bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oophorectomy and rate of dementia: a prospective cohort study
Authors: Uldbjerg Cecilie S. , Wilson Louise F. , Koch Trine , Christensen Jane , Dehlendorff Christian , Priskorn Lærke , Abildgaard Julie , Simonsen Mette K. , Lim Youn-Hee , Jørgensen Jeanette T. , Andersen Zorana J. , Juul Anders , Hickey Martha , Brauner Elvira V. 
Published: February 2022

Abstract

Objective:
Globally, dementia disproportionally affects women, which is not fully explained by higher female longevity. Oophorectomy at any age leads to the permanent loss of ovarian sex steroids, potentially increasing the risk of dementia. We aimed to investigate the association between oophorectomy and dementia and whether this was conditional on age at oophorectomy, hysterectomy or use of hormone therapy (HT).

Methods:
A prospective study of 24,851 female nurses from the Danish Nurse Cohort. Nurses were followed from age 60 years or entry into the cohort, whichever came last, until date of dementia, death, emigration or end of follow-up (December 31, 2018), whichever came first. Poisson regression models with log-transformed person-years as offset were used to estimate the associations.

Results:
During 334,420 person-years of follow-up, 1,238 (5.0%) nurses developed dementia and 1,969 (7.9%)/ 1,016 (4.1%) contributed person-time after bilateral-/unilateral oophorectomy. In adjusted analyses, an 18% higher rate of dementia was observed following bilateral oophorectomy (aRR 1.18: 95% CI, 0.89-1.56) and 13% lower rate (aRR 0.87: 95% CI, 0.59-1.23) following unilateral oophorectomy compared to nurses who retained their ovaries. Similar effects were detected after stratification according to age at oophorectomy. No statistically significant modifying effects of hysterectomy or HT were detected (P
interaction≥0.60).

Conclusions:
Bilateral, but not unilateral, oophorectomy was associated with an increased rate of incident dementia. We were unable to establish whether this association was conditional on hysterectomy or HT use. Although an increase in dementia after bilateral oophorectomy is biologically plausible, limited statistical power hampers the precision of the estimates.
Clinical implications of hepatic structure and function evaluation based on vibration-controlled transient elastography and liver maximum function capacity test in patients with nonalcoholic fatty liver disease
Authors: Blank Valentin , Petroff David , Boehlig Albrecht , Heinze Aileen , Karlas Thomas , Berg Thomas , Wiegand Johannes 
Published: February 2022

Background and aims
Transient elastography [vibration-controlled transient elastography (VCTE)] noninvasively guides risk stratification in patients with nonalcoholic fatty liver disease (NAFLD). Patients with nonalcoholic steatohepatitis (NASH) and fibrosis can be identified using the FAST-score. The liver maximum function test (LiMAx) could be helpful in more precise risk stratification. This pilot study evaluated VCTE, FAST-score, and LiMAx in NAFLD patients.

Methods
NAFLD patients prospectively underwent VCTE and LiMAx. The cutoffs for high fibrosis risk were 9.3/9.6 kPa (M/XL-probe) and 331 dB/m for steatosis. A FAST-score greater than 0.67 was used to identify patients with NASH and LiMAx values below 315 μg/kg/h for impaired liver function.

Results
In total, 57 NAFLD patients (BMI 32 ± 6 kg/m2; 60% diabetes) were included. High risk for fibrosis and steatosis was observed in 26/57 and 28/57 cases, respectively. Overall, 19/57 patients presented impaired liver function. However, 14/26 of patients with a high risk for fibrosis had impaired liver function compared to 5/31 of those without (P = 0.0026). Similarly, 12/18 patients at high risk for NASH had impaired liver function compared to 7/39 without (P < 0.001). The subgroup with diabetes had a liver stiffness a factor of 1.8 higher, FAST-score was 0.13 higher and LiMAx values were 66 μg/kg/h lower compared to nondiabetics.

Conclusion
There is a significant correlation between the functional liver capacity (LiMAx) and the structural liver assessment by VCTE. In cases with high liver stiffness or FAST-score, low LiMAx results may identify NAFLD patients at risk for disease progression and reduce the risk of false-positive categorization.
Neonatal lymphatic flow disorders: central lymphatic flow disorder and isolated chylothorax, diagnosis and treatment using novel lymphatic imaging and interventions technique
Authors: Rabinowitz Deborah , Dysart Kevin , Itkin Maxim 
Published: February 2022

Purpose of review
Neonatal lymphatic disorders (NLDs) are conditions that are relatively rare and difficult to treat. The recent development of lymphatic imaging, such as Dynamic Contrast-Enhanced MR Lymphangiography and Intranodal Lymphangiography has led to a new, better understanding of the anatomical substrate and pathophysiological mechanisms of the diseases. Consequently, this has allowed the development of new targeted therapeutic interventions as well as prognostication for this population with lymphatic flow disorders.

Recent findings
The underlying causes of all NLD is an obstruction or altered flow of the central lymphatic flow. Two types of NLD have been described: isolated neonatal chylothorax and central lymphatic flow disorder (CLFD). Isolated neonatal chylothorax can be treated successfully with oil-based contrast (lipiodol) embolization. CLFD secondary to obstruction of the thoraco-venous junction can be successfully treated with surgical thoracic duct-venous anastomosis. CLFD caused by elevated central pressure and/or thoracic duct dysplasia can be treated medically, including with new systemic therapies such as mammalian target of rapamycin inhibitors.

Summary
New diagnostic and interventional tools have recently allowed for classification, prognostication, and targeted interventions for neonatal patients with lymphatic flow disorders. Further research will build on these discoveries.
Non–Firearm-related Homicides at the Medical University of South Carolina, 2013–2018
Authors: Sullivan Christopher , Presnell Susan Erin 
Published: February 2022

Abstract
After high-profile events involving firearms, gun violence often becomes the center stage of public discourse with national media attention, overshadowing less common causes of homicidal deaths, such as sharp force injury, blunt trauma, and asphyxia. A retrospective analysis of all cases referred for medicolegal autopsy to the Medical and Forensic Autopsy Division of the Department of Pathology and Laboratory Medicine at the Medical University of South Carolina from 2013 to 2018 documented 793 deaths where the manner was classified as homicide. Of these, 18% (144) of the deaths were caused by non–firearm-inflicted injuries. Nonfirearm homicides were further categorized by method; demographic data including decedent age, race, and sex; and other variables such as incident site, decedent relationship status to the alleged perpetrator, number of other homicide fatalities associated with a homicide event, and the presence of drugs and alcohol in the decedents. Data accrued in this review were compared with national statistics published by the Centers for Disease Control and Prevention and to the overall Medical University of South Carolina firearm-related homicide decedent demographic statistics for this same period. Findings augment existing information available regarding non–gun-related homicides and may be valuable in contributing to the ongoing public and political debate regarding firearm and nonfirearm fatalities.
Frozen Fat Grafts Maintain Vascular Endothelial Growth Factor Expression and Mediate Angiogenesis During Adipose-Derived Stem Cell Enrichment for Soft Tissue Augmentation
Authors: Lin Chih-Hsun , Tsai Chi-Han , Yang I-Chen , Ma Hsu 
Published: February 2022

Background
Fresh fat grafts are commonly used in both esthetic and reconstructive surgeries, but the graft resorption rate varies. Cryopreservation of unused fat for later touch-up is one option to resolve this variation. In our previous studies, we found that fat cryopreservation may be a practical strategy for storing fat tissue. To explore the cryopreservation method, we evaluated the role of vascular endothelial growth factor (VEGF) in human frozen fat grafts.

Methods
The concentration of VEGF in human frozen fat grafts subjected to different preservation times was determined using Western blotting and enzyme-linked immunosorbent assay. The angiogenic effect of frozen fat grafts was evaluated using a chorioallantoic membrane assay. Furthermore, the impact of adding human adipose-derived stem cells (hADSCs) or different concentrations of avastin (bevacizumab) to frozen fat grafts on angiogenesis was assessed. The viability of frozen fat grafts with or without hADSCs was evaluated using a nude mouse implantation study. Explanted fat tissues were examined on days 1, 4, 7, 14, 28, and 90, and morphological and histological analyses, immunohistochemistry, and enzyme-linked immunosorbent assay (VEGF concentration) were carried out.

Results
No significant difference in VEGF concentration between fresh and frozen fat was observed with respect to preservation duration. In the chorioallantoic membrane assay, frozen fat grafts with hADSCs displayed significantly enhanced angiogenesis. Avastin was found to decrease angiogenesis in frozen fat grafts. However, in the nude mouse implantation study, frozen fat grafts displayed VEGF maintenance, with the highest concentration observed on day 7. Adding hADSCs to the graft further increased the VEGF concentration and CD31 expression. Fat graft viability was found to be higher in the frozen fat grafts containing hADSCs than in grafts without hADSCs.

Conclusions
Human fat grafts can maintain VEGF expression under frozen conditions for at least 12 months. The addition of hADSCs to the frozen fat graft could further enhance angiogenesis, VEGF expression, and fat cell viability.
Significant Broad Spectrum Antiviral activity of Bi121 Against Different Variants of SARS-CoV-2
Authors: Subhadra Bobban , Agrawal Ragini , Pal Virender Kumar , Chenine Agnes-Laurence , Mattathil Jeffy George , Singh Amit 
Published: February 2022

AbstractThe SARS-CoV-2 pandemic infected 343 million people with over 5.59 million deaths. New mutated lineages of SARS-CoV-2 such as Omicron are evolving faster. Broad-spectrum viral inhibitors that block the initial stage of infection by reducing virus proliferation and disease severity is an unmet global medical need. We studied Bi121, a standardized polyphenolic-rich compound isolated from Pelargonium sidoides, against recombinant Vesicular Stomatitis Virus (rVSV)-pseudotyped SARS-CoV-2S (spike) that represent mutations in the spike protein of six different variants of SARS-CoV-2. Bi121 was effective in neutralizing all six rVSV-ΔG-SARS-CoV-2S variants expressing different mutations. The antiviral activity of Bi121 was then assessed against three variants of SARS-CoV-2 (USA WA1/2020, Hongkong/VM20001061/2020, B.1.167.2 (Delta)) using RT-qPCR and plaque assays in two different cell lines (Vero cells and HEK-ACE2). Bi121 showed significant activity toward all the three variants tested, suggesting a broad-spectrum activity.
Cerebellar transcranial direct current stimulation disrupts neuroplasticity of intracortical motor circuits
Authors: Liao Wei-Yeh , Sasaki Ryoki , Semmler John G. , Opie George M. 
Published: February 2022

AbstractWhile previous research using transcranial magnetic stimulation (TMS) suggest that cerebellum (CB) influences the neuroplastic response of primary motor cortex (M1), the role of different indirect (I) wave inputs in M1 mediating this interaction remains unclear. The aim of this study was therefore to assess how CB influences neuroplasticity of early and late I-wave circuits. 22 young adults (22 ± 2.7 years) participated in 3 sessions in which I-wave periodicity repetitive transcranial magnetic stimulation (iTMS) was applied over M1 during concurrent application of cathodal transcranial direct current stimulation over CB (tDCSCB). In each session, iTMS either targeted early I-waves (1.5 ms interval; iTMS1.5), late I-waves (4.5 ms interval; iTMS4.5), or had no effect (variable interval; iTMSSham). Changes due to the intervention were examined with motor evoked potential (MEP) amplitude using TMS protocols measuring corticospinal excitability (MEP1mV) and the strength of CB-M1 connections (CBI). In addition, we indexed I-wave activity using short-interval intracortical facilitation (SICF) and low-intensity single-pulse TMS applied with posterior-anterior (MEPPA) and anterior-posterior (MEPAP) current directions. Following both active iTMS sessions, there was no change in MEP1mV, CBI or SICF (all P > 0.05), suggesting that tDCSCB broadly disrupted the excitatory response that is normally seen following iTMS. However, although MEPAP also failed to facilitate after the intervention (P > 0.05), MEPPA potentiated following both active iTMS sessions (both P < 0.05). This differential response between current directions suggests that the disruptive effects of CB modulation on M1 plasticity may be selectively mediated by AP-sensitive circuits (also likely recruited with MEP1mV, CBI, and SICF).
Orexin action on the dopaminergic system modulates theta during REM sleep and wakefulness
Authors: Bandarabadi Mojtaba , Li Sha , Tafti Mehdi , Colombo Giulia , Becchetti Andrea , Vassalli Anne 
Published: February 2022

AbstractBoth dopaminergic (DA) and orexinergic (OX) systems establish brain-wide neuromodulatory circuits that profoundly influence brain states and behavioral outputs. To unravel their interactions, we inactivated OX-to-DA neurotransmission by selective disruption of HcrtR1/OxR1, or HcrtR2/OxR2, or both receptors, in DA neurons. Chronic loss of OXR2 in DA neurons (OxR2Dat-CKO mice) dramatically increased electrocorticographic (EcoG) theta rhythms in wakefulness and REM sleep. Episode duration and total times spent in ‘active’ wakefulness and REMS were prolonged, and theta/fast-gamma wave coupling was enhanced in both states. Increased theta in OxR2DatCKO mice baseline wake was accompanied by diminished infra-theta and increased fast-gamma activities, i.e. the mice exhibited signs of constitutive electrocortical hyperarousal, albeit uncoupled with locomotor activity. These effects were not seen in OxR1-ablated dopaminergic mutants, which tended to show opposite phenotypes, resembling those caused by the loss of both receptors. Our data establish a clear, genetically-defined link between monosynaptic orexin-to-dopaminergic connectivity and the power of theta oscillations, with a differential role of OXR2 in cross-frequency wave coupling and attentional processes.
A novel fully-spliced accessory gene in equine lentivirus with distinct Rev-responsive element
Authors: Zhang Xiangmin , Li Jiwei , Zhang Mengmeng , Bai Bowen , Ma Weiwei , Lin Yuezhi , Guo Xing , Wang Xue-Feng , Wang Xiaojun 
Published: February 2022

AbstractAll lentiviruses encode an accessory protein Rev, whose main biological function is to mediate the nuclear export of unspliced and incompletely spliced viral transcripts by binding to a viral cis-acting element (termed the Rev-responsive element, RRE) that is located within env-encoding region. Equine infectious anemia virus (EIAV) is a member of the Lentivirus genus in the Retroviridae family, and is considered an important model for the study of lentivirus pathogenesis. Here, we identified a novel transcript from the EIAV genome that encodes a viral protein, named Mat, with unknown function. The transcript mat is fully spliced and comprises parts of the coding regions of MA and TM. Interestingly, the expression of Mat depends on Rev and the CRM1 pathway. Rev could specifically bind to Mat mRNA to promote its nuclear export. We further identified that the first exon of Mat mRNA, which is located within the Gag-encoding region, acts as an unreported RRE. Altogether, we identified a novel fully spliced transcript mat with an unusual RRE, which interacts with Rev for nuclear export through the CRM1 pathway. Our findings may help to expend the understanding of gene transcription and expression of lentivirus.Author summaryIn lentiviruses, the nuclear export of viral transcripts is an important step in controlling viral gene expression. Generally, the unspliced and incompletely spliced (that is, intron-containing) transcripts are exported via the CRM1-dependent export pathway in a process mediated by the viral Rev protein by binding to the Rev-responsive element (RRE) located within the Env-coding region. However, the completely spliced (intronless) transcripts are exported via an endogenous cellular pathway which is Rev independent. Here we identified a novel intronless transcript from EIAV and demonstrated that it encodes a viral protein, termed Mat. Interestingly, we have determined that the expression of Mat depends on Rev, and identified that the first exon of Mat mRNA could specifically bind to Rev and be exported to the cytoplasm, which suggests that first exon of Mat mRNA is a second RRE of EIAV. These findings update the EIAV genome structure and highlight the diversification of post-transcriptional regulation patterns in EIAV, and provides important insights into the Rev-dependent nuclear export of completely spliced transcripts in lentiviruses.
Stable temporal relationships as a first step towards causal inference: an application to antibiotic resistance
Authors: Baraz Avi , Chowers Michal , Nevo Daniel , Obolski Uri 
Published: February 2022

AbstractEpidemiological studies often analyze data as static, essentially averaging observed associations across time. Overlooking time trends is especially problematic in settings subject to rapid changes. A prominent example for such a setting is antibiotic resistance, which has reached concerning levels, and poses a global healthcare challenge. Bacteria constantly evolve and hence antibiotic resistance is characterized by time-varying relationships with clinical and demographic covariates. In this paper, we speculate that covariates with a causal effect are expected to have stable relationships with resistance over calendar time. To this end, we applied time-varying coefficient models in a retrospective cohort analysis of a large clinical dataset from an Israeli hospital, and have shown their advantages in describing covariate-resistance relationships. We found both time-stable and time-varying covariate-resistance relationships. These results serve as initial evidence towards causal interpretation of these relationships, as one may expect time-stable rather than time-varying relationships to correspond with causal effects. We further conducted data-driven simulations, that have illustrated how results from time-varying coefficient models must be carefully interpreted with respect to causal claims. Potentially, identification of causal covariate-resistance relationships can lead to new medical interventions and healthcare policies, and improve the generalization of existing predictive models for antibiotic resistance.
Learning probabilistic protein-DNA recognition codes from DNA-binding specificities using structural mappings
Authors: Wetzel Joshua L. , Zhang Kaiqian , Singh Mona 
Published: February 2022

AbstractKnowledge of how proteins interact with DNA is essential for understanding gene regulation. While DNA-binding specificities for thousands of transcription factors (TFs) have been determined, the specific amino acid-base interactions comprising their structural interfaces are largely unknown. This lack of resolution hampers attempts to leverage these data in order to predict specificities for uncharacterized TFs or TFs mutated in disease. Here we introduce rCLAMPS (Recognition Code Learning via Automated Mapping of Protein-DNA Structural interfaces), a probabilistic approach that uses DNA-binding specificities for TFs from the same structural family to simultaneously infer both which nucleotide positions are contacted by particular amino acids within the TF as well as a recognition code that relates each base-contacting amino acid to nucleotide preferences at the DNA positions it contacts. We apply rCLAMPS to homeodomains, the second largest family of TFs in metazoans, and demonstrate that it learns a highly effective recognition code that can predict de novo DNA-binding specificities for TFs. Furthermore, we show that the inferred amino acid-nucleotide contacts reveal whether and how nucleotide preferences at individual binding site positions are altered by mutations within TFs. Our approach is an important step towards automatically uncovering the determinants of protein-DNA specificity from large compendia of DNA-binding specificities, and inferring the altered functionalities of TFs mutated in disease.
In vitro direct regeneration and Agrobacterium tumefaciens mediated in planta transformation of Ocimum sanctum L.
Authors: Khan Sana , Husain Zakir , Rahman Laiq ur 
Published: February 2022

AbstractOcimum sanctum is a multipurpose herb with highly significant medicinal properties. An in vitro direct regeneration protocol for propagation of a valuable medicinal plant Ocimum sanctum, using petiole explants has been successfully developed. The protocol employed regeneration of shoots directly, without any intervening callus using Murashige and Skoog (MS) medium fortified with 3 mg L-1 BAP + 1 mg L-1 NAA. The maximum regeneration frequency of 98% with 9.6 shoots per explants was achieved. Agrobacterium tumefaciens mediated genetic transformation (ATMT) protocol (transient and stable) was established using LBA4404 strain harboring pBI121 with uid-A reporter gene and neomycin phosphotransferase (npt-II) as selection marker. The putative transformants were screened on MS with 50 mg L-1 kanamycin and subsequently rooted on the half-strength MS medium. The confirmation was done via polymerase chain reaction (PCR) using npt-II and gus-A gene-specific primers. The maximum stable transformation frequency 70% ± 0.35. Thus, it is apparent that the established in vitro direct regeneration and ATMT method was suitable for integrating novel genes and modulating the metabolic flux for obtaining desired agronomic trait in planta.
The evolution of coordination: A phylogenetic meta-analysis and systematic review
Authors: Keeble Liam , Wallenberg Joel C. , Price Elizabeth E. 
Published: February 2022

AbstractTo solve many cooperative problems, humans must have evolved the ability to solve physical problems in their environment by coordinating their actions. There have been many studies conducted across multiple different species regarding coordinating abilities. These studies aim to provide data which will help illuminate the evolutionary origins of cooperative problem solving and coordination. However, it is impossible to make firm conclusions about the evolutionary origins of coordinating abilities without a thorough comparative analysis of the existing data. Furthermore, there may be certain aspects of the literature that make it very difficult to confidently address evolutionary and meta-analytic questions. This study aimed to rectify this by using meta-analysis, phylogenetic analysis, and systematic review to analyse the data already obtained across multiple studies, and to assess the reliability of this data. We found that many studies did not provide the information necessary for meta analysis, or were not comparable enough to other studies to be included in analyses, meaning meta analyses were underpowered or could not be conducted due to low samples of both studies and different species. Overall, we found that many studies reported small positive effects across studies, but the standard errors of these effects frequently traversed zero.