bluuebunny/crossref_metadata_2025_split huggingface dataset:
BOS1 is a positive regulator of wounding induced cell death and plant susceptibility to Botrytis
Authors: Cui Fuqiang , Li Xiaoxiao , Wu Wenwu , Luo Wenbo , Wu Ying , Brosché Mikael , Overmyer Kirk 
Published: January 2022

AbstractProgrammed cell death (PCD) is required for many aspects of plant biology, including stress responses, immunity, and plant development including root and flower development. Our understanding of PCD regulation is incomplete, especially concerning regulators involved in multiple divergent processes. The botrytis-suscetible1 (bos1) mutant is one of the genotypes most susceptible to Botrytis cinerea (Botrytis) and has revealed the role of BOS1 in cell death propagation during plant responses to wounding. The bos1-1 allele harbours a T-DNA located in the 5’UTR upstream from the start codon that results in elevated BOS1 transcript levels. Here, we resequenced the bos1-1 genome and found a MAS promoter at the ends of the T-DNAs. Expression of the BOS1 gene under control of the MAS promoter conferred the characteristic bos1-1 Botrytis- sensitivity and wounding phenotypes in wildtype plants. We used Crispr-Cas9 to create new bos1 alleles that disrupt exons. These lines lacked the typical bos1-1 wounding and Botrytis phenotypes, but exhibited reduced fertility, as previously observed in other bos1 T-DNA alleles. With multiple overexpression lines of BOS1, we demonstrate that BOS1 is involved in regulation of cell death propagation in a dosage dependent manner. Our data support that bos1-1 is a gain-of-function mutant and that BOS1 acts as a positive regulator of wounding and Botrytis-induced PCD. Taken together these finding suggest that BOS1 function in both fertility and Botrytis response could be unified under cell death control.
Associations between maternal iron supplementation in pregnancy and offspring growth and cardiometabolic risk outcomes in infancy and childhood
Authors: Petry Clive J. , Olga Laurentya , Hughes Ieuan A. , Ong Ken K. 
Published: January 2022

AbstractIt was previously observed that maternal iron supplementation in pregnancy was associated with increased offspring size and adiposity at birth, possibly mediated through increased risk of gestational diabetes. In this study we explored associations of maternal iron supplementation in pregnancy with postnatal offspring growth in infancy and indices of cardiometabolic disease risk factors such as glucose tolerance, insulin sensitivity and blood pressure in mid-childhood (at ∼9.5 years of age) in the Cambridge Baby Growth Study. In infancy adiposity-promoting associations with maternal iron supplementation in pregnancy were evident at 3 months of age (e.g. mean difference in skinfold thickness: β=+0.15 mm, p=0.02, in n=341 whose mothers supplemented versus 222 that did not; waist circumference: β=+0.7 cm, p=0.04, in n=159 and 78, respectively) but differences lessened after this time (e.g. 3-12 month change in mean difference in skinfold thickness: β=-0.2 mm, p=0.03, in n=272 and 178, respectively). At ∼9.5 years of age associations with maternal iron supplementation in pregnancy were not evident for markers of growth, glucose tolerance, insulin sensitivity or secretion. However, children whose mothers supplemented with iron in pregnancy had lower mean arterial blood pressures (β=-1.0 mmHg, p=0.03, in n=119 and 78, respectively). These results suggest that most of the associations of maternal iron supplementation in pregnancy on growth and adiposity evident at birth disappear during infancy, but there may be some evidence of long-term nutritional programming evident later in childhood.
The economic burden of low back pain in KwaZulu-Natal, South Africa: a prevalence-based cost-of-illness analysis from the healthcare provider’s perspective
Authors: Kahere Morris , Ngcamphalala Cebisile , Östensson Ellinor , Ginindza Themba 
Published: January 2022

ABSTRACTBackgroundGlobally, low back pain (LBP) is associated with high economic costs due to healthcare expenditure and production loss. There is lack of evidence regarding this in low-and-middle-income-countries (LMICs), including South Africa. Thus, the study aimed to determine the economic burden of LBP from the providers perspective.MethodsWe used a retrospective prevalence-based cost-of-illness methodology to estimate the direct medical cost of LBP. Direct medical costs constituted costs associated with healthcare utilisation in inpatient care, outpatient care, investigations, consultations, and cost of auxiliary devices. We used diagnostic-specific data obtained from hospital clinical reports. All identifiable direct medical costs were estimated using a top-down approach for costs associated with healthcare and a bottom-up approach for costs associated with inpatient and outpatient care.ResultsThe prevalence of CLBP was 24.3% (95% CI: 23.5 – 25.1). The total annual average direct medical costs associated with LBP was US$5.4 million. Acute LBP and CLBP contributed 17% (US$0.92 million) and 83% (US$4.48 million) of the total annual average direct medical cost, respectively. The per patient total annual average direct medical cost for acute LBP and CLBP were US$99.43 and US$1,516.67, respectively. The total average cost of medication per patient for acute and CLBP were US$82.53 and US$320.31, respectively. Overall, the outpatient care costs contributed the largest share (38.9%, US$2.10 million) of the total average direct medical cost, 54.9% (US$1.15 million) of which was attributed to NSAIDs and only 10% (US$0.21 million) of the total outpatient cost was due to rehabilitation. The total average cost of diagnostic investigations was estimated at US$831,595.40, which formed 15.4% of the average total cost.ConclusionThe economic burden of LBP is high in South Africa. Majority of costs were attributed to CLBP. Action should be taken to develop culturally validated cost-effective prevention measures to mitigate the burden of LBP.
Single-Cell Transcriptomic Analyses of Tumor Ecosystems and Spatial Architectures in Human Small Cell Lung Cancer
Authors: Ouyang Huiling , Chen Jian , Xu Chaoliang , He Cong , Sheng Luoyan , Wang Jing , Pan Deshen , Lin Jun , Augert Arnaud , Zhu Yuming , Jia Deshui 
Published: January 2022

ABSTRACTSmall cell lung cancer (SCLC) is a highly heterogenous disease characterized by aggressive phenotypes and poor prognosis. In order to dissect the cellular components and their spatial distribution in SCLC ecosystems, here we performed single-cell RNA sequencing and spatial transcriptomics analyses of 12 resected human primary SCLCs. Our analysis revealed extensive heterogeneity of both tumor and non-tumor cells, and a predominant immunosuppressive microenvironment. Importantly, multiple hybrid tumor cell states were unmasked, including hybrid SCLC and lung adenocarcinoma cells as well as hybrid tumor and immune cells, indicating high phenotypic plasticity of tumor cells. Moreover, we revealed the cellular origin and evolution of these hybrid tumor cells, and critical roles of tumor-stromal cellular crosstalk in driving the development of hybrid cells. In conclusion, this study deepens our understanding of human SCLC ecosystems and provides rationales to target the hybrid tumor cells and immunosuppressive microenvironment for SCLC therapies.
Combined multiple transcriptional repression mechanisms generate ultrasensitivity and oscillations
Authors: Jeong Eui Min , Song Yun Min , Kim Jae Kyoung 
Published: January 2022

AbstractTranscriptional repression can occur via various mechanisms, such as blocking, sequestration, and displacement. For instance, the repressors can hold the activators to prevent binding with DNA or can bind to the DNA-bound activators to block their transcriptional activity. Although the transcription can be completely suppressed with a single mechanism, multiple repression mechanisms are utilized together to inhibit transcriptional activators in many systems, such as circadian clocks and NF-κB oscillators. This raises the question of what advantages arise if seemingly redundant repression mechanisms are combined. Here, by deriving equations describing the multiple repression mechanisms, we find that their combination can synergistically generate a sharply ultrasensitive transcription response and thus strong oscillations. This rationalizes why the multiple repression mechanisms are used together in various biological oscillators. The critical role of such combined transcriptional repression for strong oscillations is further supported by our analysis of formerly identified mutations disrupting the transcriptional repression of the mammalian circadian clock. The hitherto unrecognized source of the ultrasensitivity, the combined transcriptional repressions, can lead to robust synthetic oscillators with a previously unachievable simple design.
Lira: Rotational Invariant Shape and Electrostatic Descriptors for Small Molecules and Protein Pockets based on Real Spherical Harmonics
Authors: Caires Fernando R. , Silva Samuel R. , Veríssimo-Alves Marcos , Pinheiro Vitor B. , Montalvão Rinaldo W. 
Published: January 2022

AbstractMotivationModern AI-based tools are increasing the number of protein structures available, creating an opportunity and a challenge for automated high-throughput drug discovery pipelines. The amount of data is overwhelming for the current methods, thus demanding new high-performance approaches for Machine Learning-based rational drug design. As shape and electrostatics are the main components for understanding protein-ligand interaction; they are the primary targets for efficient AI-compatible descriptors and their associated comparison methods.ResultsThe Lira toolbox is a set of components devised for describing, comparing and analysing shape and electrostatics for small ligands, peptides and protein pockets. It can generate databases with descriptors for tens of millions of shapes in a few hours, which can then be queried in seconds. The Lira design, focused on performance and reliability, makes its integration into AI-driven rational drug design pipelines simple.Availability and implementationLira packages, available for download at https://pinheirolab.com/, are free to use for research and educational purposes.
A Population Response Model of Ensemble Perception
Authors: Utochkin Igor S. , Choi Jeunghwan , Chong Sang Chul 
Published: January 2022

AbstractEnsemble representations have been considered as one of the strategies that the visual system adopts to cope with its limited capacity. Thus, they include various statistical summaries such as mean, variance, and distributional properties and are formed over many stages of visual processing. The current study proposes a population coding model of ensemble perception to provide a theoretical and computational framework for these various facets of ensemble perception. The proposed model consists of a simple feature layer and a pooling layer. We assumed ensemble representations as population responses in the pooling layer and decoded various statistical properties from population responses. Our model successfully predicted averaging performance in orientation, size, color, and motion direction across different tasks. Furthermore, it predicted variance discrimination performance and the priming effects of feature distributions. Finally, it explained the well-known variance and set size effects and has a potential for explaining the adaptation and clustering effects.
The effects of electroencephalogram feature-based transcranial alternating current stimulation on working memory and electrophysiology
Authors: Zeng Lanting , Guo Mingrou , Wu Ruoling , Luo Yu , Wei Pengfei 
Published: January 2022

AbstractTranscranial alternating current stimulation (tACS) can influence cognitive functions by modulating brain oscillations. However, results regarding the effectiveness of tACS in regulating cognitive performance have been inconsistent. In the present study, we aimed to find EEG characteristics associated with the improvements in working memory performance, to select tACS stimulus targets and frequency based on this feature, and to explore effects of selected stimulus on verbal working memory. To achieve this goal, we first investigated the EEG characteristics associated with improvements in working memory performance with the aid of EEG analyses and machine learning techniques. These analyses suggested that 8 Hz activity in the prefrontal region was related to accuracy in the verbal working memory task. The tACS stimulus target and pattern were then selected based on the EEG feature. Finally, the selected tACS frequency (8 Hz tACS in the prefrontal region) was applied to modulate working memory. The performance of working memory was improved significantly using the selected stimulation than using 40 Hz and sham stimulation (Especially for participants with low verbal working memory). In conclusion, using EEG features related to positive behavioral changes to select brain regions and stimulation patterns for tACS is an effective intervention for improving working memory. Our results contribute to the groundwork for future tACS closed-loop interventions for cognitive deterioration.
Detecting Antibody Reactivities in Phage ImmunoPrecipitation Sequencing Data
Authors: Chen Athena , Kammers Kai , Larman H Benjamin , Scharpf Robert B. , Ruczinski Ingo 
Published: January 2022

AbstractPhage ImmunoPrecipitation Sequencing (PhIP-Seq) is a recently developed technology to assess antibody reactivity, quantifying antibody binding towards hundreds of thousands of candidate epitopes. The output from PhIP-Seq experiments are read count matrices, similar to RNA-Seq data; however some important differences do exist. In this manuscript we investigated whether the publicly available method edgeR1 for normalization and analysis of RNA-Seq data is also suitable for PhIP-Seq data. We find that edgeR is remarkably effective, but improvements can be made and introduce a Bayesian framework specifically tailored for data from PhIP-Seq experiments (Bayesian Enrichment Estimation in R, BEER).
Understanding immune-driven brain aging by human brain organoid microphysiological analysis platform
Authors: Song Sunghwa , Ao Zheng , Cai Hongwei , Li Xiang , Miao Yifei , Wu Zhuhao , Krzesniak Jonathan , Gu Mingxia , Lee Luke P. , Guo Feng 
Published: January 2022

AbstractThe aging of the immune system drives systemic aging and the pathogenesis of age-related diseases. However, a significant knowledge gap remains in understanding immune-driven aging, especially in brain aging, due to the limited current in vitro models of neuro-immune interaction. Here we report the development of a human brain organoid microphysiological analysis platform (MAP) to discover the dynamic process of immune-driven brain aging. We create the organoid MAP by 3D printing that can confine organoid growth and perfuse oxygen and nutrients (and immune cells) to generate standardized human cortical organoids that promote viability, maturation, and commitment to human forebrain identity. Dynamic rocking flow is incorporated for the platform that allows us to perfuse primary monocytes from young (20 to 30-year-old) and aged (>60-year-old) donors and culture human cortical organoids for modeling and analyzing the aged immune cell interacting organoid tissues systematically. We discovered the aged monocytes had increased infiltration and promoted the expression of aging-related markers (e.g., p16 in astrocytes neighboring to monocytes) within human cortical organoids, indicating that aged monocytes may drive brain aging. We believe that our human brain organoid MAP provides promising solutions for basic research and translational applications in aging, neuroimmunological diseases, autoimmune disorders, and cancers.
Cytocapsular tube network-tumor system is an integrated physical target for the highly effective and efficient pharmacotherapy of solid cancers
Authors: Yi Tingfang , Wagner Gerhard 
Published: January 2022

AbstractCancer is a leading cause of human lethality and cancer drug pan-resistant tumor metastasis (cdp-rtm) is a major source of cancer death. The integrated cytocapsular tube (CCT) networktumor system (CNTS) is essential for cancer evolution procedures including cancer cell proliferation, migration and dissemination in CCT networks, new tumor growth in CCT terminals, conventional cancer drug pan-resistance, and tumor relapse. The preclinical screening experimentations with CCTs and networks are necessary prerequisites for the discovery and development of cancer drug candidates for efficient clinical trials, and effective and precise clinical cancer pharmacotherapy. However, it is unknown whether the popularly employed conventional mouse experimentations for preclinical therapeutic development generate CCTs and networks. Here, we comprehensively investigated the cancer cell line derived xenografts (CDX) of 8 kinds of cancer cell lines, and patient cancer cells derived-xenografts (PDX) with 16 kinds of clinical primary and metastatic malignant tumor cells in multiple cancer stages by immunohistochemistry staining assays with CCT marker protein antibodies of anti-CM-01 antibodies. We found that there are no CCTs or CCT networks in all these examined 16 CDX and 22 PDX transplanted tumors. Our data evidenced that the conventional transplantation tumors for preclinical therapeutic development do not engender CCTs or CNTS, which is consistent with and provides an explanation of the poor clinical outcomes of the marketed cancer drugs. This study demonstrated that CCT network-tumor system (CNTS) is an integrated physical target for pharmacotherapy, and that preclinical experimentations engendering CNTS (such as CCT xenograft, CCTX) should be employed for the discovery and development of highly effective and efficient cancer drugs aimed for cure of solid cancers.
Selective activation of subthalamic nucleus output quantitatively scales movements
Authors: Friedman Alexander D. , Yin Henry H. 
Published: January 2022

AbstractThe subthalamic nucleus (STN), a diencephalic nucleus strongly connected with the basal ganglia, is a common target for deep brain stimulation (DBS) treatments of Parkinsonian motor symptoms. The STN is thought to suppress movement by enhancing inhibitory basal ganglia output via the indirect pathway, and disrupting STN output using DBS can restore movement in Parkinson’s patients. However, previous studies on STN DBS usually relied on electrical stimulation, which cannot selectively target STN output neurons. Moreover, most studies did not measure behavior precisely during STN manipulations. Here we selectively stimulated STN projection neurons, by expressing channelrhodopsin in vesicular glutamate transporter 2 (VGlut2)-positive projection neurons in the STN. We also quantified behavior in freely moving male mice with high spatial and temporal resolution using 3D motion capture at 200 frames per second. We found STN stimulation resulted in movements with very short latencies (10-15 ms). Unilateral stimulation quantitatively determines orientation, head yaw, and head roll consistently in the ipsiversive direction, toward thee side of stimulation. On the other hand, head raising (increased head pitch) was observed after stimulation on either side. Strikingly, a single pulse of light was sufficient to generate movement, and there was a highly linear relationship between stimulation frequency and kinematics. These results question the common assumption that STN suppresses movement; instead they suggest that STN output can precisely specific action parameters via direct projections to brainstem regions.
Persistent delirium in older hospital patients: an updated systematic review and meta-analysis
Authors: Whitby Jonathan , Nitchingham Anita , Caplan Gideon , Davis Daniel , Tsui Alex 
Published: January 2022

AbstractIntroductionPersistent delirium is recognised as a substantial problem, but there are few insights into which patient groups might be particularly affected. Delirium is associated with future dementia progression. Yet whether this occurs subclinically over months and years, or persistent delirium merges into worsened dementia is not understood.MethodsWe adopted an identical approach to a previous systematic review, only including studies using a recognised diagnostic framework for ascertaining delirium at follow-up (persistent delirium). We applied risk of bias assessments based on Standards of Reporting of Neurological Disorders criteria. Estimates were pooled across studies using random-effects meta-analysis, and we estimated associations with age and follow-up duration using meta-regression.ResultsWe identified 13 new cohorts, which we added to 8 from the previous systematic review (21 relevant studies reporting persistent delirium over 37 time points). Studies were mainly at low risk of bias. Pooled delirium prevalence estimates at discharge were 40% (95% CI 24% to 54%, 10 studies). Meta-regression showed variation in prevalence of persistent delirium over time (0.6% per week, 95% CI −1.2 to −0.1, p=0.02). Older study sample age was associated with higher prevalence of persistent delirium (8.8% per SD age, 95% CI 1.1% to 17%). The rate of improvement was the same regardless of age, but the overall burden was higher with older age such that 44% (95% CI 11% to 76%) of 95-year-olds would be expected to have persistent delirium at 12 months.ConclusionsThis systematic review emphasises the key importance of delirium as a persistent and extensive problem, particularly in the oldest-old. Addressing persistent delirium will require a whole-system, integrated approach in order to detect, follow-up and implement opportunities for recovery across all healthcare settings.
Reevaluation of Seroprevalence using a Semi-quantitative Anti-spike IgG in Health Care workers at an Academic Medical Center in Boston, Massachusetts
Authors: Cole Manisha , Duffy Elizabeth R. , Osterland Jordyn N , Gawel Susan , Ye Lei , de la Cena Kyle , Ragan Elizabeth J. , Weber Sarah E. , M- Schechter-Perkins Elissa , Bouton Tara C. , Jacobson Karen R. , Andry Chris , Kataria Yachana 
Published: January 2022

AbstractBackgroundAccurate measurement of antibodies is a necessary tool for assessing exposure to SARS-CoV-2 and facilitating understanding of the role of antibodies in immunity. Most assays are qualitative in nature and employ a threshold to determine presence of antibodies. Semi-quantitative assays are now available. Here we evaluate the semi-quantitative SARS-CoV-2 IgG II (anti-spike (S)) assay. We aim to reassess the seroprevalence using anti-S assay and subsequently compare it to the previously measured IgG (anti-nucleoprotein (N)) in health care workers at an academic medical center in Boston.Methods1743 serum samples from HCWs at Boston Medical Center were analyzed for SARS-CoV-2 anti-S IgG and IgM using the Abbott SARS-CoV-2 IgG II and□Abbott AdviseDx□SARS-CoV-2 IgM assay, respectively. Precision, linearity, positive and negative concordance with prior RT-PCR test were evaluated for anti-S IgG. Seroprevalence and its association with demographics variables was also assessed.ResultsLinearity and precision results were clinically acceptable. The positive and negative concordance for anti-S IgG with RT-PCR was 88.2% (95% CI: 79.4% - 94.2%) and 97.43% (95% CI: 95.2% - 98.8%), respectively. Overall, 126 (7.2%) of 1,743 participants were positive by anti-S IgG. Among the 1302 participants with no prior RT-PCR, 40 (3.1%) were positive for anti-S IgG antibody. The original agreement in this population with the qualitative, anti-N IgG assay was 70.6%. Upon optimizing the threshold from 1.4 to 0.49 S/CO of the anti-N IgG assay, the positive agreement of the assay increases to 84.7%.ConclusionThe anti-S IgG assay demonstrated reproducible and reliable measurements. This study highlights the presence of asymptomatic transmission among individuals with no prior history of positive RT-PCR. It also highlights the need for optimizing thresholds of the qualitative SARS-CoV-2 IgG assay for better agreement between assays by the same vendor.