bluuebunny/crossref_metadata_2025_split huggingface dataset:
Heterogeneous matrix stiffness regulates the cancer stem-like cell phenotype in hepatocellular carcinoma
Authors: Wei Jiayun , Yao Jia , Yang Chendong , Mao Yongcui , Zhu Dan , Xie Ye , Liu Pinyan , Yan Mengchao , Ren Longfei , Lin Yan , Zheng Qiuxia , Li Xun 
Published: December 2022

Abstract
Background
Solid tumors are stiffer than their surrounding normal tissues; however, their interior stiffness is not uniform. Under certain conditions, cancer cells can acquire stem-like phenotypes. However, it remains unclear how the heterogeneous physical microenvironment affects stemness expression in cancer cells. Here, we aimed to evaluate matrix stiffness heterogeneity in hepatocellular carcinoma (HCC) tissues and to explore the regulation effect of the tumor microenvironment on stem-like phenotypic changes through mechanical transduction.

Methods
First, we used atomic force microscopy (AFM) to evaluate the elastic modulus of HCC tissues. We then used hydrogel with adjustable stiffness to investigate the effect of matrix stiffness on the stem-like phenotype expression of HCC cells. Moreover, cells cultured on hydrogel with different stiffness were subjected to morphology, real-time PCR, western blotting, and immunofluorescence analyses to explore the mechanotransduction pathway. Finally, animal models were used to validate in vitro results.

Results
AFM results confirmed the heterogenous matrix stiffness in HCC tissue. Cancer cells adhered to hydrogel with varying stiffness (1.10 ± 0.34 kPa, 4.47 ± 1.19 kPa, and 10.61 kPa) exhibited different cellular and cytoskeleton morphology. Higher matrix stiffness promoted the stem-like phenotype expression and reduced sorafenib-induced apoptosis. In contrast, lower stiffness induced the expression of proliferation-related protein Ki67. Moreover, mechanical signals were transmitted into cells through the integrin–yes-associated protein (YAP) pathway. Higher matrix stiffness did not affect YAP expression, however, reduced the proportion of phosphorylated YAP, promoted YAP nuclear translocation, and regulated gene transcription. Finally, application of ATN-161 (integrin inhibitor) and verteporfin (YAP inhibitor) effectively blocked the stem-like phenotype expression regulated by matrix stiffness.

Conclusions
Our experiments provide new insights into the interaction between matrix stiffness, cancer cell stemness, and heterogeneity, while also providing a novel HCC therapeutic strategy.
Evidence of innate immune dysfunction in first-episode psychosis patients with accompanying mood disorder
Authors: Hughes Heather K. , Yang Houa , Lesh Tyler A. , Carter Cameron S. , Ashwood Paul 
Published: December 2022

Abstract
Background
Inflammation and increases in inflammatory cytokines are common findings in psychiatric disorders such as schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD). Meta-analyses of studies that measured circulating cytokines have provided evidence of innate inflammation across all three disorders, with some overlap of inflammatory cytokines such as IL-6 and TNF-α. However, differences across disorders were also identified, including increased IL-4 in BD that suggest different immune mechanisms may be involved depending on the type of disorder present.

Methods
We sought to identify if the presence or absence of an affective disorder in first-episode psychotic (FEP) patients was associated with variations in cytokine production after stimulation of peripheral blood mononuclear cells (PBMC). 98 participants were recruited and grouped into healthy controls (n = 45) and first-episode psychosis patients (n = 53). Psychosis patients were further grouped by presence (AFF; n = 22) or lack (NON; n = 31) of an affective disorder. We cultured isolated PBMC from all participants for 48 h at 37 °C under four separate conditions; (1) culture media alone for baseline, or the following three stimulatory conditions: (2) 25 ng/mL lipopolysaccharide (LPS), (3) 10 ng/mL phytohemagglutinin (PHA), and (4) 125 ng/ml α-CD3 plus 250 ng/ml α-CD28. Supernatants collected at 48 h were analyzed using multiplex Luminex assay to identify differences in cytokine and chemokine production. Results from these assays were then correlated to patient clinical assessments for positive and negative symptoms common to psychotic disorders.

Results
We found that PBMC from affective FEP patients produced higher concentrations of cytokines associated with both innate and adaptive immunity after stimulation than non-affective FEP patients and healthy controls. More specifically, the AFF PBMC produced increased tumor necrosis fctor (TNF)-α, interleukin (IL)-1β, IL-6, and others associated with innate inflammation. PBMC from AFF also produced increased IL-4, IL-17, interferon (IFN)γ, and other cytokines associated with adaptive immune activation, depending on stimulation. Additionally, inflammatory cytokines that differed at rest and after LPS stimulation correlated with Scale for the Assessment of Negative Symptoms (SANS) scores.

Conclusions
Our findings suggest that immune dysfunction in affective psychosis may differ from that of primary psychotic disorders, and inflammation may be associated with increased negative symptoms. These findings could be helpful in determining clinical diagnosis after first psychotic episode.
TREM2 activation alleviates neural damage via Akt/CREB/BDNF signalling after traumatic brain injury in mice
Authors: Yan Jin , Zhang Yuan , Wang Lin , Li Zhao , Tang Shuang , Wang Yingwen , Gu Nina , Sun Xiaochuan , Li Lin 
Published: December 2022

Abstract
Background
Neuroinflammation is one of the most important processes in secondary injury after traumatic brain injury (TBI). Triggering receptor expressed on myeloid cells 2 (TREM2) has been proven to exert neuroprotective effects in neurodegenerative diseases and stroke by modulating neuroinflammation, and promoting phagocytosis and cell survival. However, the role of TREM2 in TBI has not yet been elucidated. In this study, we are the first to use COG1410, an agonist of TREM2, to assess the effects of TREM2 activation in a murine TBI model.

Methods
Adult male wild-type (WT) C57BL/6 mice and adult male TREM2 KO mice were subjected to different treatments. TBI was established by the controlled cortical impact (CCI) method. COG1410 was delivered 1 h after CCI via tail vein injection. Western blot analysis, immunofluorescence, laser speckle contrast imaging (LSCI), neurological behaviour tests, brain electrophysiological monitoring, Evans blue assays, magnetic resonance imaging (MRI), and brain water content measurement were performed in this study.

Results
The expression of endogenous TREM2 peaked at 3 d after CCI, and it was mainly expressed on microglia and neurons. We found that COG1410 improved neurological functions within 3 d, as well as neurological functions and brain electrophysiological activity at 2 weeks after CCI. COG1410 exerted neuroprotective effects by inhibiting neutrophil infiltration and microglial activation, and suppressing neuroinflammation after CCI. In addition, COG1410 treatment alleviated blood brain barrier (BBB) disruption and brain oedema; furthermore, COG1410 promoted cerebral blood flow (CBF) recovery at traumatic injury sites after CCI. In addition, COG1410 suppressed neural apoptosis at 3 d after CCI. TREM2 activation upregulated p-Akt, p-CREB, BDNF, and Bcl-2 and suppressed TNF-α, IL-1β, Bax, and cleaved caspase-3 at 3 d after CCI. Moreover, TREM2 knockout abolished the effects of COG1410 on vascular phenotypes and microglial states. Finally, the neuroprotective effects of COG1410 were suppressed by TREM2 depletion.

Conclusions
Altogether, we are the first to demonstrate that TREM2 activation by COG1410 alleviated neural damage through activation of Akt/CREB/BDNF signalling axis in microglia after CCI. Finally, COG1410 treatment improved neurological behaviour and brain electrophysiological activity after CCI.

Graphical Abstract
Practices and attitudes towards tuberculosis and latent tuberculosis infection screening in people living with HIV/AIDS among HIV physicians in Japan
Authors: Kawatsu Lisa , Kaneko Noriyo , Imahashi Mayumi , Kamada Keisuke , Uchimura Kazuhiro 
Published: December 2022

Abstract
Background
Tuberculosis (TB) continues to be the leading cause of death for people living with HIV/AIDS (PLHIV), and HIV is the strongest known risk factor for progression to active TB disease for persons with latent TB infection (LTBI). Screening for active TB and LTBI, and TB preventive therapy (TPT) is recommended, however, clinical practices regarding LTBI screening for HIV positive population have not been uniform, resulting in low rates of LTBI screening and TPT uptake, in both low and high TB-burden countries. We sought to explore the practices and attitudes towards TB and LTBI screening in PLHIV among HIV physicians in Japan.

Methods
We conducted a cross-sectional survey whereby an on-line questionnaire was administered to physicians who are currently, or have the experience of, providing care and treatment for PLHIV in Japan.

Results
The questionnaire was sent to a total of 83 physicians, of which 59 responded (response rate; 71.1%). 52.5% (31/59) conducted routine screening and 44.0% (26/59) conducted selectively screening for active TB among HIV/AIDS patients. As for LTBI, 54.2% (32/59) conducted routine screening and 35.6% (21/59) conducted selective screening for LTBI among PLHIV. “T-SPOT only” was the most frequently used method of screening (n = 33), followed by “QFT only” (n = 11). Criteria for LTBI screening included TB burden in the country of birth of the patient, previous contact with a TB patient, and CD4+ cell count. 83.1% (49/59) either “always” or “selectively” offered TPT to PLHIV diagnosed with LTBI, and among the 49 respondents who did provide TPT, 77.6% (38/49) chose 9-months isoniazid as their first choice. None chose regimen including rifampicin.

Conclusions
Our study revealed that practices regarding TB and LTBI screening and treatment for PLHIV among HIV physicians were mixed and not necessarily in accordance with the various published guidelines. Building and disseminating scientific evidence that takes into consideration the local epidemiology of TB and HIV in Japan is urgently needed to assist physicians make decisions.
Is plasma amyloid-β 1–42/1–40 a better biomarker for Alzheimer’s disease than AβX–42/X–40?
Authors: Klafki Hans-Wolfgang , Morgado Barbara , Wirths Oliver , Jahn Olaf , Bauer Chris , Esselmann Hermann , Schuchhardt Johannes , Wiltfang Jens 
Published: December 2022

Abstract
Background
A reduced amyloid-β (Aβ)42/40 peptide ratio in blood plasma represents a peripheral biomarker of the cerebral amyloid pathology observed in Alzheimer’s disease brains. The magnitude of the measurable effect in plasma is smaller than in cerebrospinal fluid, presumably due to dilution by Aβ peptides originating from peripheral sources. We hypothesized that the observable effect in plasma can be accentuated to some extent by specifically measuring Aβ1–42 and Aβ1–40 instead of AβX–42 and AβX–40.

Methods
We assessed the plasma AβX–42/X–40 and Aβ1–42/1–40 ratios in an idealized clinical sample by semi-automated Aβ immunoprecipitation followed by closely related sandwich immunoassays. The amyloid-positive and amyloid-negative groups (dichotomized according to Aβ42/40 in cerebrospinal fluid) were compared regarding the median difference, mean difference, standardized effect size (Cohen’s d) and receiver operating characteristic curves. For statistical evaluation, we applied bootstrapping.

Results
The median Aβ1–42/1–40 ratio was 20.86% lower in amyloid-positive subjects than in the amyloid-negative group, while the median AβX–42/X–40 ratio was only 15.56% lower. The relative mean difference between amyloid-positive and amyloid-negative subjects was −18.34% for plasma Aβ1–42/1–40 compared to −15.50% for AβX–42/X–40. Cohen’s d was 1.73 for Aβ1–42/1–40 and 1.48 for plasma AβX–42/X–40. Unadjusted p-values < 0.05 were obtained after .﻿﻿632 bootstrapping for all three parameters. Receiver operating characteristic analysis indicated very similar areas under the curves for plasma Aβ1–42/1–40 and AβX–42/X–40.

Conclusions
Our findings support the hypothesis that the relatively small difference in the plasma Aβ42/40 ratio between subjects with and without evidence of brain amyloidosis can be accentuated by specifically measuring Aβ1–42/1–40 instead of AβX–42/X–40. A simplified theoretical model explaining this observation is presented.
Exogenous laminin exhibits a unique vascular pattern in the brain via binding to dystroglycan and integrins
Authors: Ruan Jingsong , McKee Karen K. , Yurchenco Peter D. , Yao Yao 
Published: December 2022

Abstract
Background
Unlike other proteins that exhibit a diffusion pattern after intracerebral injection, laminin displays a vascular pattern. It remains unclear if this unique vascular pattern is caused by laminin-receptor interaction or laminin self-assembly.

Methods
We compared the distribution of various wild-type laminin isoforms in the brain after intracerebral injection. To determine what causes the unique vascular pattern of laminin in the brain, laminin mutants with impaired receptor-binding and/or self-assembly activities and function-blocking antibodies to laminin receptors were used. In addition, the dynamics of laminin distribution and elimination were examined at multiple time points after intracerebral injection.

Results
We found that β2-containing laminins had higher affinity for the vessels compared to β1-containing laminins. In addition, laminin mutants lacking receptor-binding domains but not that lacking self-assembly capability showed substantially reduced vascular pattern. Consistent with this finding, dystroglycan (DAG1) function-blocking antibody significantly reduced the vascular pattern of wild-type laminin-111. Although failed to affect the vascular pattern when used alone, integrin-β1 function-blocking antibody further decreased the vascular pattern when combined with DAG1 antibody. EDTA, which impaired laminini-DAG1 interaction by chelating Ca2+, also attenuated the vascular pattern. Immunohistochemistry revealed that laminins were predominantly located in the perivascular space in capillaries and venules/veins but not arterioles/arteries. The time-course study showed that laminin mutants with impaired receptor-engaging activity were more efficiently eliminated from the brain compared to their wild-type counterparts. Concordantly, significantly higher levels of mutant laminins were detected in the cerebral-spinal fluid (CSF).

Conclusions
These findings suggest that intracerebrally injected laminins are enriched in the perivascular space in a receptor (DAG1/integrin)-dependent rather than self-assembly-dependent manner and eliminated from the brain mainly via the perivascular clearance system.
Mental health assessment of healthcare workers in the emergency department of a low middle-income country during COVID-19 pandemic
Authors: Waheed Shahan , Kumar Nirdosh , Qureshi Bushra Qaiser , Rahim Ahmed 
Published: December 2022

AbstractIntroductionEmergency department (ED) healthcare workers in Pakistan during the COVID-19 pandemic are facing an acute rise in mental illnesses. In this study, the authors aim to assess the frequency of anxiety and depression among healthcare workers in the ED.MethodsA cross-sectional online google form-based survey was conducted in the ED of Aga Khan University Hospital, Karachi, Pakistan between July and August 2020. The Hospital Anxiety and Depression (HAD) scale was used for mental illness assessment among ED healthcare workers. Descriptive analysis of grading as per the Likert scale is done through frequencies, means, and standard deviations. Categorical variables were expressed as frequency (%). Mann–WhitneyUtest was used to compare scores of various groups and sub-groups and the Chi-square test was used to assess the association of depression and anxiety categories among the groups.ResultsIn the ED, 127 healthcare workers (physicians and nurses) were included in this survey. The median depression score was 8 (IQR 6–10) with 21% (27) falling under depression and 39% (50) under borderline depression. The median anxiety score was 9 (IQR 7–12) with 33% (42) having abnormal, and 38% (48) having borderline anxiety. Healthcare workers working for > 45 h per week have odds of 3.62 [1.374–9.549] of developing depression compared to anxiety with ap-value of 0.009. Similarly, nurses and medical officers develop depression with odds of 2.18 [1.016–4.686]p-value 0.045 and 5.18 [0.197–1.02]p-value 0.002, respectively.ConclusionED healthcare workers during the COVID-19 pandemic suffered high levels of anxiety and depression, which is a matter of concern. Comprehensive support and training of ED healthcare workers are needed to promote physical and mental well-being and to develop guidelines that should be used during situations that can affect the mental health of healthcare workers.
Metastatic colorectal cancer as the primary phenotype in a hereditary breast and ovarian cancer patient with Germline BRCA1 mutation: a case report
Authors: Liu Ying , Zhu Jing , Wei Xiao , Yang Duoxia , Li Si , Qian Xiaoping , Li Li 
Published: December 2022

AbstractHereditary breast and ovarian cancer (HBOC) syndrome has increased predisposition to breast and/or ovarian cancer, and 24% of families with HBOC were associated with the germline pathogenic variants in BRCA1/2. Timely diagnosis and identification of mutation carriers is of utmost importance to improve survival benefit and quality of life. Cancers that have been included into screening of BRCA1/2 associated HBOC included prostate and pancreatic cancers etc. In this case, we reported a patient who firstly presented symptoms of CRC and was finally diagnosed as BRCA1 associated HBOC with advanced peritoneal carcinoma. With strategies of cetuximab based treatment and olaparib, and debulking surgeries, she has achieved an overall survival (OS) > 35 months. The aim was to indicate that HBOC might also first present as CRC, and comprehensive next-generation sequencing analysis might be a key complement for screening and diagnose of HBOC.
Shaking up the silence: consequences of HMGN1 antagonizing PRC2 in the Down syndrome brain
Authors: Farley Sean J. , Grishok Alla , Zeldich Ella 
Published: December 2022

AbstractIntellectual disability is a well-known hallmark of Down Syndrome (DS) that results from the triplication of the critical region of human chromosome 21 (HSA21). Major studies were conducted in recent years to gain an understanding about the contribution of individual triplicated genes to DS-related brain pathology. Global transcriptomic alterations and widespread changes in the establishment of neural lineages, as well as their differentiation and functional maturity, suggest genome-wide chromatin organization alterations in trisomy. High Mobility Group Nucleosome Binding Domain 1 (HMGN1), expressed from HSA21, is a chromatin remodeling protein that facilitates chromatin decompaction and is associated with acetylated lysine 27 on histone H3 (H3K27ac), a mark correlated with active transcription. Recent studies causatively linked overexpression of HMGN1 in trisomy and the development of DS-associated B cell acute lymphoblastic leukemia (B-ALL). HMGN1 has been shown to antagonize the activity of the Polycomb Repressive Complex 2 (PRC2) and prevent the deposition of histone H3 lysine 27 trimethylation mark (H3K27me3), which is associated with transcriptional repression and gene silencing. However, the possible ramifications of the increased levels of HMGN1 through the derepression of PRC2 target genes on brain cell pathology have not gained attention. In this review, we discuss the functional significance of HMGN1 in brain development and summarize accumulating reports about the essential role of PRC2 in the development of the neural system. Mechanistic understanding of how overexpression of HMGN1 may contribute to aberrant brain cell phenotypes in DS, such as altered proliferation of neural progenitors, abnormal cortical architecture, diminished myelination, neurodegeneration, and Alzheimer’s disease-related pathology in trisomy 21, will facilitate the development of DS therapeutic approaches targeting chromatin.
Helicobacter pylori infection: is there circulating vacuolating cytotoxin A or cytotoxin-associated gene A protein?
Authors: Imoto Ichiro , Oka Satoko , Katsurahara Masaki , Nakamura Misaki , Yasuma Taro , Akada Junko , D’Alessandro-Gabazza Corina N. , Toda Masaaki , Horiki Noriyuki , Gabazza Esteban C. , Yamaoka Yoshio 
Published: December 2022

AbstractBackgroundHelicobacter pyloriinfection is a well-recognized cause of gastric diseases, including chronic gastritis, peptic ulcer, and gastric cancer. Vacuolating cytotoxin-A (VacA) and cytotoxin-associated gene A protein (CagA) play a role in the pathogenesis ofH. pylori-related gastric diseases. Also, extragastric disorders are frequent morbid complications in patients withH. pyloriinfection. However, the direct pathologic implication of these virulence factors in extragastric manifestations remains unclear. Our hypothesis in the present study is that VacA and CagA released byH. pyloriin the gastric mucosa leak into the systemic circulation, and therefore they can be measured in serum.ResultsSixty-two subjects were enrolled. They were allocated intothe H. pylori-positive and H. pylori-negative groups. VacA and CagA were measured by immunoassays. The serum levels of VacA and CagA above an upper limit cut-off (mean plus two standard deviations of the mean in patients withoutH. pyloriinfection) were considered positive for antigen circulating level. Five out of 25H. pylori-positive patients were positive for both serum VacA and serum CagA. The serum levels of VacA and CagA were significantly correlated with the serum levels of anti-H. pyloriantibody and interleukin-12p70 among allH. pylori-positive and H. pylori-negative patients.ConclusionsThis study suggests that spill-over of VacA and CagA antigens in the systemic circulation may occur in some patients withH. pyloriinfection.
CAULIFINDER: a pipeline for the automated detection and annotation of caulimovirid endogenous viral elements in plant genomes
Authors: Vassilieff Héléna , Haddad Sana , Jamilloux Véronique , Choisne Nathalie , Sharma Vikas , Giraud Delphine , Wan Mariène , Serfraz Saad , Geering Andrew D. W. , Teycheney Pierre-Yves , Maumus Florian 
Published: December 2022

AbstractPlant, animal and protist genomes often contain endogenous viral elements (EVEs), which correspond to partial and sometimes entire viral genomes that have been captured in the genome of their host organism through a variety of integration mechanisms. While the number of sequenced eukaryotic genomes is rapidly increasing, the annotation and characterization of EVEs remains largely overlooked. EVEs that derive from members of the family Caulimoviridae are widespread across tracheophyte plants, and sometimes they occur in very high copy numbers. However, existing programs for annotating repetitive DNA elements in plant genomes are poor at identifying and then classifying these EVEs. Other than accurately annotating plant genomes, there is intrinsic value in a tool that could identify caulimovirid EVEs as they testify to recent or ancient host-virus interactions and provide valuable insights into virus evolution. In response to this research need, we have developed CAULIFINDER, an automated and sensitive annotation software package. CAULIFINDER consists of two complementary workflows, one to reconstruct, annotate and group caulimovirid EVEs in a given plant genome and the second to classify these genetic elements into officially recognized or tentative genera in the Caulimoviridae. We have benchmarked the CAULIFINDER package using the Vitis vinifera reference genome, which contains a rich assortment of caulimovirid EVEs that have previously been characterized using manual methods. The CAULIFINDER package is distributed in the form of a Docker image.