian ethnicities, with the lowest probabilities of substance use among Chinese and Vietnamese Americans, and the highest among multiracial Asian Americans. Acculturation indicators were also strongly, independently associated with increased substance use, and attenuated many of the observed ethnic disparities, particularly for multiracial, multiethnic, and Japanese Asian Americans. This study argues that ignoring the diversity of Asian ethnicities masks the presence of high-risk Asian American groups. Moreover, results indicate that, among Asian Americans, substance use is strongly positively associated with acculturation to U.S. cultural norms, and generally peaks at later ages than the U.S. average.
Deficient goal-directed control in a population characterized by extreme goal pursuit
Authors: Foerde Karin , Daw Nathaniel D. , Rufin Teresa , Walsh B Timothy , Shohamy Daphna , Steinglass Joanna E. 
Published: July 2019

AbstractComputational neuroscience has contributed to understanding compulsive behavior by distinguishing habitual from goal-directed choice through model-free and model-based learning. Yet, questions remain about applying this approach to psychiatric conditions that are characterized by complex behaviors that occur outside the laboratory. Here, we compared individuals with anorexia nervosa (AN), whose self-starvation appears both excessively goal-directed and habitual, with healthy controls (HC) to assess: 1) whether their behavior is characterized by enhanced or diminished model-based behavior, 2) the domain specificity of any abnormalities by comparing learning in a food-specific context as well as in a monetary context, and 3) whether impairments are secondary to starvation by comparing learning before and after initial treatment. Across all conditions, individuals with AN showed an impairment in model-based, but not model-free, learning, suggesting a general and persistent contribution of habitual over goal-directed control, across domains and timepoints.
Horse gluteus is a null-sarcolipin muscle with enhanced sarcoplasmic reticulum calcium transport
Authors: Autry Joseph M. , Karim Christine B. , Svensson Bengt , Carlson Samuel F. , Cocco Mariana , Perumbakkam Sudeep , Chen Zhenhui , Espinoza-Fonseca L. Michel , Finno Carrie J. , Thomas David D. , Valberg Stephanie J. 
Published: July 2019

AbstractWe have analyzed gene transcription, protein expression, and enzymatic activity of the Ca2+-transporting ATPase (SERCA) in horse gluteal muscle. Horses are bred for peak athletic performance but exhibit a high incidence of exertional rhabdomyolysis, with myosolic Ca2+suggested as a correlative linkage. To assess Ca2+regulation in horse gluteus, we developed an improved protocol for isolating horse sarcoplasmic reticulum (SR) vesicles. RNA-seq and immunoblotting determined that theATP2A1gene (protein product SERCA1) is the predominant Ca2+-ATPase expressed in horse gluteus, as in rabbit muscle. Gene expression was assessed for four regulatory peptides of SERCA, finding that sarcolipin (SLN) is the predominant regulatory peptide transcript expressed in horse gluteus, as in rabbit muscle. Surprisingly, the RNA transcription ratio ofSLN-to-ATP2A1in horse gluteus is an order of magnitude higher than in rabbit muscle, but conversely, the protein expression ratio of SLN-to-SERCA1 in horse gluteus is an order of magnitude lower than in rabbit. Thus, theSLNgene is not translated to a stable protein in horse gluteus, yet the supra-high level ofSLNRNA suggests a non-coding role. Gel-stain analysis revealed that horse SR expresses calsequestrin (CASQ) protein abundantly, with a CASQ-to-SERCA ratio ∼3-fold greater than rabbit SR. The Ca2+transport rate of horse SR vesicles is ∼2-fold greater than rabbit SR, suggesting horse myocytes have enhanced luminal Ca2+stores that increase intracellular Ca2+release and muscular performance. The absence of SLN inhibition of SERCA and the abundant expression of CASQ may potentiate horse muscle contractility and susceptibility to exertional rhabdomyolysis.
Automated osteosclerosis grading of clinical biopsies using infrared spectroscopic imaging
Authors: Mankar Rupali , Bueso-Ramos Carlos E. , Yin C. Cameron , Hidalgo-Lopez Juliana E. , Berisha Sebastian , Kansiz Mustafa , Mayerich David 
Published: July 2019

AbstractOsteosclerosis and myefibrosis are complications of myeloproliferative neoplasms. These disorders result in excess growth of trabecular bone and collagen fibers that replace hematopoietic cells, resulting in abnormal bone marrow function. Treatments using imatinib and JAK2 pathway inhibitors can be effective on osteosclerosis and fibrosis, therefore accurate grading is critical for tracking treatment effectiveness. Current grading standards use a four-class system based on analysis of biopsies stained with three histological stains: hematoxylin and eosin (H&E), Masson’s trichrome, and reticulin. However, conventional grading can be subjective and imprecise, impacting the effectiveness of treatment. In this paper, we demonstrate that mid-infrared spectroscopic imaging may serve as a quantitative diagnostic tool for quantitatively tracking disease progression and response to treatment. The proposed approach is label-free and provides automated quantitative analysis of osteosclerosis and collagen fibrosis.
In situ, fluorescence lifetime-based measurements of cell membrane micromechanics
Authors: Son S , Muddana HS , Huang C , Zhang S , Butler PJ 
Published: July 2019

ABSTRACTMicroscopic in situ measurements of the mechanical properties of lipid bilayers were derived from the mean and variance of the fluorescence lifetime distributions of 1’-dioctadecyl-3,3,3’3’-tetramethylindocarbocyanine perchlorate (DiI). In this method, DiI, incorporated into membranes, acts as a membrane-targeted molecular rotor whose fluorescence lifetime is sensitive to local lipid viscosity. A new model was developed in which changes in area per lipid were derived from the first and second moments of a stretched exponential distribution of fluorescence lifetimes of DiI, which were subsequently used to compute mean area per lipid and its variance, quantities directly related to bilayer compressibility and bending moduli. This method enabled molecular scale assays of surface micromechanics of membrane-bound entities, such as nanoliposomes and human red blood cells.STATEMENT OF SIGNIFICANCEDespite the progress in cell deformability studies, and in understanding mechanical properties of purified lipid bilayers, there has not, to date, been a method to measure the mechanics of the lipid bilayer in cells in situ. The current manuscript describes such a method. Using a fluorescent molecular rotor, DiI, embedded in the membrane, along with time resolved fluorescence, we directly measure area per lipid, and its temporal and spatial variance, properties directly related to bilayer mechanical moduli. Such a method will allow investigators to start exploring the relationship between lipid bilayer mechanics and cellular health and disease.
Single Cell Analysis Reveals Partial Reactivation of X-chromosome Instead of Chromosome-wide Dampening in Naïve Human Pluripotent Stem Cells
Authors: Mandal S , Chandel D , Kaur H , Majumdar S , Arava M , Gayen S 
Published: July 2019

AbstractRecently, a unique form of X-chromosome dosage compensation has been demonstrated in human preimplantation embryos, which happens through the dampening of X-linked gene expression from both X-chromosomes. Subsequently, X-chromosome dampening has also been demonstrated in female human pluripotent stem cells (hPSCs) during the transition from primed to naïve state. However, the existence of dampened X-chromosomes remains controversial in both embryos and hPSCs. Specifically, in preimplantation embryos it has been shown that there is inactivation of X-chromosome instead of dampening. Here, we have performed allelic analysis of X-linked genes at the single cell level in hPSCs and found that there is partial reactivation of the inactive X-chromosome instead of chromosome-wide dampening upon conversion from primed to naïve state. In addition, our analysis suggests that the reduced X-linked gene expression in naïve hPSCs might be the consequence of erasure of active X-chromosome upregulation.
Pre- and post-synaptic roles for DCC in memory consolidation in the adult mouse hippocampus
Authors: Glasgow Stephen D. , Wong Edwin W. , Thompson-Steckel Greta , Séguéla Philippe , Ruthazer Edward S. , Kennedy Timothy E. 
Published: July 2019

AbstractThe receptor deleted in colorectal cancer (DCC) and its ligand netrin-1 are essential for axon guidance during development and are expressed by neurons in the mature brain. Netrin-1 recruits GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) and is critical for long-term potentiation (LTP) at CA3-CA1 hippocampal Schaffer collateral synapses, while conditional DCC deletion from glutamatergic neurons impairs hippocampal-dependent spatial memory and severely disrupts LTP induction. DCC co-fractionates with the detergent-resistant component of the postsynaptic density, yet is enriched in axonal growth cones that differentiate into presynaptic terminals during development. Specific presynaptic and postsynaptic contributions of DCC to the function of mature neural circuits have yet to be identified. Employing hippocampal subregion-specific conditional deletion of DCC, we show that DCC loss from CA1 hippocampal pyramidal neurons results in deficits in spatial memory, increased resting membrane potential, abnormal dendritic spine morphology, and weaker spontaneous excitatory postsynaptic activity. In contrast, deletion of DCC from CA3 neurons did not induce detectable changes in spine morphology or intrinsic electrophysiological properties of CA1 pyramidal neurons, but resulted in impaired performance on the novel object place recognition task as well as compromised excitatory synaptic transmission and long-term potentiation (LTP) at the Schaffer collateral synapse. Together, these findings reveal that DCC makes specific pre- and post-synaptic contributions to hippocampal synaptic plasticity underlying spatial memory.
AAV mediated delivery of a novel anti-BACE1 VHH reduces Abeta in an Alzheimer’s disease mouse model
Authors: Rincon Melvin Y. , Zhou Lujia , Marneffe Catherine , Voytyuk Iryna , Wouters Yessica , Dewilde Maarten , Duqué Sandra I. , Vincke Cécile , Levites Yona , Golde Todd E. , Muyldermans Serge , De Strooper Bart , Holt Matthew G. 
Published: July 2019

ABSTRACTSingle domain antibodies (VHH) are potentially disruptive therapeutics, with important biological value for treatment of several diseases, including neurological disorders. However, VHH have not been widely used in the central nervous system (CNS), as it is hard to reach therapeutic levels, both because of their restricted blood-brain-barrier penetration and their apparent rapid clearance from the parenchyma. Here, we propose a gene transfer strategy based on adeno-associated virus (AAV)-based vectors to deliver VHH directly into the CNS, ensuring continuous production at therapeutic levels. As a proof-of-concept, we explored the potential of AAV-delivered VHH to inhibit BACE1, a well-characterized target in Alzheimer’s disease. First, we generated a panel of VHHs targeting BACE1. One of them, VHH-B9, showed high selectivity for BACE1 and efficacy in lowering BACE1 activity in vitro. We then went on to demonstrate significant reductions in amyloid beta (Aβ) levels after AAV-based delivery of VHH-B9 into the CNS of a mouse model of cerebral amyloidosis. These results constitute a novel therapeutic approach for neurodegenerative diseases, which is applicable to a range of CNS disease targets.
Transfer of Septin Rings to Cytokinetic Remnants Directs Age-Sensitive ER stress Surveillance Cell Cycle Re-entry
Authors: Chao Jesse T. , Piña Francisco , Onishi Masayuki , Cohen Yifat , Schuldiner Maya , Niwa Maho 
Published: July 2019

SUMMARYDuring cell division, cells must actively pass on organelles. Previously, we discovered the endoplasmic reticulum (ER) stress surveillance (ERSU) pathway that ensures the inheritance of functional ER. Activation of the ERSU causes the septin ring to mislocalize, which blocks ER inheritance and cytokinesis. Here, we found that the septin ring mislocalizes to previously utilized cell division sites called cytokinetic remnants (CRMs). The transfer of the septin ring to CRMs requires Nba1, a negative polarity component that normally prevents septin ring formation at CRMs. Furthermore, septin ring movement to CRMs relies on the ERSU component Slt2, which is recruited by binding Bem1. During ER stress, Bem1 also binds the GTP exchange factor Cdc24, without activating Cdc42, a GTPase that normally establishes polarized growth. Failure to translocate septin rings to CRMs delays the cell’s ability to re-enter cell division when ER homeostasis is re-established. Thus, ER stress considers the history of previous cell cycle for future cell cycle re-entry upon ER stress recovery.
Rectus femoris hyperreflexia predicts knee flexion angle in Stiff-Knee gait after stroke
Authors: Akbas Tunc , Kim Kyoungsoon , Doyle Kathleen , Manella Kathleen , Lee Robert , Spicer Patrick , Knikou Maria , Sulzer James 
Published: July 2019

AbstractStiff-knee gait (SKG) after stroke is often accompanied by decreased knee flexion angle during the swing phase. The decreased knee flexion has been hypothesized to originate from excessive quadriceps activation. However, it is unclear whether this activation is due to poor timing or hyperreflexia, both common post-stroke impairments. The goal of this study was to investigate the relation between quadriceps hyperreflexia in post-stroke SKG with knee flexion angle during walking. The rectus femoris (RF) H-reflex was recorded in eleven participants with post-stroke SKG and ten healthy controls during standing and walking during toe-off. In order to separate the effects of poorly timed quadriceps muscle activation from hyperreflexia, healthy individuals voluntarily increased quadriceps activity using RF electromyographic (EMG) biofeedback during standing and pre-swing upon H-reflex stimulation. We observed a negative correlation (R = −0.92, p=0.001) between knee flexion angle and RF H-reflexes in post-stroke SKG. In contrast, H-reflex amplitude in healthy individuals in presence (R = 0.47, p = 0.23) or absence (R = −0.17, p = 0.46) of increased RF activity had no correlation with knee flexion angle. The RF H-reflex amplitude differed between standing and walking in healthy individuals, including when RF activity was increased voluntarily (d = 2.86, p = 0.007), but was not observed post-stroke (d =0.73, p = 0.296). Thus, RF reflex modulation is impaired in post-stroke SKG. Further, RF hyperreflexia, as opposed to overactivity, may play a role in knee flexion kinematics in post-stroke SKG. Interventions targeting self-regulated quadriceps hyperreflexia may be effective in promoting better neural control of the knee joint and thus better quality of walking post-stroke.
Enhancing rigor and reproducibility in maternal immune activation models: practical considerations and predicting resilience and susceptibility using baseline immune responsiveness before pregnancy
Authors: Estes Myka L. , Farrelly Kathleen , Cameron Scott , Aboubechara John Paul , Haapanen Lori , Schauer Joseph D. , Horta Aurora , Prendergast Kathryn , MacMahon Jeremy A. , Shaffer Christine I. , Le Catherine T. , Kincheloe Greg N. , Tan Danielle John , van der List Deborah , Bauman Melissa D. , Carter Cameron S. , Van de Water Judy , McAllister A. Kimberley 
Published: July 2019

AbstractDespite the potential of rodent models of maternal immune activation (MIA) to identify new biomarkers and therapeutic interventions for a range of psychiatric disorders, their value is currently limited by issues of scientific rigor and reproducibility. Here, we report three sources of variability—the immunogenicity of the poly(I:C), the baseline immune responsiveness (BIR) of the females prior to pregnancy, and differences in immune responses in C57/B6 dams across vendors. Similar to the variable effects of human maternal infection, MIA in mice does not cause disease-related phenotypes in all offspring and the magnitude and type of maternal response, determined by a combination of poly(I:C) dose and BIR, predicts offspring outcome. Together, our results provide recommendations for optimization of MIA protocols to enhance rigor and reproducibility and reveal new factors that drive susceptibility of some pregnancies and resilience of others to MIA-induced abnormalities in offspring.
In-depth and 3-Dimensional Exploration of the Budding Yeast Phosphoproteome
Authors: Lanz Michael Charles , Yugandhar Kumar , Gupta Shagun , Sanford Ethan , Faça Vitor , Vega Stephanie , Joiner Aaron , Fromme Chris , Yu Haiyuan , Smolka Marcus Bustamante 
Published: July 2019

AbstractPhosphorylation is one of the most dynamic and widespread post-translational modifications regulating virtually every aspect of eukaryotic cell biology. Here we present a comprehensive phosphoproteomic dataset for budding yeast, comprised of over 30,000 high confidence phosphorylation sites identified by mass spectrometry. This single dataset nearly doubles the size of the known phosphoproteome in budding yeast and defines a set of cell cycle-regulated phosphorylation events. With the goal of enhancing the identification of functional phosphorylation events, we performed computational positioning of phosphorylation sites on available 3D protein structures and systematically identified events predicted to regulate protein complex architecture. Results reveal a large number of phosphorylation sites mapping to or near protein interaction interfaces, many of which result in steric or electrostatic “clashes” predicted to disrupt the interaction. Phosphorylation site mutants experimentally validate our predictions and support a role for phosphorylation in negatively regulating protein-protein interactions. With the advancement of Cryo-EM and the increasing number of available structures, our approach should help drive the functional and spatial exploration of the phosphoproteome.
Maximum likelihood estimation of species trees from gene trees in the presence of ancestral population structure
Authors: Koch Hillary , DeGiorgio Michael 
Published: July 2019

AbstractThough large multilocus genomic datasets have led to overall improvements in phylogenetic inference, they have posed the new challenge of addressing conflicting signals across the genome. In particular, ancestral population structure, which has been uncovered in a number of diverse species, can skew gene tree frequencies, thereby hindering the performance of species tree estimators. Here we develop a novel maximum likelihood method, termed TASTI, that can infer phylogenies under such scenarios, and find that it has increasing accuracy with increasing numbers of input gene trees, contrasting with the relatively poor performances of methods not tailored for ancestral structure. Moreover, we propose a supertree approach that allows TASTI to scale computationally with increasing numbers of input taxa. We use genetic simulations to assess TASTI’s performance in the four-taxon setting, and demonstrate the application of TASTI on a six-species Afrotropical mosquito dataset. Finally, we have implemented TASTI in an open-source software package for ease of use by the scientific community.
P38α Regulates Expression of DUX4 in Facioscapulohumeral Muscular Dystrophy
Authors: Rojas L. Alejandro , Valentine Erin , Accorsi Anthony , Maglio Joseph , Shen Ning , Robertson Alan , Kazmirski Steven , Rahl Peter , Tawil Rabi , Cadavid Diego , Thompson Lorin A. , Ronco Lucienne , Chang Aaron N. , Cacace Angela M. , Wallace Owen 
Published: July 2019

ABSTRACTFSHD is caused by the loss of repression at the D4Z4 locus leading to DUX4 expression in skeletal muscle, activation of its early embryonic transcriptional program and muscle fiber death. While progress toward understanding the signals driving DUX4 expression has been made, the factors and pathways involved in the transcriptional activation of this gene remain largely unknown. Here, we describe the identification and characterization of p38α as a novel regulator of DUX4 expression in FSHD myotubes. By using multiple highly characterized, potent and specific inhibitors of p38α/β, we show a robust reduction of DUX4 expression, activity and cell death across FSHD1 and FSHD2 patient-derived lines. RNA-seq profiling reveals that a small number of genes are differentially expressed upon p38α/β inhibition, the vast majority of which are DUX4 target genes. Our results reveal a novel and apparently critical role for p38α in the aberrant activation of DUX4 in FSHD and support the potential of p38α/β inhibitors as effective therapeutics to treat FSHD at its root cause.VISUAL ABSTRACT