bluuebunny/crossref_metadata_2025 huggingface dataset:
Transitions Between Preexposure Prophylaxis Eligibility States and HIV Infection in the Lisbon Cohort of HIV-Negative Men Who Have Sex With Men: A Multistate Model Analysis
Authors: Meireles Paula , Moreira Carla , Rocha Miguel , Plankey Michael , Barros Henrique
Published: October 2021

We aimed to describe transitions between preexposure prophylaxis (PrEP) eligibility and human immunodeficiency virus (HIV) infection among HIV-negative men who have sex with men (MSM). We used data from 1,885 MSM, who had not used PrEP, enrolled in the Lisbon Cohort of MSM, with at least 2 consecutive measurements of PrEP eligibility from 2014–2020. A time-homogeneous Markov multistate model was applied to describe the transitions between states of PrEP eligibility—eligible and ineligible—and from these to HIV infection (HIV). The intensities of the transitions were closer for ineligible-to-eligible and eligible-to-ineligible transitions (intensity ratio, 1.107, 95% confidence interval (CI): 1.080, 1.176), while the intensity of the eligible-to-HIV transition was higher than that for ineligible-to–HIV transition (intensity ratio, 9.558, 95% CI: 0.738, 65.048). The probabilities of transitions increased with time; for 90 days, the probabilities were similar for the ineligible-to-eligible and eligible-to-ineligible transitions (0.285 (95% CI: 0.252, 0.319) vs. 0.258 (95% CI: 0.228, 0.287)), while the eligible-to-HIV transition was more likely than ineligible-to-HIV (0.004 (95% CI: 0.003, 0.007) vs. 0.001 (95% CI: 0.001, 0.008)) but tended to become closer with time. Being classified as ineligible was a short-term indicator of a lower probability of acquiring HIV. Once an individual moved to eligible, he was at a higher risk of seroconversion, demanding a timely delivery ofPrEP.
Single Center and Surgeon’s Long-Term (15-19 Years) Patient Satisfaction and Revision Rate of Round Textured Eurosilicone Breast Implants
Authors: Kooiman Laurens , Torensma Bart , Stevens Hieronymus , van der Lei Berend
Published: October 2021

Background

Breast augmentation is one of the most commonly performed aesthetic plastic surgical procedures, with over 250,000 procedures in the United States in 2020 alone. However, the safety of breast implants should be closely researched and monitored, especially in the long term.

Objectives

This study was undertaken to evaluate the long-term results of round micro-textured Eurosilicone (Eurosilicone S.A.S, Apt Cedex, France) Cristalline Paragel breast implants from a single-center, single-surgeon experience regarding both patient-reported outcome measures and revisions.

Methods

A retrospective cohort study was undertaken of 84 patients who underwent primary breast augmentation with round micro-textured Eurosilicone Cristalline Paragel breast implants, either submuscular (dual-plane) or subglandular placed, between 2001 and 2004. All patients were contacted for informed consent, and after approval, the validated BREAST-Q questionnaire was sent and utilized to analyze patient satisfaction. In addition, objective data regarding revisions, including capsular contracture, rupture rate, pain, and/or aesthetic causes needing revision surgery, were analyzed.

Results

High BREAST-Q scores (67%-100% for 0-100 scale variables and 66.0%-77.3% of the patients scored “very satisfied” on categorical variables) were found without clinically significant differences between patients with dual-plane–placed implants and subglandular-placed implants. The overall revision rate was 29.8%, also with no significant differences between groups (P = 0.317).

Conclusions

This study showed high patient satisfaction and relatively low revision rates after 15 to 19 years of follow-up of round micro-textured Eurosilicone Cristalline Paragel breast implants. No clinically relevant significant differences were found between dual-plane and subglandular placement of the implants.

Level of Evidence: 4
Finerenone reduces renal RORgt gd T-Cells and protects against cardiorenal damage
Authors: Luettges K , Bode M , Thiele A , Ritter D , Klopfleisch R , Kappert K , Foryst-Ludwig A , Kolkhof P , Wenzel U , Kintscher U
Published: October 2021

Chronic activation of the mineralocorticoid receptor (MR) through the agonist aldosterone leads to pathological processes like inflammation, fibrosis, and increased blood pressure. Therefore, MR antagonists (MRA) belong to guideline-based therapy for hypertension and heart failure with reduced ejection fraction. The nonsteroidal, selective MRA finerenone (FIN) induces distinct pharmacological actions when compared to steroidal MRAs including less adverse effects and improved efficacy (e.g. anti-fibrosis). In this study, we investigated the effects of FIN in a deoxycorticosterone acetate (DOCA)-salt model which induces an increase of blood pressure and end organ damage including hypertrophy, fibrosis, and inflammatory cell infiltration in heart and kidney.

Male C57BL6/J mice were either uni-nephrectomized in addition to DOCA-pellet application (2.4mg/d) and 0.9% NaCl in the drinking water (DOCA/UNX) or received a sham operation. One week prior to the surgery, oral treatment with FIN (10mg/kg/d) or vehicle (VEH) started and lasted throughout the experiment. Five weeks after the procedure, final examinations including blood pressure (BP) measurement, urine analysis, speckle-tracking echocardiography (STE), and FACS analysis of the heart and kidney were performed.

BP was significantly reduced by FIN treatment. FACS analysis revealed a notable immune response due to DOCA/ UNX exposure. Especially infiltrating renal RORγt γδ T-Cells were upregulated, which was significantly ameliorated by the FIN-treatment. This was accompanied by an improvement of kidney function shown by a reduction of the urinary albumin/creatinine ratio in FIN-treated mice. In the heart, FIN reduced DOCA/ UNX-induced cardiac hypertrophy, cardiac fibrosis and led to an improvement of the global longitudinal strain (GLS) in the STE-analysis. Cardiac actions of FIN were not associated with a regulation of cardiac RORγt γδ T-Cells.

The present study shows cardiac and renal protective effects of FIN in a DOCA/UNX model. The cardiorenal protection was accompanied by a reduction of renal RORγt γδ T-Cells. Anti-inflammatory actions of FIN may provide a potential mechanism of its clinical efficacy recently observed in clinical trials.

Funding Acknowledgement

Type of funding sources: Private company. Main funding source(s): Bayer AG
High- and Low-Arousal Daily Affect Dynamics Vary Across the Adult Lifespan
Authors: Mak Hio Wa , Schneider Stefan
Published: October 2021

Objectives

Age differences in affective experience across adulthood are widely documented. According to the circumplex model of affect consists of 2 aspects—valence (positive vs negative) and arousal (low activation vs high activation). Prior research on age differences has primarily focused on the valence aspect. However, little is known about age differences in daily affect of high and low arousal.

Method

The present study examined age differences in daily dynamics (i.e., mean levels, variability, and inertia) of negative affect (NA) and positive affect (PA) of high and low arousal in a sample of 492 adults aged 21–91. Participants completed daily affect ratings for 21 consecutive days.

Results

Age was negatively and linearly related to mean levels of both high-arousal and low-arousal NA. Both high-arousal and low-arousal PA mean levels showed increases after middle age. Further, age was related to lower variability in both NA and PA regardless of arousal. Additionally, high-arousal NA inertia showed a linear decrease with age, whereas low-arousal PA inertia showed an inverted-U pattern with age. After controlling for mean levels of affect, the associations between age and affect variability remained significant, whereas the associations between age and affect inertia did not.

Discussion

The affective profile of older age is characterized by lower mean levels of NA, higher mean levels of PA, lower affect variability, and less persistence in high-arousal NA and low-arousal PA in daily life. Our results contribute to a nuanced understanding of which affective processes improve with age and which do not.
Lobectomy versus segmentectomy: a propensity score-matched comparison of postoperative complications, pulmonary function and prognosis
Authors: Nomori Hiroaki , Yamazaki Ikuo , Machida Youichi , Otsuki Ayumu , Cong Yue , Sugimura Hiroshi , Oyama Yu
Published: October 2021

OBJECTIVES

To demonstrate the differences in clinical outcomes between lobectomy and segmentectomy for non-small cell lung cancer using propensity score matching.

METHODS

A single-centre, retrospective, matched cohort study was conducted in clinical T1N0M0 non-small cell lung cancer patients treated by surgery between 2012 and 2019. Differences in freedom from recurrence, overall survival, postoperative complications, chest drainage and preservation of pulmonary function between lobectomy and segmentectomy were evaluated using the propensity score model. Matched variables of patients were age, sex, comorbidity index and pulmonary function. Matched variables of tumours were tumour size, T-stage, fluorodeoxyglucose uptake on positron emission tomography, histopathology, lobe site and tumour distance ratio from the hilum.

RESULTS

Of the 112 patients treated by lobectomy and 233 patients treated by segmentectomy, 93 patients each from both groups were selected after the matching. The median tumour distance ratio from hilum was 0.7 in lobectomy and 0.8 in segmentectomy group (P = 0.59), i.e. almost outer third tumour location. There were no significant differences in freedom from recurrence (P = 0.38), overall survival (P = 0.51), postoperative complications (P = 0.94), drainage period (P = 0.53) and prolonged air leakage (P = 0.82) between the two. Median preservation of pulmonary function was 93.2% after segmentectomy, which was significantly higher than 85.9% after lobectomy (P < 0.001).

CONCLUSIONS

Freedom from recurrence, overall survival, postoperative complications and chest drainage were similar between segmentectomy and lobectomy. Segmentectomy could be one of the options for clinical T1N0M0 non-small cell lung cancer located outer third as well as being able to preserve pulmonary function better than lobectomy.

Clinical trial registration
The transcription factor Sox4 is required for thymic tuft cell development
Authors: Mino Nanami , Muro Ryunosuke , Ota Ayami , Nitta Sachiko , Lefebvre Veronique , Nitta Takeshi , Fujio Keishi , Takayanagi Hiroshi
Published: October 2021

Medullary thymic epithelial cells (mTECs) help shape the thymic microenvironment for T-cell development by expressing a variety of peripheral tissue-restricted antigens (TRAs). The self-tolerance of T cells is established by negative selection of autoreactive T cells that bind to TRAs. To increase the diversity of TRAs, a fraction of mTECs terminally differentiates into distinct subsets resembling atypical types of epithelial cells in specific peripheral tissues. As such, thymic tuft cells that express peripheral tuft cell genes have recently emerged. Here, we show that the transcription factor SRY-box transcription factor 4 (Sox4) is highly expressed in mTECs and is essential for the development of thymic tuft cells. Mice lacking Sox4 specifically in TECs had a significantly reduced number of thymic tuft cells with no effect on the differentiation of other mTEC subsets, including autoimmune regulator (Aire)+ and Ccl21a+ mTECs. Furthermore, Sox4 expression was diminished in mice deficient in TEC-specific lymphotoxin β receptor (LTβR), indicating a role for the LTβR-Sox4 axis in the differentiation of thymic tuft cells. Given that Sox4 promotes differentiation of peripheral tuft cells, our findings suggest that mTECs employ the same transcriptional program as peripheral epithelial cells. This mechanism may explain how mTECs diversify peripheral antigen expression to project an immunological self within the thymic medulla.
Short-chain fatty acid administration via water acidifier improves feed efficiency and modulates fecal microbiota in weaned piglets
Authors: Lingbeek Mandy M , Borewicz Klaudyna , Febery Erica , Han Yanming , Doelman John , van Kuijk Sandra J A
Published: October 2021

This study examined the effect of a water acidifier containing free and buffered short-chain fatty acids (SCFA-WA) on growth performance and microbiota of weaned piglets. In total, 192 male piglets, approximately 4 wk of age, were allocated to 24 pens (12 per treatment) with 8 piglets per pen. The piglets received either regular drinking water (negative control) or drinking water with the acidifier supplied at 2 L/1,000 L. Body weight and feed intake were measured weekly on pen level. During the first 2 wk, daily visual assessment and scoring of the feces was conducted. Fecal samples of three piglets per pen were collected on days 14 and 42 for high-throughput sequencing analysis of the microbiota. Piglets offered SCFA-WA had significantly improved feed efficiency in the third week (P = 0.025) and over the whole study period (days 0 to 42, P = 0.042) compared with piglets in the negative control group, with a strong tendency observed during the first feeding phase (days 0 to 21, P = 0.055). Furthermore, the water acidifier group had a higher water intake than piglets provided with control water during the second feeding phase (days 21 to 42, P = 0.028) and over the whole study period (days 0 to 42, P = 0.043). There was no significant difference in body weight, average daily gain, or average daily feed intake (days 0 to 21, 21 to 42, 0 to 42). Furthermore, there was no overall significant difference in fecal scoring between the treatments. In terms of the fecal microbiota response, piglets offered the water acidifier showed a significantly higher relative abundance (RA) of genus Clostridium sensu stricto 1 and a lower RA of genus Streptococcus compared to the control. Furthermore, the redundancy analysis showed a positive association between improved feed efficiency and daily weight gain and RA of Butyricicoccus and Faecalibacterium. In conclusion, consumption of the water acidifier containing free and buffered SCFA modulated the microbiota and improved feed efficiency in piglets.
Measurement Invariance of the GAD-7 and CESD-R-10 Among Adolescents in Canada
Authors: Romano Isabella , Ferro Mark A , Patte Karen A , Leatherdale Scott T
Published: October 2021

Objective

The primary objective of our study was to assess measurement invariance (by grade and sex) of the 7-item Generalized Anxiety Disorder (GAD-7) and 10-item Center for Epidemiologic Studies Depression Revised (CESD-R-10) scales in a sample of adolescents in Canada. If measurement invariance was demonstrated, our secondary objective was to estimate differences in scale scores across these subgroups.

Methods

We used data from 59,052 adolescents in Year 7 (2018–19) of the COMPASS school-based study. Measurement invariance was tested within a multigroup confirmatory factor analysis framework. Differences in scale scores were estimated using mixed linear regression which accounted for school-level clustering and adjusted for relevant confounders.

Results

Both the GAD-7 and CESD-R-10 demonstrated strict measurement invariance by sex and grade in our sample. Mean scale scores were higher among adolescents in grade 12 compared to grade 9 (βGAD-7 = 0.91, p < .001; βCESD-R-10 = 0.99, p < .001) and among female adolescents compared to males (βGAD-7 = 3.36, p < .001; βCESD-R-10 = 2.58, p < .001).

Conclusions

Findings support the validity of the GAD-7 and CESD-R-10 for screening risk of generalized anxiety and depression among Canadian adolescents, and further indicate that differences observed in scale scores across subgroups reflect actual differences in risk for generalized anxiety and major depression, respectively.
Altered H3K27 trimethylation contributes to flowering time variations in polyploid Arabidopsis thaliana ecotypes
Authors: Cheng Jinping , Zhang Guiqian , Xu Linhao , Liu Chang , Jiang Hua
Published: October 2021

Polyploidy is a widespread phenomenon in flowering plant species. Polyploid plants frequently exhibit considerable transcriptomic alterations after whole-genome duplication (WGD). It is known that the transcriptomic response to tetraploidization is ecotype-dependent in Arabidopsis; however, the biological significance and the underlying mechanisms are unknown. In this study, we found that 4x Col-0 presents a delayed flowering time whereas 4x Ler does not. The expression of FLOWERING LOCUS C (FLC), the major repressor of flowering, was significantly increased in 4x Col-0 but only a subtle change was present in 4x Ler. Moreover, the level of a repressive epigenetic mark, trimethylation of histone H3 at lysine 27 (H3K27me3), was significantly decreased in 4x Col-0 but not in 4x Ler, potentially leading to the differences in FLC transcription levels and flowering times. Hundreds of other genes in addition to FLC showed H3K27me3 alterations in 4x Col-0 and 4x Ler. LIKE HETEROCHROMATIN PROTEIN 1 (LHP1) and transcription factors required for H3K27me3 deposition presented transcriptional changes between the two ecotypes, potentially accounting for the different H3K27me3 alterations. We also found that the natural 4x Arabidopsis ecotype Wa-1 presented an early flowering time, which was associated with low expression of FLC. Taken together, our results demonstrate a role of H3K27me3 alterations in response to genome duplication in Arabidopsis autopolyploids, and that variation in flowering time potentially functions in autopolyploid speciation.
Associations between ACE Genotypes, +8.5 Gz Tolerance, and Body Composition in F-15 Pilot Candidates
Authors: Shin Seunghwan , Son Seokhee
Published: October 2021

Introduction

Pilots' +8.5Gz tolerance is related with their selection, safety and special mission suitability. The preliminary study about F-15 pilot candidates were rare, especially related with genetic effect like ACE (angiotensin converting enzyme) gene.

Background

This study aimed to investigate the associations between the +8.5 Gz test qualification and angiotensin converting enzyme (ACE) genotypes in Korean F-15 pilot candidates for pilot special mission suitability and cadet body composition education.

Materials and methods

We performed +8.5Gz test (15 seconds), target gene (ACE) identified and body composition measurements from twenty Korean F-15 pilot candidates (ages 23.0-28.6 years). The +8.5Gz test results (pass and not-passed), body composition parameters and their relationship with the ACE genotype were evaluated.

Results

Four (20%), six (30%), and 10 (50%) pilots had the DD, DI, and II genotypes based on the ACE gene identification results, respectively. Ten (50%) pilots passed by maintaining consciousness during the +Gz test. Of them, three (75%, 3/4), four (66.7%, 4/6), and three (30%, 3/10) had the DD, DI, and II genotypes (P < .05, DD > II), respectively. Compared with other genotypes, the DD genotype was associated with overall higher values of body composition indices, and this association was more prominent among pilots who passed the +8.5 Gz test.

Discussion

In some ethnic groups, the DD genotype has been found to have an effect on elite players’ high-intensity performance, including muscle power and strength. The DD genotype exhibited the highest performance in terms of passing rate, longest mean breathing interval(s), and higher values of body composition parameters in pilots who passed the +8.5 Gz test.

Conclusions

In this study, the group with the DD genotype exhibited a higher pass rate and heavier body composition parameters than the group with the II genotype. These results require further investigation to determine their significance and applicability in other ethnic groups.
Characterization of the metalloproteome of Pseudoalteromonas (BB2-AT2): biogeochemical underpinnings for zinc, manganese, cobalt, and nickel cycling in a ubiquitous marine heterotroph
Authors: Mazzotta Michael G , McIlvin Matthew R , Moran Dawn M , Wang David T , Bidle Kay D , Lamborg Carl H , Saito Mak A
Published: October 2021

Pseudoalteromonas (BB2-AT2) is a ubiquitous marine heterotroph, often associated with labile organic carbon sources in the ocean (e.g. phytoplankton blooms and sinking particles). Heterotrophs hydrolyze exported photosynthetic materials, components of the biological carbon pump, with the use of diverse metalloenzymes containing zinc (Zn), manganese (Mn), cobalt (Co), and nickel (Ni). Studies on the metal requirements and cytosolic utilization of metals for marine heterotrophs are scarce, despite their relevance to global carbon cycling. Here, we characterized the Zn, Mn, Co, and Ni metallome of BB2-AT2. We found that the Zn metallome is complex and cytosolic Zn is associated with numerous proteins for transcription (47.2% of the metallome, obtained from singular value decomposition of the metalloproteomic data), translation (33.5%), proteolysis (12.8%), and alkaline phosphatase activity (6.4%). Numerous proteolytic enzymes also appear to be putatively associated with Mn, and to a lesser extent, Co. Putative identification of the Ni-associated proteins, phosphoglucomutase and a protein in the cupin superfamily, provides new insights for Ni utilization in marine heterotrophs. BB2-AT2 relies on numerous transition metals for proteolytic and phosphatase activities, inferring an adaptative potential to metal limitation. Our field observations of increased alkaline phosphatase activity upon addition of Zn in field incubations suggest that such metal limitation operates in sinking particulate material collected from sediment traps. Taken together, this study improves our understanding of the Zn, Mn, Co, and Ni metallome of marine heterotrophic bacteria and provides novel and mechanistic frameworks for understanding the influence of nutrient limitation on biogeochemical cycling.
Multidimensional genome-wide screening in yeast provides mechanistic insights into europium toxicity
Authors: Pallares Roger M , An Dahlia D , Hébert Solène , Faulkner David , Loguinov Alex , Proctor Michael , Villalobos Jonathan A , Bjornstad Kathleen A , Rosen Chris J , Vulpe Christopher , Abergel Rebecca J
Published: October 2021

Europium is a lanthanide metal that is highly valued in optoelectronics. Even though europium is used in many commercial products, its toxicological profile has only been partially characterized, with most studies focusing on identifying lethal doses in different systems or bioaccumulation in vivo. This paper describes a genome-wide toxicogenomic study of europium in Saccharomyces cerevisiae, which shares many biological functions with humans. By using a multidimensional approach and functional and network analyses, we have identified a group of genes and proteins associated with the yeast responses to ameliorate metal toxicity, which include metal discharge paths through vesicle-mediated transport, paths to regulate biologically relevant cations, and processes to reduce metal-induced stress. Furthermore, the analyses indicated that europium promotes yeast toxicity by disrupting the function of chaperones and cochaperones, which have metal-binding sites. Several of the genes and proteins highlighted in our study have human orthologues, suggesting they may participate in europium-induced toxicity in humans. By identifying the endogenous targets of europium as well as the already existing paths that can decrease its toxicity, we can determine specific genes and proteins that may help to develop future therapeutic strategies.
Improved dsDNA recombineering enables versatile multiplex genome engineering of kilobase-scale sequences in diverse bacteria
Authors: Wang Xue , Zheng Wentao , Zhou Haibo , Tu Qiang , Tang Ya-Jie , Stewart A Francis , Zhang Youming , Bian Xiaoying
Published: October 2021

Recombineering assisted multiplex genome editing generally uses single-stranded oligonucleotides for site directed mutational changes. It has proven highly efficient for functional screens and to optimize microbial cell factories. However, this approach is limited to relatively small mutational changes. Here, we addressed the challenges involved in the use of double-stranded DNA substrates for multiplex genome engineering. Recombineering is mediated by phage single-strand annealing proteins annealing ssDNAs into the replication fork. We apply this insight to facilitate the generation of ssDNA from the dsDNA substrate and to alter the speed of replication by elevating the available deoxynucleoside triphosphate (dNTP) levels. Intracellular dNTP concentration was elevated by ribonucleotide reductase overexpression or dNTP addition to establish double-stranded DNA Recombineering-assisted Multiplex Genome Engineering (dReaMGE), which enables rapid and flexible insertional and deletional mutagenesis at multiple sites on kilobase scales in diverse bacteria without the generation of double-strand breaks or disturbance of the mismatch repair system. dReaMGE can achieve combinatorial genome engineering works, for example, alterations to multiple biosynthetic pathways, multiple promoter or gene insertions, variations of transcriptional regulator combinations, within a few days. dReaMGE adds to the repertoire of bacterial genome engineering to facilitate discovery, functional genomics, strain optimization and directed evolution of microbial cell factories.
Assessing genome-wide dynamic changes in enhancer activity during early mESC differentiation by FAIRE-STARR-seq
Authors: Glaser Laura V , Steiger Mara , Fuchs Alisa , van Bömmel Alena , Einfeldt Edda , Chung Ho-Ryun , Vingron Martin , Meijsing Sebastiaan H
Published: October 2021

Embryonic stem cells (ESCs) can differentiate into any given cell type and therefore represent a versatile model to study the link between gene regulation and differentiation. To quantitatively assess the dynamics of enhancer activity during the early stages of murine ESC differentiation, we analyzed accessible genomic regions using STARR-seq, a massively parallel reporter assay. This resulted in a genome-wide quantitative map of active mESC enhancers, in pluripotency and during the early stages of differentiation. We find that only a minority of accessible regions is active and that such regions are enriched near promoters, characterized by specific chromatin marks, enriched for distinct sequence motifs, and modeling shows that active regions can be predicted from sequence alone. Regions that change their activity upon retinoic acid-induced differentiation are more prevalent at distal intergenic regions when compared to constitutively active enhancers. Further, analysis of differentially active enhancers verified the contribution of individual TF motifs toward activity and inducibility as well as their role in regulating endogenous genes. Notably, the activity of retinoic acid receptor alpha (RARα) occupied regions can either increase or decrease upon the addition of its ligand, retinoic acid, with the direction of the change correlating with spacing and orientation of the RARα consensus motif and the co-occurrence of additional sequence motifs. Together, our genome-wide enhancer activity map elucidates features associated with enhancer activity levels, identifies regulatory regions disregarded by computational prediction tools, and provides a resource for future studies into regulatory elements in mESCs.
JASPAR 2022: the 9th release of the open-access database of transcription factor binding profiles
Authors: Castro-Mondragon Jaime A , Riudavets-Puig Rafael , Rauluseviciute Ieva , Berhanu Lemma Roza , Turchi Laura , Blanc-Mathieu Romain , Lucas Jeremy , Boddie Paul , Khan Aziz , Manosalva Pérez Nicolás , Fornes Oriol , Leung Tiffany Y , Aguirre Alejandro , Hammal Fayrouz , Schmelter Daniel , Baranasic Damir , Ballester Benoit , Sandelin Albin , Lenhard Boris , Vandepoele Klaas , Wasserman Wyeth W , Parcy François , Mathelier Anthony
Published: October 2021

JASPAR (http://jaspar.genereg.net/) is an open-access database containing manually curated, non-redundant transcription factor (TF) binding profiles for TFs across six taxonomic groups. In this 9th release, we expanded the CORE collection with 341 new profiles (148 for plants, 101 for vertebrates, 85 for urochordates, and 7 for insects), which corresponds to a 19% expansion over the previous release. We added 298 new profiles to the Unvalidated collection when no orthogonal evidence was found in the literature. All the profiles were clustered to provide familial binding profiles for each taxonomic group. Moreover, we revised the structural classification of DNA binding domains to consider plant-specific TFs. This release introduces word clouds to represent the scientific knowledge associated with each TF. We updated the genome tracks of TFBSs predicted with JASPAR profiles in eight organisms; the human and mouse TFBS predictions can be visualized as native tracks in the UCSC Genome Browser. Finally, we provide a new tool to perform JASPAR TFBS enrichment analysis in user-provided genomic regions. All the data is accessible through the JASPAR website, its associated RESTful API, the R/Bioconductor data package, and a new Python package, pyJASPAR, that facilitates serverless access to the data.
Inactivating transcription factorOsWRKY5enhances drought tolerance through abscisic acid signaling pathways
Authors: Lim Chaemyeong , Kang Kiyoon , Shim Yejin , Yoo Soo-Cheul , Paek Nam-Chon
Published: October 2021

During crop cultivation, water-deficit conditions retard growth, thus reducing crop productivity. Therefore, uncovering the mechanisms behind drought tolerance is a critical task for crop improvement. Here, we show that the rice (Oryza sativa) WRKY transcription factor OsWRKY5 negatively regulates drought tolerance. We determined that OsWRKY5 was mainly expressed in developing leaves at the seedling and heading stages, and that its expression was reduced by drought stress and by treatment with NaCl, mannitol, and abscisic acid (ABA). Notably, the genome-edited loss-of-function alleles oswrky5-2 and oswrky5-3 conferred enhanced drought tolerance, measured as plant growth under water-deficit conditions. Conversely, the overexpression of OsWRKY5 in the activation-tagged line oswrky5-D resulted in higher susceptibility under the same conditions. The loss of OsWRKY5 activity increased sensitivity to ABA, thus promoting ABA-dependent stomatal closure. Transcriptome deep sequencing and reverse transcription quantitative polymerase chain reaction analyses demonstrated that the expression of abiotic stress-related genes including rice MYB2 (OsMYB2) was upregulated in oswrky5 knockout mutants and downregulated in oswrky5-D mutants. Moreover, dual-luciferase, yeast one-hybrid, and chromatin immunoprecipitation assays showed that OsWRKY5 directly binds to the W-box sequences in the promoter region of OsMYB2 and represses OsMYB2 expression, thus downregulating genes downstream of OsMYB2 in the ABA signaling pathways. Our results demonstrate that OsWRKY5 functions as a negative regulator of ABA-induced drought stress tolerance, strongly suggesting that inactivation of OsWRKY5 or manipulation of key OsWRKY5 targets could be useful to improve drought tolerance in rice cultivars.
Increasing loop flexibility affords low-temperature adaptation of a moderate thermophilic malate dehydrogenase from Geobacillus stearothermophilus
Authors: Shimozawa Yuya , Himiyama Tomoki , Nakamura Tsutomu , Nishiya Yoshiaki
Published: October 2021

Malate dehydrogenase (MDH) catalyzes the reversible reduction of nicotinamide adenine dinucleotide from oxaloacetate to L-malate. MDH from moderate thermophilic Geobacillus stearothermophilus (gs-MDH) has high thermal stability and substrate specificity and is used as a diagnostic reagent. In this study, gs-MDH was engineered to increase its catalytic activity at low temperatures. Based on sequential and structural comparison with lactate dehydrogenase from G. stearothermophilus, we selected G218 as a mutation site to increase the loop flexibility pivotal for MDH catalysis. The G218 mutants showed significantly higher specific activities than the wild type at low temperatures and maintained thermal stability. The crystal structure of the G218Y mutant, which had the highest catalytic efficiency among all the G218 mutants, suggested that the flexibility of the mobile loop was successfully increased by the bulky side chain. Therefore, this study demonstrated the low-temperature adaptation of MDH by facilitating conformational changes during catalysis.
Calcium silicate enhances immunosuppressive function of MSCs to indirectly modulate the polarization of macrophages
Authors: Li Haiyan , Wang Wenrui , Chang Jiang
Published: October 2021

Bioactive silicate ceramics (BSCs) have been widely reported to be able to induce bone tissue regeneration, but the underlying mechanisms have not been fully elucidated. Previous studies have reported that ionic products of BSCs can promote bone regeneration by directly simulating osteogenic differentiation of mesenchymal stem cells (MSCs) and modulating the polarization of macrophages to create a favorable inflammation microenvironment for initiating bone regeneration cascades. However, the immunomodulatory ability of MSCs also plays a critical role in bone regeneration but the effects of BSCs on the immunomodulatory ability of MSCs have been rarely investigated. This study aims to investigate the effects of ionic products of BSCs on the immunoregulatory ability of MSCs to further understand the mechanism of BSCs enhancing bone regeneration. Results showed that ionic products of calcium silicate (CS), one of the representative BSCs, could enhance the immunosuppressive function of human bone marrow mesenchymal stem cells (HBMSCs) by up-regulating the expression of immunosuppressive factors in HBMSCs via NF-κB pathway. In addition, CS-activated HBMSCs showed stronger stimulatory effects on M2 polarization of macrophages than CS ionic products. Furthermore, the macrophages educated by CS-activated HBMSCs showed stronger stimulatory effects on the early osteogenic differentiation of HBMSCs than the ones regulated by CS ionic products. These results not only provide further understanding on the mechanism of BSCs enhancing bone regeneration but also suggest that it is critical to consider the effects of biomaterials on the immunomodulatory function of the tissue forming cells when the immunomodulatory function of biomaterials is investigated.
Plasma exosomal RNAs have potential as both clinical biomarkers and therapeutic targets of dermatomyositis
Authors: Li Liya , Zuo Xiaoxia , Liu Di , Luo Hui , Zhang Huali , Peng Qinglin , Wang Guochun , Zhu Honglin
Published: October 2021

Objectives

DM is characterized by skeletal muscle weakness and cutaneous manifestations. Plasma exosomes (EXOs) contain proteins, RNAs, DNA, and lipid cargoes and are transferred among cells. If thoroughly investigated, plasma EXO RNAs could potentially improve our understanding of DM pathogenesis. We aimed to identify potential new biomarkers and therapeutic targets for DM.

Methods

The RNA (mRNA, miRNA and lncRNA) profiles of plasma EXOs were evaluated by sequencing on the Illumina HiSeq 3000 platform. Differentially expressed (DE) RNAs and bioinformatic analyses were performed. Human skeletal muscle myoblasts cells (HSkMCs) were stimulated with plasma EXOs, rapamycin or IFN-β. Real-time PCR and western blot analysis were used to detect related genes and proteins.

Results

A total of 689 DE mRNAs, 53 DE miRNAs and 452 DE lncRNAs were identified in DM plasma EXOs. Bioinformatic analysis inferred that plasma EXOs were secreted mainly by CD8+ T cells, regulatory T cells and natural killer cells. The DE miRNAs participated in the autophagy, TGF-β and Wnt signalling pathways. Three DE miRNAs (hsa-miR-125a-3p, hsa-miR-1246 and hsa-miR-3614-5p) were correlated with serological indices, organ involvement and myositis-specific autoantibodies. The DE lncRNAs participated in autophagy, IFN-β production and mTOR signalling. DM plasma EXOs can induce autophagy in HSkMCs by regulating three miRNAs (hsa-miR-125a-3p, hsa-miR-1246 and hsa-miR-3614-5p) and three lncRNAs (ENST00000584157.1, ENST00000523380.1 and ENST00000560054.1), which formed an autophagy network, playing a role in muscle damage.

Conclusion

Our study provides an overview of distinct RNA profiles in DM plasma EXOs, and verified some miRNAs as potential biomarkers and therapeutic targets. The findings provide important clues for more in-depth explorations of plasma EXOs in DM.
Global, regional and national trends in sex- and age-specific disability-adjusted life years of musculoskeletal disorders, 1990–2019
Authors: Jin Ziyi , Feng Xuebing , Wang Dandan , Zhu Yun , Liang Jun , Zhang Huayong , Zhao Jinkou , Sun Lingyun
Published: October 2021

Objective

To quantify the temporal trend of sex- and age-specific disability-adjusted life years (DALYs) for musculoskeletal (MSK) disorders by region and cause.

Methods

Data were collected from the Global Burden of Diseases Study 2019. The estimated annual percentage change (EAPC) by sex, age, region and cause was calculated to examine the temporal trend of the age-standardized DALYs rate (ASDR). The sociodemographic index (SDI) and risk exposures were also examined.

Results

Between 1990 and 2019, the global ASDR for MSK disorders remained almost stable by sex and age group but decreased among females ages 0–14 years (EAPC = −0.27). Such age and sex patterns were nearly the same by SDI, except for high SDI regions, where ASDR increased in all subgroups except those ages 15–49 years. The trend in ASDR of MSK disorders for females and males ages 50–74 and ≥75 years increased in ∼80% of countries and territories. The greatest increase was in El Salvador for males ages 15–49 years (EAPC = 1.30), followed by Nicaragua. The association between EAPC and SDI was positive in developing regions, particularly among females ages 15–49 years, and negative in developed regions. A decreasing trend in ASDR was mainly driven by the decrease in low back pain, while the increasing trend was largely due to other MSK disorders and gout across sexes and age groups.

Conclusions

There are great disparities in the age- and sex-specific trends in ASDR by cause on the global, regional and national levels. More differentiated prevention and management strategies are needed for MSK disorders.
Performance of Doppler-Based Resistive Index and Semiquantitative Renal Perfusion in Predicting Persistent Acute Kidney Injury According to Operator Experience: Post Hoc Analysis of a Prospective Multicenter Study*
Authors: Saade Anastasia , Bourmaud Aurelie , Schnell David , Darmon Michael ,   for the R2D2 Study Group
Published: October 2021

OBJECTIVES:

The Doppler-based resistive index and semiquantitative evaluation of renal perfusion using color Doppler failed to discriminate renal recovery patterns in a recent study. The influence of operator experience on resistive index and semiquantitative evaluation of renal perfusion performances is however unknown. This study aimed at evaluating the performance of resistive index and semiquantitative evaluation of renal perfusion according to the operator experience to predict short-term renal prognosis in critically ill patients.

DESIGN:

Preplanned ancillary analysis of a prospective multicenter cohort study.

SETTING:

Seven ICUs.

PATIENTS:

Unselected ICU patients.

INTERVENTION:

Renal Doppler was performed at admission to the ICU. The diagnostic performance of resistive index and semiquantitative evaluation of renal perfusion to predict persistent acute kidney injury at day 3 was evaluated.

MAIN RESULTS:

Overall, 371 patients were included, of whom 351 could be assessed for short-term renal recovery. Two thirds of the included patients had acute kidney injury (n = 233; 66.3%), of whom 136 had persistent acute kidney injury (58.4%). Overall performance in discriminating persistent acute kidney injury was however null with an area under the receiver operating characteristic curve less than 0.6 for both resistive index and semiquantitative evaluation of renal perfusion, and no difference across operator experience. A multivariate analysis using logistic regression with the center as a random effect adjusted on the operator experience showed no association between resistive index (odds ratio, 0.02 per international units (95% CI, 0.00–18.60 international units]) or semiquantitative evaluation of renal perfusion (odds ratio, 0.96 per international units [95% CI, 0.43–2.11 international units]) and persistent acute kidney injury. Similar results were obtained within subgroups of expert and nonexpert operators.

CONCLUSIONS:

Doppler-based measurements performed by an expert or a nonexpert operator did not discriminate renal recovery patterns and neither modified the risk stratification of acute kidney injury persistence.
The Smile Index: Part 3. A Simple, Prognostic Severity Scale for Unilateral Cleft Palate
Authors: Yao Caroline A. , Vartanian Emma D. , Nagengast Eric , McCullough Meghan , Auslander Allyn , Magee William P.
Published: October 2021

Background:

Unilateral cleft palates have a large spectrum of variability. Key morphologic factors such as cleft width and palatal length are not represented in current classification systems. Palate length and velopharyngeal port size are clinically linked to speech outcomes, as the soft palate must close the posterior pharynx for proper phonation. This study investigates the relationship between objective preoperative measures and postoperative velopharyngeal port size, to define a reproducible severity scale.

Methods:

Surgical data were prospectively collected from unilateral cleft palate patients in Morocco, Bolivia, Vietnam, and Madagascar. Key measurements were cleft width and palate width at the hard–soft palate junction, alveolar cleft width, vertical alveolar discrepancy, velopharyngeal port size. Cleft width ratio (CWR) was defined as the width of the cleft at the hard–soft junction, divided by the palate width.

Results:

Seventy-six patients were evaluated. Thirty-one had complete clefts and average age at surgical repair was 2.9 years. Mean CWR was 0.50 ± 0.12. Palate length was increased by an average of 2.2 mm (11%) after palatoplasty. Multivariate analysis determined greater CWR and larger preoperative velopharyngeal ports were significantly correlated with a smaller percent change in palate length after palatoplasty (P < 0.01).

Conclusions:

A wider palatal cleft decreases the surgeon’s ability to decrease velopharyngeal port size through palatoplasty. Given the ease of measurement even in low-resource settings, CWR may be a valuable tool for setting expectations for speech results, modifying surgical technique, and correlating future speech outcomes in evidence-based cleft care.
Scarless Total Breast Reconstruction with a Fat-augmented Latissimus Dorsi Flap
Authors: Maitani Kosuke , Tomita Koichi , Taminato Mifue , Kubo Tateki
Published: October 2021

Total breast reconstruction with a fat-augmented latissimus dorsi flap (F-LDF) is a breakthrough approach that surmounts the shortcomings of the latissimus dorsi flap (LDF), such as volume insufficiency. Unlike the abdominal flap, the LDF can be harvested as a sole muscle flap without a skin paddle. This makes it possible to perform breast reconstruction with no donor-site scar when breast skin replacement is not required (eg, nipple-sparing mastectomy, two-stage reconstruction using a tissue expander). Here we describe a new approach for total breast reconstruction, namely scarless F-LDF reconstruction. First, the dorsal and ventral planes of the LDF are widely dissected through an inferolateral incision with monopolar electrocautery. The origin of the muscle is then separated using an energy-based device inserted through a stab incision, and immediate fat grafting is performed concurrently to the LDF and pectoralis major muscle. This new method was used in five cases, with a mean specimen weight of 285 g (range, 181–420), mean flap weight of 174 g (125–230), mean total fat graft volume of 214 ml (126–335), and mean duration of reconstruction surgery of 213 minutes (161–260). In all cases, sufficient volume was obtained postoperatively with satisfactory esthetic results. In addition to avoiding a donor-site scar, this method could reduce postoperative pain and donor-site seroma. The scarless F-LDF can be used for total breast reconstruction in certain populations, especially in cases requiring no skin replacement and for small- to medium-sized breasts.
Proprioceptive Neuromuscular Facilitation Improves Symptoms Among Older Adults With Knee Osteoarthritis During Stair Ascending
Authors: Shen Peixin , Li Li , Song Qipeng , Sun Wei , Zhang Cui , Fong Daniel T.P. , Mao Dewei
Published: October 2021

Objective

This study aimed to investigate the effects of a 6-wk proprioceptive neuromuscular facilitation stretching on pain, proprioception, joint range of motion, and joint moments during stair ascending among older adults with knee osteoarthritis.

Design

This study is a randomized, controlled, and assessor-blinded trial. Thirty-six older adults with knee osteoarthritis were randomly assigned to the proprioceptive neuromuscular facilitation and the control groups. They received proprioceptive neuromuscular facilitation stretching and health lecture series, respectively, for 6 wks. Final data analysis included 14 participants of the proprioceptive neuromuscular facilitation group and 13 of the control group. Pain score, joint proprioception, range of motion, and joint moments during stair ascending were measured before and after the stretching. Two-way (group by time) analysis of variance with repeated measures was used to evaluate stretching effects.

Results

Significant interactions were detected in pain score, joint proprioception, external knee adduction moment, and external knee extension moment. Compared with week 0, the pain score, joint proprioception threshold, and external knee adduction moment decreased, whereas the external knee extension moment increased among older adults in the proprioceptive neuromuscular facilitation group at week 7.

Conclusions

Proprioceptive neuromuscular facilitation could be recommended as one of the clinical treatments for knee osteoarthritis to relieve pain, improve proprioception, and balance load distribution between medial and lateral compartments at the knee.