bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cdc42GAP deficiency contributes to the Alzheimer’s disease phenotype
Authors: Zhu Mengjuan , Xiao Bin , Xue Tao , Qin Sifei , Ding Jiuyang , Wu Yue , Tang Qingqiu , Huang Mengfan , Zhao Na , Ye Yingshan , Zhang Yuning , Zhang Boya , Li Juan , Guo Fukun , Jiang Yong , Zhang Lin , Zhang Lu 
Published: May 2023

Abstract
Alzheimer’s disease, the most common cause of dementia, is a chronic degenerative disease with typical pathological features of extracellular senile plaques and intracellular neurofibrillary tangles and a significant decrease in the density of neuronal dendritic spines. Cdc42 is a member of the small G protein family that plays an important role in regulating synaptic plasticity and is regulated by Cdc42GAP, which switches Cdc42 from active GTP-bound to inactive GDP-bound states regulating downstream pathways via effector proteins. However, few studies have focused on Cdc42 in the progression of Alzheimer’s disease.
In a heterozygous Cdc42GAP mouse model that exhibited elevated Cdc42-GTPase activity accompanied by increased Cdc42-PAK1-cofilin signalling, we found impairments in cognitive behaviours, neuron senescence, synaptic loss with depolymerization of F-actin and the pathological phenotypes of Alzheimer’s disease, including phosphorylated tau (p-T231, AT8), along with increased soluble and insoluble Aβ1–42 and Aβ1–40, which are consistent with typical Alzheimer’s disease mice. Interestingly, these impairments increased significantly with age. Furthermore, the results of quantitative phosphoproteomic analysis of the hippocampus of 11-month-old GAP mice suggested that Cdc42GAP deficiency induces and accelerates Alzheimer’s disease-like phenotypes through activation of GSK-3β by dephosphorylation at Ser9, Ser389 and/or phosphorylation at Tyr216. In addition, overexpression of dominant-negative Cdc42 in the primary hippocampal and cortical neurons of heterozygous Cdc42GAP mice reversed synaptic loss and tau hyperphosphorylation. Importantly, the Cdc42 signalling pathway, Aβ1–42, Aβ1–40 and GSK-3β activity were increased in the cortical sections of Alzheimer’s disease patients compared with those in healthy controls.
Together, these data indicated that Cdc42GAP is involved in regulating Alzheimer’s disease-like phenotypes such as cognitive deficits, dendritic spine loss, phosphorylated tau (p-T231, AT8) and increased soluble and insoluble Aβ1–42 and Aβ1–40, possibly through the activation of GSK-3β, and these impairments increased significantly with age. Thus, we provide the first evidence that Cdc42 is involved in the progression of Alzheimer’s disease-like phenotypes, which may provide new targets for Alzheimer’s disease treatment.
MAITs and their mates: “Innate-like” behaviors in conventional and unconventional T cells
Authors: Hackstein Carl-Philipp , Klenerman Paul 
Published: May 2023

Summary
Most CD4 and CD8 T cells are restricted by conventional major histocompatibility complex (MHC) molecules and mount TCR-dependent adaptive immune responses. In contrast, MAIT, iNKT, and certain γδ TCR bearing cells are characterized by their abilities to recognize antigens presented by unconventional antigen-presenting molecules and to mount cytokine-mediated TCR-independent responses in an “innate-like” manner. In addition, several more diverse T-cell subsets have been described that in a similar manner are restricted by unconventional antigen-presenting molecules but mainly depend on their TCRs for activation. Vice versa, innate-like behaviour was reported in defined subpopulations of conventional T cells, particularly in barrier sites, showing that these two features are not necessarily linked. The abilities to recognize antigens presented by unconventional antigen-presenting molecules or to mount TCR-independent responses creates unique niches for these T cells and is linked to wide range of functional capabilities. This is especially exemplified by unconventional and innate-like T cells present at barrier sites where they are involved in pathogen defense, tissue homeostasis as well as in pathologic processes.
Outcome of immunotherapy in adrenocortical carcinoma: a retrospective cohort study
Authors: Remde Hanna , Schmidt-Pennington Laura , Reuter Miriam , Landwehr Laura-Sophie , Jensen Marie , Lahner Harald , Kimpel Otilia , Altieri Barbara , Laubner Katharina , Schreiner Jochen , Bojunga Joerg , Kircher Stefan , Kunze Catarina Alisa , Pohrt Anne , Teleanu Maria-Veronica , Hübschmann Daniel , Stenzinger Albrecht , Glimm Hanno , Fröhling Stefan , Fassnacht Martin , Mai Knut , Kroiss Matthias 
Published: May 2023

Abstract

Objective
Clinical trials with immune checkpoint inhibitors (ICI) in adrenocortical carcinoma (ACC) have yielded contradictory results. We aimed to evaluate treatment response and safety of ICI in ACC in a real-life setting.

Design
Retrospective cohort study of 54 patients with advanced ACC receiving ICI as compassionate use at 6 German reference centres between 2016 and 2022.

Methods
Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAE) were assessed.

Results
In 52 patients surviving at least 4 weeks after initiation of ICI, ORR was 13.5% (6-26) and DCR was 24% (16-41). PFS was 3.0 months (95% CI, 2.3-3.7). In all patients, median OS was 10.4 months (3.8-17). 17 TRAE occurred in 15 patients, which was associated with a longer PFS of 5.5 (1.9-9.2) vs 2.5 (2.0-3.0) months (HR 0.29, 95% CI, 0.13-0.66, P = 0.001) and OS of 28.2 (9.5-46.8) vs 7.0 (4.1-10.2) months (HR 0.34, 95% CI, 0.12-0.93). Positive tissue staining for programmed cell death ligand 1 (PD-L1) was associated with a longer PFS of 3.2 (2.6-3.8) vs 2.3 (1.6-3.0, P &lt; 0.05) months. Adjusted for concomitant mitotane use, treatment with nivolumab was associated with lower risk of progression (HR 0.36, 0.15-0.90) and death (HR 0.20, 0.06-0.72) compared to pembrolizumab.

Conclusions
In the real-life setting, we observe a response comparable to other second-line therapies and an acceptable safety profile in ACC patients receiving different ICI. The relevance of PD-L1 as a marker of response and the potentially more favourable outcome in nivolumab-treated patients require confirmation.
Biological characteristics of microRNAs secreted by exosomes of periodontal ligament stem cells due to mechanical force
Authors: Zheng Xiaowen , Zhao Ning , Peng Liying , Li Zhenxia , Liu Chao , You Qingling , Fang Bing 
Published: June 2023

Summary

Background
Orthodontic tooth movement (OTM) has previously been considered an inflammatory process. However, recent studies suggest that exosomes may play an important role in the cellular microenvironment of OTM. microRNAs (miRNAs) are one of the major constituents of exosomes. This study aims to investigate the biological characteristics of miRNAs secreted by exosomes of periodontal ligament stem cells (PDLSCs) due to mechanical forces.

Materials and methods
First, we established a mechanical stress model. The PDLSCs were loaded under different force values and exosomes were extracted after 48 h. High-throughput sequencing of exosomal miRNAs was performed to further evaluate their biological functions and underlying mechanisms.

Results
The morphology and functions of exosomes were not significantly different between the loading and non-loading PDLSC groups. The optimal loading time and force were 48 h and 1 g/cm2, respectively. After sequencing, gene ontology (GO) and Kyoto encyclopaedia of genes and genomes (KEGG) pathway and network analyses were performed and 10 differentially expressed miRNAs were identified according to a literature search. These are miR-99a-5p, miR-485-3P, miR-29a-3p,miR-21-5p, miR-146a-5p, miR140-3p, miR-1306-5p, miR-126-5p, miR-125a-5p, and miR-23a-3p.

Limitations
Extracting exosomes needs a large amount of PDLSCs. More functional experiments need to be done to confirm the exact mechanism of exosomal miRNAs of PDLSCs due to mechanical force.

Conclusions
The expression levels of miRNAs secreted by PDLSC-derived exosomes due to mechanical force were very different compared to PDLSC-derived exosomes under nonmechanical stress. The function of many of the identified exosomal miRNAs was found to be related to osteoblasts and osteoclasts. Further validation is required. A functional investigation of these miRNA could provide novel insights into their mechanism.
The accuracy of photographic soft-tissue profile analysis to determine Class II and vertical skeletal relationships in children
Authors: Becking Bibi E , Fledderus Anne C , van Merkesteyn J P Richard , Jonkman Ronald E G 
Published: May 2023

Summary

Background
Lateral cephalometric analysis (LCA) is the reference standard for identifying common skeletal relationships in orthodontics, such as Cl II and hyperdivergent skeletal discrepancies, but it entails radiation exposure. Therefore, photographic soft-tissue profile analysis (PSPA) could be a useful alternative for these diagnoses, particularly for paediatric patients. This study aims to estimate the accuracy of PSPA for determining common skeletal discrepancies in children.

Methods
Cephalometric radiographs and profile photographs of a consecutive series of 100 children (8.0–17.6 years old) made on the same day were included. The validity of PSPA was verified against comparable LCA. First, by assessing the Pearson correlation and then estimating the sensitivity, specificity, receiver operating characteristic (ROC) curves and area under the curve (AUC) in sample A (n = 50). After external validation in a new sample B (n = 50), the ROC–AUC, diagnostic odds ratio, best cut-off points and discriminative validity were assessed in the total sample. Interrater reliability was estimated using the intraclass correlation coefficient, the standard error of measurement and Bland–Altman plots.

Results
The measurement properties of the PSPA angles A’N’B’, Gl’-Sn-Pog, N’-Sn-Pog’, and N’-Tra-Me’ were valid (ROC–AUC &gt; 0.7) and reliable (ICCs &gt; 0.92). The angles A’N’B’, Gl’-Sn-Pog’, and N’-Sn-Pog’, with the respective cut-off points ≥7.7’, ≥12.8’, and ≤163.5’, were accurate values for determining Cl II discrepancy. The N’-Tra-Me’-angle (≥63’) was an accurate estimate for a hyperdivergent discrepancy.

Conclusions
These validated PSPA angles could be used in clinical settings as a minimally invasive diagnostic tool to screen children suspected of having skeletal Cl II and hyperdivergent discrepancies.
Evolution of reproductive isolation in a long-term evolution experiment with Drosophila melanogaster: 30 years of divergent life-history selection
Authors: Robinson Chloe E , Thyagarajan Harshavardhan , Chippindale Adam K 
Published: May 2023

Abstract
We ask if three decades and over 1,500 generations of divergent life-history selection on age at reproduction has resulted in the evolution of reproductive isolation (RI) between laboratory populations of Drosophila melanogaster. We tested for premating, postmating-prezygotic, and postzygotic reproductive isolation between three replicate population pairs. Large, evolved differences in body size between selection treatments suggested the potential for prezygotic barriers driven by sexual selection or physical incompatibilities between the sexes. Although a simple prediction would be preference for larger size, creating directional isolation, our results from individual mate choice trials indicate that populations from both selection treatments show a marked bias towards homotypic mate choice; indicative of prezygotic RI driven by sexual selection or sexual conflict. Hybridization between the focal populations resulted in the production of viable adult flies with intermediate size and developmental traits. We observed a suggestive but statistically nonsignificant trend of fitness decline in the F2 generation of hybrids, but no significant evidence suggesting the evolution of postmating-prezygotic or postzygotic RI. Our findings are in accord with extant literature that posits that premating RI evolves before postmating forms of RI.
VqMAPK3/VqMAPK6, VqWRKY33, and VqNSTS3 constitute a regulatory node in enhancing resistance to powdery mildew in grapevine
Authors: Liu Wandi , Yan Chaohui , Li Ruimin , Chen Guanyu , Wang Xinqi , Wen Yingqiang , Zhang Chaohong , Wang Xiping , Xu Yan , Wang Yuejin 
Published: May 2023

Abstract
Grapevine powdery mildew is caused by Erysiphe necator, which seriously harms grape production in the world. Stilbene synthase makes phytoalexins that contribute to the resistance of grapevine against powdery mildew. A novel VqNSTS3 was identified and cloned from Chinese wild Vitis quinquangularis accession Danfeng-2. The novel VqNSTS3 was transferred into susceptible ‘Thompson Seedless’ by Agrobacterium-mediated transformation. The transgenic plants showed resistance to the disease and activated other resistance-related genes. VqNSTS3 expression in grapevine is regulated by VqWRKY33, and which binds to TTGACC in the VqNSTS3 promoter. Furthermore, VqWRKY33 was phosphorylated by VqMAPK3/VqMAPK6 and thus led to enhanced signal transduction and increased VqNSTS3 expression. ProVqNSTS3::VqNSTS3-GFP of transgenic VqNSTS3 in Arabidopsis thaliana was observed to move to and wrap the pathogen’s haustoria and block invasion by Golovinomyces cichoracearum. These results demonstrate that stilbene accumulation of novel VqNSTS3 of the Chinese wild Vitis quinquangularis accession Danfeng-2 prevented pathogen invasion and enhanced resistance to powdery mildew. Therefore, VqNSTS3 can be used in generating powdery mildew-resistant grapevines.
Impact of Inflammatory Bowel Disease on Patients’ Caregivers: Results From a French Survey
Authors: El Hajj Weam , Buisson Anne , Olympie Alain , Ravel Marie Hélène , Devos Corinne , Trang-Poisson Caroline , Macaigne Gilles , Nahon Stéphane 
Published: June 2023

Abstract

Background
The impact of inflammatory bowel disease (IBD) on caregivers has rarely been investigated. Our work aims to explore the burden of IBD on the different aspects of caregivers’ lives.

Methods
We conducted an online survey via the social network of the French IBD patient organization addressed to patients’ caregivers who were asked to fill in a questionnaire covering the impact of the disease on different aspects of their lives. Impacts were measured by a visual analog scale (VAS). A VAS score ≥5 of 10 was considered significantly high. We then performed uni- and multivariate analyses of predictors of higher impact on parents and partners, separately.

Results
A total of 853 caregivers participated, predominantly women (77%). The mean age was 48.5 years. Their relationship with the patient was mainly parents in 57.1% and partners in 30.6%. The type of IBD was Crohn’s disease in 63% and ulcerative colitis in 35%. The psychological burden was the highest among parents and was mainly correlated with a lack of knowledge about IBD and professional compromise (P &lt; .05). The impact on leisure was the highest among partners and was affected by psychological, sexual, and professional burdens (P &lt; .05). About 50% of partners experienced an absent sexual relationship for weeks/months and decreased libido regardless of IBD type. Professional impact was greater in parents compared with partners, and 36% of caregivers needed work arrangements.

Conclusions
IBD has a high impact on different aspects of life of patients’ caregivers. Therefore, interventions to reduce the disease burden in this population are needed.
One-Year Clinical Outcomes of Subcutaneous Infliximab Maintenance Therapy Compared With Intravenous Infliximab Maintenance Therapy in Patients With Inflammatory Bowel Disease: A Prospective Cohort Study
Authors: Hong Sung Noh , Hye Song Joo , Jin Kim Sung , Ha Park Yoon , Wan Choi Chang , Eun Kim Ji , Ran Kim Eun , Kyung Chang Dong , Kim Young-Ho 
Published: June 2023

Abstract

Background
Although the pharmacokinetic profile of subcutaneous (SC) infliximab (IFX) is superior to conventional intravenous (IV) IFX, long-term efficacy and safety of SC IFX in patients with inflammatory bowel disease (IBD) have not been reported yet. This study aimed to evaluate long-term clinical outcomes of IBD patients treated with SC IFX compared with those of IBD patients treated with IV IFX during maintenance therapy.

Methods
This prospective cohort study enrolled 61 IBD patients in clinical remission who received scheduled IFX maintenance therapy. Of them, 38 patients were switched to SC IFX, while 23 patients continued IV IFX with dose optimization. Enrolled patients were followed up for 1 year. The primary outcome was durable remission defined as clinical remission (Crohn’s disease, Harvey-Bradshaw index &lt;5; ulcerative colitis, partial Mayo score &lt;2) and biochemical remission (C-reactive protein &lt;0.5 mg/dL) with IFX trough level ≥3 µg/mL throughout the follow-up period.

Results
One-year clinical remission, 1-year biochemical remission, and mucosal healing did not differ between the IV and SC IFX groups (n = 20 of 23 vs 33 of 38; P = 1.000; n = 22 of 23 vs 34 of 38; P = .641; and n = 10 of 18 vs 17 of 25; P = .414, respectively). During follow-up, the number of patients with IFX trough level &lt;3 μg/mL was significantly lower in the SC IFX group (n = 0 of 38, 0%) than in the IV IFX group (n = 10 of 23, 43%) (P &lt; .001). The SC IFX group showed higher 1-year durable remission than the IV IFX group (n = 31 of 38, 82% vs n = 11 of 23, 48%; P = .013). The incidence of IFX-related adverse events did not differ significantly between both groups (26% vs 39%; P = .446).

Conclusion
The SC IFX switch induced a higher 1-year durable remission rate than continuing IV IFX in patients with IBD during scheduled maintenance therapy, showing similar safety.
Use of Immune Checkpoint Inhibitors in Patients With Inflammatory Bowel Disease After Ileal Pouch-Anal Anastomosis
Authors: Karime Christian , Farraye Francis A , Hashash Jana G 
Published: June 2023

Lay Summary
It is unknown if immune checkpoint inhibitor therapy increases risk of pouch-related complications in patients with inflammatory bowel disease after ileal-pouch anal anastomosis. In our study, pembrolizumab therapy was not associated with significant gastrointestinal immune-related adverse events or pouch-related complications.
Halāl Habichuelas: Food, Belonging, and the Conundrums of Being a Puerto Rican Muslim
Authors: Chitwood Ken 
Published: May 2023

AbstractBased on multiple years of ethnographic fieldwork alongside Puerto Rican Muslims in Puerto Rico and the United States, this article explores issues of identification and belonging among Puerto Rican converts to Islam, as expressed in their food practices. As “quadruple minorities”—Muslim among Puerto Ricans, Puerto Rican among Muslims, and both Puerto Rican and Muslim in the shadow of American empire—I suggest that Puerto Rican converts seek ways to restore a sense of coherence and selfhood through cooking, consuming, and forming community around food. For Puerto Rican Muslim converts, halāl consumption practices are about more than making their food, drink, or actions permissible; they are also about making their very identifications permissible, what one interlocutor called “Boricua halāl.” This focus on religious actors’ food practices showcases affective encounters with what we call religion in the everyday, showing matter’s ability to reflect the quotidian complexity of late-modern lifeworlds.
Evaluation of integrase resistance in individuals who failed a regimen containing dolutegravir in French and Italian clinical settings
Authors: Armenia Daniele , Santoro Maria M , Charpentier Charlotte , Bertoli Ada , Forbici Federica , Calvez Vincent , Descamps Diane , Ceccherini-Silberstein Francesca , Marcelin Anne-Genevieve , Flandre Philippe 
Published: June 2023

Abstract

Background
This work aims to evaluate integrase resistance and its predictors in HIV-1 infected combined antiretroviral therapy (cART) experienced individuals failing a dolutegravir-based regimen.

Methods
Major resistance mutations (MRM) and genotypic susceptibility score (GSS) of dolutegravir companion drugs were evaluated on plasma genotypic resistance test (GRT) performed at dolutegravir failure. Logistic regression was used to evaluate factors associated to the risk of integrase strand-transfer inhibitors (INSTI)-resistance at dolutegravir failure.

Results
We retrospectively analysed 467 individuals. At failure GRT, individuals had been under dolutegravir for a median (IQR) time of 11 (5–20) months; around half of them had never been exposed to INSTI (52%) and 10.7% were at first-line regimen. Fifty-eight (12.4%) individuals showed ≥1 INSTI MRM. Among them, people INSTI-exposed showed significantly higher prevalence of INSTI resistance compared to those who were INSTI naïve [46 (21.2%) versus 9 (3.9%), P &lt; 0.001].
N155H was the most prevalent MRM (5.4%), followed by G140S (4.5%) and Q148H (4.3%). These MRM were more probably present in INSTI-experienced individuals compared to those INSTI naïve. Despite failure, 89.5% of individuals harboured viral strains fully susceptible to dolutegravir and bictegravir and 85.0% to all INSTI. No INSTI exposure before receiving dolutegravir [OR: 0.35 (0.16–0.78), P &lt; 0.010] and a GSS for companion drugs ≥2 (OR: 0.09 [0.04–0.23], P &lt; 0.001) were negatively associated with INSTI resistance at failure.

Conclusions
In a large set of individuals failing dolutegravir in real-life, INSTI resistance was low and mainly related to previous first-generation INSTI exposure. Surveillance of integrase resistance remains crucial to preserve efficacy of INSTI class in the future.
Mechanism of tRNA recognition by heterotetrameric glycyl-tRNA synthetase from lactic acid bacteria
Authors: Nagato Yasuha , Yamashita Seisuke , Ohashi Azusa , Furukawa Haruyuki , Takai Kazuyuki , Tomita Kozo , Tomikawa Chie 
Published: June 2023

Abstract
Glycyl-tRNA synthetases (GlyRSs) have different oligomeric structures depending on the organisms. While a dimeric α2 GlyRS species is present in archaea, eukaryotes and some eubacteria, a heterotetrameric α2β2 GlyRS species is found in most eubacteria. Here, we present the crystal structure of heterotetrameric α2β2 GlyRS, consisting of the full-length α and β subunits, from Lactobacillus plantarum (LpGlyRS), gram-positive lactic bacteria. The α2β2LpGlyRS adopts the same X-shaped structure as the recently reported Escherichia coli α2β2 GlyRS. A tRNA docking model onto LpGlyRS suggests that the α and β subunits of LpGlyRS together recognize the L-shaped tRNA structure. The α and β subunits of LpGlyRS together interact with the 3′-end and the acceptor region of tRNAGly, and the C-terminal domain of the β subunit interacts with the anticodon region of tRNAGly. The biochemical analysis using tRNA variants showed that in addition to the previously defined determinants G1C72 and C2G71 base pairs, C35, C36 and U73 in eubacterial tRNAGly, the identification of bases at positions 4 and 69 in tRNAGly is required for efficient glycylation by LpGlyRS. In this case, the combination of a purine base at Position 4 and a pyrimidine base at Position 69 in tRNAGly is preferred.