bluuebunny/crossref_metadata_2025 huggingface dataset:
Down‐regulation of human long non‐coding RNA LINC01187 is associated with nephropathies
Authors: Manolakou Theodora , Kaltezioti Valeria , Prakoura Niki , Kavvadas Panagiotis , Reichelt‐Wurm Simone , Gakiopoulou Harikleia , Banas Miriam , Banas Bernhard , Lindenmeyer Maja T. , Cohen Clemens D. , Boor Peter , Djudjaj Sonja , Boumpas Dimitrios T. , Chatziantoniou Christos , Charonis Aristidis , Politis Panagiotis K.
Published: April 2023

Chronic kidney diseases affect a substantial percentage of the adult population worldwide. This observation emphasizes the need for novel insights into the molecular mechanisms that control the onset and progression of renal diseases. Recent advances in genomics have uncovered a previously unanticipated link between the non‐coding genome and human kidney diseases. Here we screened and analysed long non‐coding RNAs (lncRNAs) previously identified in mouse kidneys by genome‐wide transcriptomic analysis, for conservation in humans and differential expression in renal tissue from healthy and diseased individuals. Our data suggest that LINC01187 is strongly down‐regulated in human kidney tissues of patients with diabetic nephropathy and rapidly progressive glomerulonephritis, as well as in murine models of kidney diseases, including unilateral ureteral obstruction, nephrotoxic serum‐induced glomerulonephritis and ischemia/reperfusion. Interestingly, LINC01187 overexpression in human kidney cells in vitro inhibits cell death indicating an anti‐apoptotic function. Collectively, these data suggest a negative association of LINC01187 expression with renal diseases implying a potential protective role.
Editorial: Is autism overdiagnosed?
Authors: Fombonne Eric
Published: April 2023

After attention was drawn in the late 1960s to the poor reproducibility of psychiatric diagnosis between clinicians, methods and procedures used to diagnose psychiatric disorders were greatly improved. Sources of variance contributing to the poor reliability of psychiatric diagnosis were identified that included: information variance (how clinicians go about enquiring about symptoms), interpretation variance (how clinicians weigh the observed symptomatology towards diagnostic formulations), and criterion variance (how clinicians arrange symptom constellations to generate specific diagnoses). To improve the reliability of diagnosis, progresses were made in two major directions. First, diagnostic instruments were developed to standardize the way symptoms are elicited, evaluated, and scored. These diagnostic interviews were either highly structured for use in large‐scale studies (e.g. the DIS), by lay interviewers without a clinical background, and with a style of questioning that emphasized adherence to the exact wording of probes, reliance on closed questions with simple response formats (Yes/No) and recording respondents' answers without interviewer's judgment contribution. By contrast, semi‐structured interviews (e.g. the SADS) were designed to be used by clinically trained interviewers and adopted a more flexible, conversational style, using open‐ended questions, utilizing all behavioral descriptions generated in the interview, and developing scoring conventions that called upon the clinical judgment of the interviewer. Second, diagnostic criteria and algorithms were introduced in nosographies in 1980 for the DSM and soon after in ICD. Algorithm‐derived diagnoses could subsequently be tested for their validity using follow‐up, family history, treatment response studies, or other external criteria.
Morphology of proximal and distal human semitendinosus compartments and the effects of distal tendon harvesting for anterior cruciate ligament reconstruction
Authors: Kositsky Adam , Maas Huub , Barrett Rod S. , Kennedy Ben , Stenroth Lauri , Korhonen Rami K. , Vertullo Christopher J. , Diamond Laura E. , Saxby David J.
Published: April 2023

The human semitendinosus muscle is characterized by a tendinous inscription separating proximal and distal neuromuscular compartments. As each compartment is innervated by separate nerve branches, potential exists for independent operation and control of compartments. However, the morphology and function of each compartment have not been thoroughly examined in an adult human population. Further, the distal semitendinosus tendon is typically harvested for use in anterior cruciate ligament reconstruction surgery, which induces long‐term morphological changes to the semitendinosus muscle‐tendon unit. It remains unknown if muscle morphological alterations following anterior cruciate ligament reconstruction are uniform between proximal and distal semitendinosus compartments. Here, we performed magnetic resonance imaging on 10 individuals who had undergone anterior cruciate ligament reconstruction involving an ipsilateral distal semitendinosus tendon graft 14 ± 4 months prior, extracting morphological parameters of the whole semitendinosus muscle and each individual compartment from both the (non‐injured) contralateral and surgical legs. In the contralateral leg, volume and length of the proximal compartment were smaller than the distal compartment. No between‐compartment differences in volume or length were found for anterior cruciate ligament reconstructed legs, likely due to greater shortening of the distal compared to the proximal compartment after anterior cruciate ligament reconstruction. The maximal anatomical cross‐sectional area of both compartments was substantially smaller on the anterior cruciate ligament reconstructed leg but did not differ between compartments on either leg. The absolute and relative between‐leg differences in proximal compartment morphology on the anterior cruciate ligament reconstructed leg were strongly correlated with the corresponding between‐leg differences in distal compartment morphological parameters. Specifically, greater between‐leg morphological differences in one compartment were highly correlated with large between‐leg differences in the other compartment, and vice versa for smaller differences. These relationships indicate that despite the heterogeneity in compartment length and volume, compartment atrophy is not independent or random. Further, the tendinous inscription endpoints were generally positioned at the same proximodistal level as the compartment maximal anatomical cross‐sectional areas, providing a wide area over which the tendinous inscription could mechanically interact with compartments. Overall, results suggest the two human semitendinosus compartments are not mechanically independent.
A proteomics study to explore differential proteins associated with the pathogenesis of ameloblastoma
Authors: Cui Yunyi , Li Hexiang , Xiao Tiepeng , Zhang Xudong , Hou Yali , Li Haiyang , Li Xiangjun
Published: April 2023

Background

Reports on the proteomic studies of ameloblastoma and other common odontogenic lesions are limited. We thus explored the differential proteins among ameloblastoma, odontogenic keratocyst, dentigerous cyst, and normal gingival tissue using proteomics and identified hub proteins involved in the local aggressiveness and recurrence of ameloblastoma.

Methods

Samples were obtained from 14 patients with ameloblastoma, 6 with odontogenic keratocyst, 9 with a dentigerous cyst, and 5 with normal gingival tissue. Proteins were then extracted, purified, quantified, and analysed using Easy‐nLC chromatography and mass spectrometry. Further functional annotation and enrichment analyses were performed using Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes on the target protein collection. Protein clustering and protein–protein interaction network analyses were used to screen the hub proteins. Proteins with significant interactions were screened according to their degree index. These results were verified by immunohistochemical staining. Proteins meeting the screening criteria of expression difference ploidy >1.2‐fold (upregulation and downregulation) andp < 0.05 were considered differential proteins.

Results

In ameloblastoma, 808 differential proteins were upregulated and 505 were downregulated compared with those in odontogenic keratocyst; 309 were upregulated and 453 were downregulated compared with those in dentigerous cyst; and 2210 were upregulated and 829 were downregulated compared with those in normal gingival tissue. The three groups of differential proteins were associated with cellular exosomes, antigen binding, complement activation, human papillomavirus infection, focal adhesion, cell adhesion molecules, and metabolic pathways.

Conclusion

CDH3 is associated with the local aggressiveness and recurrence of ameloblastoma and is a potential therapeutic target.
MicroRNA‐27a inhibits porcine type I muscle fibre gene expression by directly targeting peroxisome proliferator‐activated receptor‐γ coactivator‐1α
Authors: Wang Weiwei , Yu Qinping , Cao Qingyun , Ye Hui , Zhang Changming , Dong Zemin , Feng Dingyuan , Zuo Jianjun
Published: April 2023

MicroRNAs are one of the key determinants of muscle fibre development and phenotype in mammals. The preliminary experiment implied that microRNA‐27a (miR‐27a) might involve in regulation of muscle fibre type composition of pigs. Thereby, the present study aimed to confirm the regulatory effect of miR‐27a on porcine type I muscle fibre‐encoding gene (myosin heavy chain gene 7, MYH7) expression and its related mechanism. We firstly observed opposite expression patterns between miR‐27a and MYH7 as well as between miR‐27a and peroxisome proliferator‐activated receptor‐γ coactivator‐1α (PGC‐1α) during differentiation of porcine skeletal muscle satellite cells. Through the subsequent transfection analysis in porcine myotubes, we found that miR‐27a suppressed the expression of MYH7 and PGC‐1α. Besides, miR‐27a induced inhibition of PGC‐1α downstream targets, namely myocyte enhancer factor‐2C (MEF2C) along with mitochondrial biogenesis and oxidative metabolism‐related factors such as nuclear respiratory factor 1 (NRF‐1), mitochondrial transcription factor A (mtTFA), cytochrome c (Cytc) and cytochrome oxidase IV (COX Ⅳ) and succinodehydrogenase (SDH). Dual‐luciferase reporter analysis revealed that miR‐27a could bind to the predicted target site in the 3ʹ‐untranslated regions of PGC‐1α mRNA, confirming a direct targeting of PGC‐1α by miR‐27a. Moreover, PGC‐1α silencing abolished the promotive effects of miR‐27a inhibitor on MYH7, PGC‐1α and its downstream targets (MEF2C, NRF‐1, mtTFA, COX Ⅳ, Cytc and SDH) in porcine myotubes. Collectively, miR‐27a inhibits porcine MYH7 expression by negatively regulating PGC‐1α and PGC‐1α‐controlled MEF2C expression as well as mitochondrial biogenesis and oxidative metabolism. Our findings may provide a molecular target for genetic or nutritional control of muscle fibre phenotype of pigs, probably having an important implication for regulating pork quality.
Gender differences of authors of major Hepatology society guidelines during the past 15 years
Authors: Tang Xiaowei , Luo Bei , Huang Shu , Jiang Jiao , Chen Yuan , Shi Xiaomin , Zhang Wei , Shi Lei , Zhong Xiaolin , Lü Muhan
Published: April 2023

Background and Objective

Recent studies have shown that women are underrepresented as authors of medical research and clinical practice guidelines. This study aimed to evaluate gender disparities of authors of major hepatology guidelines.

Methods

We reviewed the hepatology guidelines published by the following major gastroenterology societies from January 2008 to September 2022: the American Gastroenterological Association (AGA), American College of Gastroenterology (ACG), American Association for the Study of Liver Diseases (AASLD), Asian‐Pacific Association for the Study of the Liver (APASL), British Society of Gastroenterology (BSG), European Association for the Study of the Liver (EASL) and Korean Association for the Study of the Liver (KASL). We determined the topic and the gender of all authors of each guideline. The numbers of men authors, women authors and total authors were collected. The trends of women first authors, women senior authors and total women authors were assessed. A logistic regression analysis was performed to analyse the relationship between the gender of the first or senior author and related factors.

Results

We identified 103 hepatology guidelines published between January 2008 and September 2022 published by the AGA, ACG, AASLD, APASL, BSG, EASL, and KASL. The gender of 1096 of 1100 (99.6%) authors was determined. Therefore, a total of 1096 authors were included: 223 (20.3%) authors were women and 873 (79.7%) authors were men. Women comprised 14.6% of all first authors, and 20.4% of all senior authors were women. Only the AASLD had writing committees comprising more than 30% total women authors. The proportions of women senior authors and total women authors increased significantly during the study period (p < .05). Women first authors and women senior authors were more likely to publish guidelines with more women authors. Women first authors were less likely to be co‐authors with men authors.

Conclusions

Over the course of the past decade, the proportion of women authors of major hepatology guidelines has been low; however, this gender gap appears to be closing.
Faculty development in the complex academic culture
Authors: Sellmann Timur , Marsch Stephan
Published: April 2023

The authors propose a bench‐to‐bedside approach to shift current faculty development from focusing mainly on teachers towards consideration of student needs.
Thematic Units and Developments. On the Persistence of ‘Organic Form’ in Chamber Music Between 1910 and 1930
Authors: Borio Gianmario
Published: April 2023

TheFormenlehre(theory of the musical form), inaugurated by Adolf Bernhard Marx after Beethoven's death and witnessed by several treatises at the end of the nineteenth and the beginning of the twentieth centuries, has left traces in the writings and works of Béla Bartók, Alban Berg, Paul Hindemith, Arnold Schoenberg and Anton Webern. Chamber music (especially string quartets) is the area in which the dialogue with the past is most tangible. The adoption of traditional concepts is associated with significant changes of thematic structures and developmental techniques. Thus, the transformations of the harmonic thinking are paralleled by the way the composers dealt with phrase organisation and syntactic functions.
A case of adult‐onset diffuse midline glioma diagnosed by histone H3K27M immunostaining after death, which required differentiation from brainstem encephalitis and myelitis
Authors: Togawa Natsuko , Mitsuhashi Masahiro , Yamashita Hirofumi , Minamiguchi Sachiko , Arakawa Yoshiki , Ayaki Takashi , Kuzuya Akira , Ikeda Akio , Takahashi Ryosuke
Published: April 2023

H3K27M‐mutant diffuse midline glioma is a malignant glioma that was newly added to the World Health Organization classification in 2016. In diffuse midline glioma, the H3K27M‐mutant sometimes develops sub‐acutely and requires a differential diagnosis from encephalomyelitis. Here, we report a case of adult‐onset diffuse midline glioma that was diagnosed by immunostaining for histone H3K27M after death. The present case required a differential diagnosis of autoimmune cervical myelitis and brainstem encephalitis.
SCIMP: A Novel Targeted Gene for Postmenopausal Osteoporosis Progression
Authors: Sun Xiaolei , Tian Aixian , Li Peng , Zhao Jin , Hou Xin , Ma Xinlong , Yuan Xubo
Published: April 2023

Objective

The literature suggests that not all postmenopausal women suffer from osteoporosis, and the occurrence of postmenopausal osteoporosis is closely related to the genetic susceptibility of genes in the population and the cellular pathways of related genes. To systematically understand the functions of SCIMP gene for osteoporosis, both in vitro and in vivo experiments were analyzed in depth in this integrated study.

Methods

The significantly differentially expressed genes of postmenopausal osteoporosis (PMOP) patients from GEO database were selected. Meanwhile, the primary target gene was also confirmed in clinically recruited individuals using ELISA method; 50 postmenopausal osteoporosis patients with a T‐score of ‐2.5 were randomly enrolled; postmenopausal women with a T‐score > −2.5 were included in the non‐osteoporotic group (including osteopenia and normal bone mineral density). The associated processes and signaling pathways were deeply investigated with GO and KEGG enrichment analysis. The downstream signaling factors including Erk‐1/2, Akt, and IkB‐related signaling pathways for the potential gene were evaluated using MG‐63 cell line; the MTT, CCK‐8, and flow cytometry assays were performed to exam MG‐63 cell viability, proliferation, as well as apoptosis, respectively, under different treatments.

Results

Based on the differentially expressed gene analysis for GEO database, PMOP patients displayed 845 differentially expressed genes, including 709 down‐regulated and 136 up‐regulated ones. Ten genes including SCIMP were significantly differentially expressed (at least three‐fold difference). SCIMP was the most markedly decreased in PMOP patients’ specimens. Using clinical recruited individuals, the concentration of SCIMP was 96.6 ± 20.8 ng/μL in the PMOP group compared with 168.8 ± 23.5 ng/μL in the control group (p < 0.05). At the same time, the osteoclast differentiation signaling pathway was significantly up‐regulated while hedgehogs as well as other signaling pathways were down‐regulated based on the KEGG analysis. The phosphorylation level of Akt was markedly blocked in si‐SCIMP treatment. Up‐regulation of SCIMP increased cell proliferation, inhibited cell apoptosis, and enhanced cell viability in MG‐63 cells, which was markedly rescued by AKT phosphorylation inhibitor. Finally, in vivo experiments also confirmed that the upregulation of SCIMP enhanced the structural parameters of rat trabecular bone and the osteogenic activity of bone tissue.

Conclusion

SCIMP plays a critical role in the pathogenesis of postmenopausal osteoporosis in women. SCIMP influences osteoclasts function through an akt‐dependent molecular pathway, and subsequently influences the equilibrium process of bone metabolism. This provides a new insight into the pathogenesis of postmenopausal osteoporosis as well as the clinical treatment of osteoporosis.
Hip Pain after Distal Femoral Derotational Osteotomy for a Patient with Patellar Instability: A Case Report
Authors: Fu De‐Jie , Lei Kai , Liu Li‐Ming , Guo Lin
Published: April 2023

Background

Increased torsional deformity of femur is one of the most important factors in recurrent patellofemoral instability. And distal femoral derotational osteotomy is an effective treatment option in patients with increased femoral torsional deformity. However, groin pain is a rare complication after femoral derotational osteotomy.

Case presentation

The patient was a 23‐year‐old female suffering from anterior knee pain and patellar instability in her left leg. Continuous CT scans of the hip, knee, and ankle were performed and the femoral anteversion was 44.99°. Considering the significant enlargement of the femoral internal torsion which may contribute most for dislocation of patella, we did a derotational osteotomy of distal femur. The anterior knee pain and patellar instability were resolved after surgery. The femoral internal torsion angle was corrected to 21.47°. But she developed left hip pain in the groin area which she had never encountered before 1 year after the surgery. We believed that the hip pain was closely related to the surgery. And the imaging and follow‐up partly confirmed this.

Conclusions

The situation of the hip joint should be carefully evaluated before doing derotational osteotomy in recurrent patellofemoral instability and patient should be informed that derotational osteotomy may cause hip pain. Clinical studies are needed to further clarify the impact of derotational osteotomy on the hip.
Genetic and phenotypic heterogeneity of multiple lentigines and precise diagnosis in four Chinese families with multiple lentigines
Authors: Guo Kexin , Liu Jia‐Wei , Zhang Rui , Wang Rongrong , Ma Dong‐Lai , Zhang Xue
Published: April 2023

Lentigines are well‐defined, small, brown macules resulting from the accumulation of melanin content in the basement membrane zone with an increase in the number of melanocytes. Hereditary multiple lentigines (ML) can be associated with multiple genes and are not commonly encountered in clinical practice. Patients can solely have skin involvement or present with multisystemic deformative phenotypes. This study aimed to describe four unrelated Chinese families presenting with ML as their first visit symptom. We performed whole‐exome sequencing (WES) and Sanger sequencing on all patients and immediate family members for precise molecular diagnosis. Two novel variants c.1548 T > A (p.Ser516Arg) and c.1811C > A (p.Thr604Lys) in SASH1, and two recurrent variants c.1403C > T (p.Thr468Met) and c.1493G > T (p.Arg498Leu) in PTPN11, were identified in these four families. We also summarized the genes associated with ML and differential diagnosis of pigment abnormality. We suggested that the molecular diagnosis of ML should be emphasized because it can help in the clinical differential diagnosis and further genetic counseling and prognosis.
Could a trade agreement strengthen the enforcement of domestic environmental laws? Envisioning the impacts of the US–Peru environmental submissions mechanism
Authors: Peña Pablo
Published: April 2023

Could a trade agreement strengthen the enforcement of domestic environmental laws? This article explores this question in the context of the US–Peru Trade Promotion Agreement (TPA). The article examines, in particular, the potential role of the Secretariat for Submissions on Environmental Enforcement Matters (SEEM) of the TPA. The SEEM is an advisory mechanism to the parties to the TPA which allows citizens to bring direct submissions. This article considers the extent to which the SEEM can facilitate the enforcement of domestic Peruvian environmental law thus helping secure Peruvians' constitutional right to a healthy environment. Existing domestic mechanisms of administrative, civil or criminal law are already available to Peruvian citizens. These can apply to varied situations and provide a range of remedies, but often, they are also costly and lengthy. The SEEM began operating in 2018, and its first six submissions already hint at its potential to become a useful complement to domestic legal avenues. The SEEM could become increasingly used in the future due to Peru's prevalent institutional problems and its interest in maintaining good commercial relations with the United States. The mechanism also has the potential to provide a way to address the autonomous actions of the Peruvian Congress or its subnational governments that sometimes act in defiance of the environmental laws and regulations enforced by the executive branch of the national government. Importantly, however, citizens need to be aware of the limitations of the SEEM as a non‐adjudicatory mechanism and the fact that it is not a policymaking forum. Future research on the SEEM could provide a better understanding of how the process of increasingly mainstreaming the environment in international trade law is beginning to have concrete effects.
Risk management for second‐hand clothing imports in least developed countries: Legislations and perception of public‐sector corruption
Authors: Guo Shu , Choi Tsan‐Ming
Published: April 2023

The second‐hand clothing imports are very popular in the least developed countries (LDCs). The social health risk (SHR) associated with second‐hand clothing products and the lack of relevant legislations in LDCs, however, bring substantial challenges. This article is therefore developed to explore the sterilization legislation design for second‐hand clothing supply chains in LDCs. To address LDCs’ different import requirements of fumigation, both the extended exporter responsibility (EER) legislation scheme and the extended importer responsibility (EIR) legislation scheme are considered. We also examine whether the perception of public‐sector corruption in LDCs may affect the performance of sterilization legislation schemes. We compare the performance of sterilization legislation schemes under different public‐sector corruption cases, different sterilization legislation structures, as well as market competition. Interestingly, our analyses show that the EER and EIR legislation schemes can achieve the same performance under a per unit SHR duty, no matter whether there is public‐sector corruption or not. However, these two legislation schemes perform differently under the lump‐sum SHR duty. Besides, with the presence of the public‐sector corruption perception, the prospect of financial benefits from bribing the regulatory agency can induce the firm to choose a higher optimal sterilization level when the bribe is sufficiently small. These implications complement the extant knowledge on risk management of second‐hand clothing in LDCs, and provide an important guidance regarding the design of sterilization legislations on second‐hand clothing imports.
Uniform boundedness and eventual Hölder continuity to a cancer invasion model with remodeling of ECM and nonlinear diffusion
Authors: Jin Chunhua
Published: April 2023

This paper is concerned with a class of cancer invasion model with nonlinear diffusion and remodeling of ECM. The primary difficulty that arises here is that due to nonlinear diffusion, the good coupling structure between the diffusion term and haptotactic term is destroyed, rendering the effective methods used in the linear diffusion model no longer applicable. Fortunately, we have found a new effective combination between the diffusion term and the haptotactic term, which allows the diffusion term to dominate the haptotactic term, thus preliminarily improving the regularity of the weak solution. Based on these results, we can prove part of long‐time asymptotic behavior of the solution, thereby finally proving the uniform boundedness of the weak solution. Subsequently, by improving the convergence of cancer cells u from ‐norm to ‐norm, it is also proved that after a long time, the weak solution will eventually be Hölder continuous for some slow diffusion cases.
Statistical inference with semiparametric nonignorable nonresponse models
Authors: Uehara Masatoshi , Lee Danhyang , Kim Jae‐Kwang
Published: April 2023

How to deal with nonignorable response is often a challenging problem encountered in statistical analysis with missing data. Parametric model assumption for the response mechanism is sensitive to model misspecification. We consider a semiparametric response model that relaxes the parametric model assumption in the response mechanism. Two types of efficient estimators, profile maximum likelihood estimator and profile calibration estimator, are proposed, and their asymptotic properties are investigated. Two extensive simulation studies are used to compare with some existing methods. We present an application of our method using data from the Korean Labor and Income Panel Survey.
Regularized t$$ t $$ distribution: definition, properties, and applications
Authors: Hu Zongliang , Yang Yiping , Li Gaorong , Tong Tiejun
Published: April 2023

For gene expression data analysis, an important task is to identify genes that are differentially expressed between two or more groups. Nevertheless, as biological experiments are often measured with a relatively small number of samples, how to accurately estimate the variances of gene expression becomes a challenging issue. To tackle this problem, we introduce a regularized distribution and derive its statistical properties including the probability density function and the moment generating function. The noncentral regularized distribution is also introduced for computing the statistical power of hypothesis testing. For practical applications, we apply the regularized distribution to establish the null distribution of the regularized statistic, and then formulate it as a regularized ‐test for detecting the differentially expressed genes. Simulation studies and real data analysis show that our regularized ‐test performs much better than the Bayesian ‐test in the “limma” package, in particular when the sample sizes are small.
PECT1, a rate‐limiting enzyme in phosphatidylethanolamine biosynthesis, is involved in the regulation of stomatal movement in Arabidopsis
Authors: Negi Juntaro , Obata Tomoki , Nishimura Sakura , Song Boseok , Yamagaki Sho , Ono Yuhei , Okabe Makoto , Hoshino Natsumi , Fukatsu Kohei , Tabata Ryo , Yamaguchi Katsushi , Shigenobu Shuji , Yamada Masashi , Hasebe Mitsuyasu , Sawa Shinichiro , Kinoshita Toshinori , Nishida Ikuo , Iba Koh
Published: April 2023

An Arabidopsis mutant displaying impaired stomatal responses to CO2, cdi4, was isolated by a leaf thermal imaging screening. The mutated gene PECT1 encodes CTP:phosphorylethanolamine cytidylyltransferase. The cdi4 exhibited a decrease in phosphatidylethanolamine levels and a defect in light‐induced stomatal opening as well as low‐CO2‐induced stomatal opening. We created RNAi lines in which PECT1 was specifically repressed in guard cells. These lines are impaired in their stomatal responses to low‐CO2 concentrations or light. Fungal toxin fusicoccin (FC) promotes stomatal opening by activating plasma membrane H+‐ATPases in guard cells via phosphorylation. Arabidopsis H+‐ATPase1 (AHA1) has been reported to be highly expressed in guard cells, and its activation by FC induces stomatal opening. The cdi4 and PECT1 RNAi lines displayed a reduced stomatal opening response to FC. However, similar to in the wild‐type, cdi4 maintained normal levels of phosphorylation and activation of the stomatal H+‐ATPases after FC treatment. Furthermore, the cdi4 displayed normal localization of GFP‐AHA1 fusion protein and normal levels of AHA1 transcripts. Based on these results, we discuss how PECT1 could regulate CO2‐ and light‐induced stomatal movements in guard cells in a manner that is independent and downstream of the activation of H+‐ATPases. [Correction added on 15 May 2023, after first online publication: The third sentence is revised in this version.]
Current transfusion practice and need for new blood products to ensure blood supply for patients with major hemorrhage in Europe
Authors: Apelseth Torunn Oveland , Doyle Barry , Evans Ryan , George Chloe , Humbrecht Catherine , Klei Thomas , Najdovski Tome , Sigurjónsson Ólafur Eysteinn , Wiltshire Michael , de Korte Dirk
Published: April 2023

Background

New blood products are considered for treatment of patients with major hemorrhage. The aim of this report is to describe the current transfusion practices in Europe for patients with major hemorrhage and explore the need for new or modified blood products to ensure prehospital and in‐hospital blood supply.

Study Design and Method

The European Blood Alliance (EBA) Working Group on Innovation and New Blood Products' subgroup on major hemorrhage performed a survey among the EBA member states.

Results

The response rate was 58% (17 responses from 15 of the 26 EBA member states). Of these, sixteen (94%) provide massive transfusion packages (MTPs) with balanced ratio of red blood cells and plasma. Seven of the respondents included platelets from the start of treatment. Eleven (65%) provide prehospital blood products, mainly red cell concentrates or dried and/or thawed plasma with 5 days of extended storage. Two countries provide prehospital whole blood. Twelve respondents (71%) saw a need for implementation of new or modified blood components in their institution. The top three priorities were whole blood (12 of 12, 100%), dried plasma (8 of 12, 67%), and cold‐stored platelets (7 of 12, 58%).

Discussion

Current national guidelines for use of blood products in patients with major hemorrhage in Europe agree on the use of balanced transfusion, however the timing and source of platelets differ. Blood products for prehospital transfusion are available in several European countries. An interest in new or modified blood products for patients with major hemorrhage was observed, especially for whole blood.
Regular high‐frequency whole blood donation and risk of cardiovascular disease in middle‐aged and older blood donors in Australia
Authors: Karki Surendra , Bell Katy J. L. , Hayen Andrew , Liu Bette , Cust Anne E. , Olynyk John K. , Irving David O.
Published: April 2023

Background

Previous mixed findings on the associations between whole blood (WB) donation and risk of cardiovascular diseases (CVD) may in part reflect inadequate adjustment for the “healthy donor effect” (HDE).

Methods

We used the Sax Institute's 45 and Up Study linked with blood donation history and other health‐related databases to examine the association between regular, high‐frequency WB donation and the risk of CVD. To mitigate the impact of HDE, we used a “5‐years qualification period,” in which donors must donate at least 1 WB donation in the 1st and 5th year of “qualification period.” We then compared the risk of CVD in the years following the “qualification period” between the regular high‐frequency WB donors (≥2 WB donation in each qualification year) and others using Cox proportional‐hazards models. Analyses were adjusted for potential confounders, such as sociodemographic, lifestyle, and health‐related variables, and results are reported separately for male and female donors.

Results

A total of 2736 male and 2917 female donors were included in the analyses. The median years of follow‐up per donor was 5.84 years (Q1‐Q3, 5.47–6.23). The rate of CVD hospitalization was 11.20 and 4.50 per 1000 person‐years for males and females, respectively. In fully adjusted models, the risk (hazard ratio) of CVD in regular high‐frequency donors compared to other donors was 0.93 (95% Confidence Interval (CI), 0.68–1.29) for males and 0.79 (95% CI, 0.49–1.28) for females.

Conclusions

We did not observe a statistically significant reduction of CVD risk in regular, high‐frequency WB donors when adjusted for potential confounders.
Stretch‐induced reactive oxygen species contribute to the Frank–Starling mechanism
Authors: Kaihara Keiko , Kai Hiroaki , Chiba Yumiko , Naruse Keiji , Iribe Gentaro
Published: April 2023

Myocardial stretch physiologically activates NADPH oxidase 2 (NOX2) to increase reactive oxygen species (ROS) production. Although physiological low‐level ROS are known to be important as signalling molecules, the role of stretch‐induced ROS in the intact myocardium remains unclear. To address this, we investigated the effects of stretch‐induced ROS on myocardial cellular contractility and calcium transients in C57BL/6J and NOX2−/− mice. Axial stretch was applied to the isolated cardiomyocytes using a pair of carbon fibres attached to both cell ends to evaluate stretch‐induced modulation in the time course of the contraction curve and calcium transient, as well as to evaluate maximum cellular elastance, an index of cellular contractility, which is obtained from the end‐systolic force–length relationship. In NOX2−/− mice, the peak calcium transient was not altered by stretch, as that in wild‐type mice, but the lack of stretch‐induced ROS delayed the rise of calcium transients and reduced contractility. Our mathematical modelling studies suggest that the augmented activation of ryanodine receptors by stretch‐induced ROS causes a rapid and large increase in the calcium release flux, resulting in a faster rise in the calcium transient. The slight increase in the magnitude of calcium transients is offset by a decrease in sarcoplasmic reticulum calcium content as a result of ROS‐induced calcium leakage, but the faster rise in calcium transients still maintains higher contractility. In conclusion, a physiological role of stretch‐induced ROS is to increase contractility to counteract a given preload, that is, it contributes to the Frank–Starling law of the heart.

image

Key points

Myocardial stretch increases the production of reactive oxygen species by NADPH oxidase 2.

We used NADPH oxidase 2 knockout mice to elucidate the physiological role of stretch‐induced reactive oxygen species in the heart.

We showed that stretch‐induced reactive oxygen species modulate the rising phase of calcium transients and increase myocardial contractility.

A mathematical model simulation study demonstrated that rapid activation of ryanodine receptors by reactive oxygen species is important for increased contractility.

This response is advantageous for the myocardium, which must contract against a given preload.
Objective Measures of Strain and Subjective Muscle Soreness Differ Between Positional Groups and Season Phases in American College Football
Authors: McKay Benjamin A. , Delaney Jace A. , Simpkin Andrew , Larkin Theresa , Murray Andrew , Daniels Diarmuid , Pedlar Charles R. , Sampson John A.
Published: April 2023

Purpose: To assess objective strain and subjective muscle soreness in “Bigs” (offensive and defensive line), “Combos” (tight ends, quarterbacks, line backers, and running backs), and “Skills” (wide receivers and defensive backs) in American college football players during off-season, fall camp, and in-season phases. Methods: Twenty-three male players were assessed once weekly (3-wk off-season, 4-wk fall camp, and 3-wk in-season) for hydroperoxides (free oxygen radical test [FORT]), antioxidant capacity (free oxygen radical defense test [FORD]), oxidative stress index (OSI), countermovement-jump flight time, Reactive Strength Index (RSI) modified, and subjective soreness. Linear mixed models analyzed the effect of a 2-within-subject-SD change between predictor and dependent variables. Results: Compared to fall camp and in-season phases, off-season FORT (P ≤ .001 and <.001), FORD (P ≤ .001 and <.001), OSI (P ≤ .001 and <.001), flight time (P ≤ .001 and <.001), RSI modified (P ≤ .001 and <.001), and soreness (P ≤ .001 and <.001) were higher for “Bigs,” whereas FORT (P ≤ .001 and <.001) and OSI (P = .02 and <.001) were lower for “Combos.” FORT was higher for “Bigs” compared to “Combos” in all phases (P ≤ .001, .02, and .01). FORD was higher for “Skills” compared with “Bigs” in off-season (P = .02) and “Combos” in-season (P = .01). OSI was higher for “Bigs” compared with “Combos” (P ≤ .001) and “Skills” (P = .01) during off-season and to “Combos” in-season (P ≤ .001). Flight time was higher for “Skills” in fall camp compared with “Bigs” (P = .04) and to “Combos” in-season (P = .01). RSI modified was higher for “Skills” during off-season compared with “Bigs” (P = .02) and “Combos” during fall camp (P = .03), and in-season (P = .03). Conclusion: Off-season American college football training resulted in higher objective strain and subjective muscle soreness in “Bigs” compared with fall camp and during in-season compared with “Combos” and “Skills” players.
TEAD1 trapping by the Q353R–Lamin A/C causes dilated cardiomyopathy
Authors: Yamada Shintaro , Ko Toshiyuki , Ito Masamichi , Sassa Tatsuro , Nomura Seitaro , Okuma Hiromichi , Sato Mayuko , Imasaki Tsuyoshi , Kikkawa Satoshi , Zhang Bo , Yamada Takanobu , Seki Yuka , Fujita Kanna , Katoh Manami , Kubota Masayuki , Hatsuse Satoshi , Katagiri Mikako , Hayashi Hiromu , Hamano Momoko , Takeda Norifumi , Morita Hiroyuki , Takada Shuji , Toyoda Masashi , Uchiyama Masanobu , Ikeuchi Masashi , Toyooka Kiminori , Umezawa Akihiro , Yamanishi Yoshihiro , Nitta Ryo , Aburatani Hiroyuki , Komuro Issei
Published: April 2023

Mutations in the
LMNA
gene encoding Lamin A and C (Lamin A/C), major components of the nuclear lamina, cause laminopathies including dilated cardiomyopathy (DCM), but the underlying molecular mechanisms have not been fully elucidated. Here, by leveraging single-cell RNA sequencing (RNA-seq), assay for transposase-accessible chromatin using sequencing (ATAC-seq), protein array, and electron microscopy analysis, we show that insufficient structural maturation of cardiomyocytes owing to trapping of transcription factor TEA domain transcription factor 1 (TEAD1) by mutant Lamin A/C at the nuclear membrane underlies the pathogenesis of Q353R
-LMNA–
related DCM. Inhibition of the Hippo pathway rescued the dysregulation of cardiac developmental genes by TEAD1 in
LMNA
mutant cardiomyocytes. Single-cell RNA-seq of cardiac tissues from patients with DCM with the
LMNA
mutation confirmed the dysregulated expression of TEAD1 target genes. Our results propose an intervention for transcriptional dysregulation as a potential treatment of
LMNA
-related DCM.
A conditional knockout rat resource of mitochondrial protein-coding genes via a DdCBE-induced premature stop codon
Authors: Tan Lei , Qi Xiaolong , Kong Weining , Jin Jiachuan , Lu Dan , Zhang Xu , Wang Yue , Wang Siting , Dong Wei , Shi Xudong , Chen Wei , Wang Jianying , Li Keru , Xie Yuan , Gao Lijuan , Guan Feifei , Gao Kai , Li Chaojun , Wang Cheng , Hu Zhibin , Zhang Lianfeng , Guo Xuejiang , Shen Bin , Ma Yuanwu
Published: April 2023

Hundreds of pathogenic variants of mitochondrial DNA (mtDNA) have been reported to cause mitochondrial diseases, which still lack effective treatments. It is a huge challenge to install these mutations one by one. We repurposed the DddA-derived cytosine base editor to incorporate a premature stop codon in the mtProtein-coding genes to ablate mitochondrial proteins encoded in the mtDNA (mtProteins) instead of installing pathogenic variants and generated a library of both cell and rat resources with mtProtein depletion. In vitro, we depleted 12 of 13 mtProtein-coding genes with high efficiency and specificity, resulting in decreased mtProtein levels and impaired oxidative phosphorylation. Moreover, we generated six conditional knockout rat strains to ablate mtProteins using
Cre/loxP
system

. Mitochondrially encoded ATP synthase membrane subunit 8 and NADH:ubiquinone oxidoreductase core subunit 1 were specifically depleted in heart cells or neurons, resulting in heart failure or abnormal brain development. Our work provides cell and rat resources for studying the function of mtProtein-coding genes and therapeutic strategies.
Exploiting compositional disorder in collectives of light-driven circle walkers
Authors: Siebers Frank , Jayaram Ashreya , Blümler Peter , Speck Thomas
Published: April 2023

Emergent behavior in collectives of “robotic” units with limited capabilities that is robust and programmable is a promising route to perform tasks on the micro and nanoscale that are otherwise difficult to realize. However, a comprehensive theoretical understanding of the physical principles, in particular steric interactions in crowded environments, is still largely missing. Here, we study simple light-driven walkers propelled through internal vibrations. We demonstrate that their dynamics is well captured by the model of active Brownian particles, albeit with an angular speed that differs between individual units. Transferring to a numerical model, we show that this polydispersity of angular speeds gives rise to specific collective behavior: self-sorting under confinement and enhancement of translational diffusion. Our results show that, while naively perceived as imperfection, disorder of individual properties can provide another route to realize programmable active matter.
M2 macrophages drive leukemic transformation by imposing resistance to phagocytosis and improving mitochondrial metabolism
Authors: Weinhäuser Isabel , Pereira-Martins Diego A. , Almeida Luciana Y. , Hilberink Jacobien R. , Silveira Douglas R. A. , Quek Lynn , Ortiz Cesar , Araujo Cleide L. , Bianco Thiago M. , Lucena-Araujo Antonio , Mota Jose Mauricio , Hogeling Shanna M. , Sternadt Dominique , Visser Nienke , Diepstra Arjan , Ammatuna Emanuele , Huls Gerwin , Rego Eduardo M. , Schuringa Jan Jacob
Published: April 2023

It is increasingly becoming clear that cancers are a symbiosis of diverse cell types and tumor clones. Combined single-cell RNA sequencing, flow cytometry, and immunohistochemistry studies of the innate immune compartment in the bone marrow of patients with acute myeloid leukemia (AML) reveal a shift toward a tumor-supportive M2-polarized macrophage landscape with an altered transcriptional program, with enhanced fatty acid oxidation and NAD
+
generation. Functionally, these AML-associated macrophages display decreased phagocytic activity and intra–bone marrow coinjection of M2 macrophages together with leukemic blasts strongly enhances in vivo transformation potential. A 2-day in vitro exposure to M2 macrophages results in the accumulation of CALR
low
leukemic blast cells, which are now protected against phagocytosis. Moreover, M2-exposed “trained” leukemic blasts display increased mitochondrial metabolism, in part mediated via mitochondrial transfer. Our study provides insight into the mechanisms by which the immune landscape contributes to aggressive leukemia development and provides alternatives for targeting strategies aimed at the tumor microenvironment.
Myelin Oligodendrocyte Glycoprotein as an Autoantigen in Inflammatory Demyelinating Diseases of the Central Nervous System
Authors: Eliseeva Daria D. , Zakharova Maria N.
Published: April 2023

Demyelinating diseases of the central nervous system are caused by an autoimmune attack on the myelin sheath surrounding axons. Myelin structural proteins become antigenic, leading to the development of myelin lesions. The use of highly specialized laboratory diagnostic techniques for identification of specific antibodies directed against myelin components can significantly improve diagnostic approaches. Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) currently includes demyelinating syndromes with known antigens. Based on the demonstrated pathogenic role of human IgG against MOG, MOGAD was classified as a distinct nosological entity. However, generation of multiple MOG isoforms by alternative splicing hinders antigen detection even with the most advanced immunofluorescence techniques. On the other hand, MOG conformational changes ensure the structural integrity of other myelin proteins and maintain human-specific mechanisms of immune autotolerance.
The effect of initial damage induced by stress on the time-dependent behaviour of Beishan granite
Authors: Yu Peiyang , Pan Peng-Zhi , Chen Jianqiang , Miao Shuting , Wang Zhaofeng , Wu Zhenhua
Published: April 2023

To understand the time-dependent fracture behaviour of hard rock in the excavation damage zone, a series of stress paths are designed to obtain the same initial damage extent induced by excavation. The influence of initial damage under different stress states on the creep process of Beishan granite is investigated experimentally. A unified indicator, i.e., the time-dependent fracture potential index ( ξTFPI), is proposed to conveniently describe the effect of applied stress on the creep process. The results show that the time-dependent strain increases with increasing initial damage extent and is significantly affected by the applied stress at a given initial damage extent. Under the same initial damage extent, with the increase in ξTFPI, the larger the primary creep strain rate and secondary creep strain rate are, and this phenomenon is more obvious in the lateral creep results. The secondary creep strain rate increases with increasing ξTFPI, and the increasing trend of the axial secondary creep strain rate with ξTFPI is greater with a higher initial damage. Finally, a quantitative relationship of the secondary creep strain rate with the initial damage and ξTFPI is established and validated against the experimental results.