bluuebunny/crossref_metadata_2025 huggingface dataset:
Arginyltransferase 1 modulates p62-driven autophagy via mTORC1/AMPk signaling
Authors: Bonnet Laura V. , Palandri Anabela , Flores-Martin Jesica B. , Hallak Marta E.
Published: January 2024

Background

Arginyltransferase (Ate1) orchestrates posttranslational protein arginylation, a pivotal regulator of cellular proteolytic processes. In eukaryotic cells, two interconnected systems—the ubiquitin proteasome system (UPS) and macroautophagy—mediate proteolysis and cooperate to maintain quality protein control and cellular homeostasis. Previous studies have shown that N-terminal arginylation facilitates protein degradation through the UPS. Dysregulation of this machinery triggers p62-mediated autophagy to ensure proper substrate processing. Nevertheless, how Ate1 operates through this intricate mechanism remains elusive.

Methods

We investigated Ate1 subcellular distribution through confocal microscopy and biochemical assays using cells transiently or stably expressing either endogenous Ate1 or a GFP-tagged Ate1 isoform transfected in CHO-K1 or MEFs, respectively. To assess Ate1 and p62-cargo clustering, we analyzed their colocalization and multimerization status by immunofluorescence and nonreducing immunoblotting, respectively. Additionally, we employed Ate1 KO cells to examine the role of Ate1 in autophagy. Ate1 KO MEFs cells stably expressing GFP-tagged Ate1-1 isoform were used as a model for phenotype rescue. Autophagy dynamics were evaluated by analyzing LC3B turnover and p62/SQSTM1 levels under both steady-state and serum-starvation conditions, through immunoblotting and immunofluorescence. We determined mTORC1/AMPk activation by assessing mTOR and AMPk phosphorylation through immunoblotting, while mTORC1 lysosomal localization was monitored by confocal microscopy.

Results

Here, we report a multifaceted role for Ate1 in the autophagic process, wherein it clusters with p62, facilitates autophagic clearance, and modulates its signaling. Mechanistically, we found that cell-specific inactivation of Ate1 elicits overactivation of the mTORC1/AMPk signaling hub that underlies a failure in autophagic flux and subsequent substrate accumulation, which is partially rescued by ectopic expression of Ate1. Statistical significance was assessed using a two-sided unpaired t test with a significance threshold set at P<0.05.

Conclusions

Our findings uncover a critical housekeeping role of Ate1 in mTORC1/AMPk-regulated autophagy, as a potential therapeutic target related to this pathway, that is dysregulated in many neurodegenerative and cancer diseases.
Development of a highly sensitive and specific intact proviral DNA assay for HIV-1 subtype B and C
Authors: Buchholtz N. V. E. J. , Nühn M. M. , de Jong T. C. M. , Stienstra T. A. T. , Reddy K. , Ndung’u T. , Ndhlovu Z. M. , Fisher K. , Palmer S. , Wensing A. M. J. , Symons J. , Nijhuis M.
Published: January 2024

Introduction

HIV reservoir quantification is essential for evaluation of HIV curative strategies and may provide valuable insights about reservoir dynamics during antiretroviral therapy. The Intact Proviral DNA Assay (IPDA) provides the unique opportunity to quantify the intact and defective reservoir. The current IPDA is optimized for HIV-1 subtype B, the dominant subtype in resource-rich settings. However, subtype C is dominant in Sub-Saharan Africa, jointly accounting for around 60% of the pandemic. We developed an assay capable of quantifying intact and defective proviral HIV-1 DNA of subtype B and C.

Methods

Primer and probe sequences were strategically positioned at conserved regions in psi and env and adapted to subtype B&C. In silico analysis of 752 subtype B and 697 subtype C near-full length genome sequences (nFGS) was performed to predict  the specificity and sensitivity. Gblocks were used to determine the limit of blank (LoB), limit of detection (LoD), and different annealing temperatures were tested to address impact of sequence variability.

Results

The in silico analysis showed that the HIV-1 B&C IPDA correctly identified 100% of the intact subtype B, and 86% of the subtype C sequences. In contrast, the original IPDA identified 86% and 12% of these subtype B and C sequences as intact. Furthermore, the HIV-1 B&C IPDA correctly identified hypermutated (87% and 88%) and other defective sequences (73% and 66%) for subtype B and C with comparable specificity as the original IPDA for subtype B (59% and 63%). Subtype B cis-acting sequences were more frequently identified as intact by the HIV-1 B&C IPDA compared to the original IPDA (39% and 2%). The LoB for intact proviral DNA copies was 0, and the LoD for intact proviral DNA copies was 6 (> 95% certainty) at 60 °C. Quantification of 2–6 copies can be performed with > 80% certainty. Lowering the annealing temperature to 55 °C slightly lowered the specificity but prevented exclusion of samples with single mutations in the primer/probe region.

Conclusions

We developed a robust and sensitive assay for the quantification of intact and defective HIV-1 subtype B and C proviral DNA, making this a suitable tool to monitor the impact of (large-scale) curative interventions.
Clarification of the molecular mechanisms underlying glyphosate-induced major depressive disorder: a network toxicology approach
Authors: Li Jianan , Bi Haoran
Published: January 2024

Major depressive disorder (MDD) is predicted to become the second most common cause of disability in the near future. Exposure to glyphosate (Gly)-based herbicides has been linked to the onset of MDD. However, the underlying mechanisms remain unclear. The aim of this study was to investigate the potential molecular mechanisms of MDD induced by Gly using network toxicology approach. The MDD dataset GSE76826 from the Gene Expression Omnibus database was referenced to identify differentially expressed genes (DEGs) in peripheral blood leukocytes of MDD patients and controls. The potential intersection targets of Gly-induced MDD were screened by network toxicology. The intersection targets were used for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and to construct protein–protein interaction networks. The binding potentials of hub targets with Gly were validated by molecular docking. In total, 1216 DEGs associated with Gly-induced MDD were identified. Subsequent network pharmacology further refined the search to 43 targets. GO and KEGG enrichment analyses revealed multiple signaling pathways involved in GLY-induced MDD. Six potential core targets (CD40, FOXO3, FOS, IL6, TP53, and VEGFA) were identified. Finally, molecular docking demonstrated that Gly exhibited strong binding affinity to the core targets. The results of this study identified potential molecular mechanisms underlying Gly induced MDD and provided new insights for prevention and treatment.
Developing a protocol on antimicrobial resistance through WHO’s pandemic treaty will protect lives in future pandemics
Authors: Ruckert Arne , Lake Shajoe , Van Katwyk Susan Rogers
Published: January 2024

Addressing antimicrobial resistance (AMR) through the pandemic treaty is a crucial aspect of pandemic prevention, preparedness, and response. At the moment, AMR-related provisions in the draft text do not go far enough and will likely lead countries to commit to the status-quo of AMR action. We suggest that the protocol mechanism of the treaty proposed under Article 31 offers an opportunity to develop a subsidiary agreement (or protocol) to further codify the specific obligations and enforcement mechanisms necessary to meet the treaty’s AMR provisions. We also highlight experiences with previous treaty implementation that relied on protocols to inform design of a future AMR protocol.
Stunt performers’ reluctance to self-report head trauma: a qualitative study
Authors: Russell Jeffrey A. , Beverly Elizabeth A. , Stewart Lori J. , McMichael Leslie P. , Senn Ariana B.
Published: January 2024

Background

Mild traumatic brain injuries receive voluminous attention in the research literature, but this is confined almost entirely to sports and military contexts. As an occupation, performing stunts in film, television, and entertainment places the head at high risk of repetitive impact and whiplash, but stunt performers do not enjoy the same level of healthcare supervision and access as that provided to sports participants. Therefore, the aim of this study was to evaluate stunt performers’ qualitative perceptions of reporting and management of head trauma in their industry.

Methods

After giving their informed consent, 87 motion picture and television stunt performers responded to a query about their views of ways to improve how stunt performers’ occupational head trauma—specifically head impacts and head whips that could cause a concussion—are reported and managed. We analyzed their responses via content and thematic analyses. Two researchers independently marked and categorized key words, phrases, and texts to identify codes that described participants’ comments. They then revised, discussed, and resolved coding discrepancies through consensus to establish inter-coder reliability. Next, we identified thematic patterns that described participants’ understanding of the stunt performer industry and what must change to facilitate reporting of head trauma. We derived themes from data that occurred multiple times, both within and across short answer responses.

Results

We identified three primary themes cited by the stunt performers as needs in their industry: (1) Need to Reduce the Stigma of Reporting a Stunt-Related Injury, (2) Need to Eliminate the “Cowboy Culture,” and (3) Need to Improve the Quality of the Work Environment.

Conclusions

Stunt performers are crucial members of a global entertainment industry valued at approximately US$100 billion annually. A large segment of the world’s population consumes their work in motion pictures, television, and live entertainment. When they are given an anonymous opportunity to speak, stunt performers offer insight into and recommendations for industry changes—primarily cultural and educational in nature—that could improve their physical and mental health, career longevity, and employability when they are confronted with head trauma.
Analysis of the natural collapse course of non-traumatic osteonecrosis of the femoral head based on the matrix model
Authors: Zhao Rushun , Wang Mengfei , Hao Yangquan , Xu Peng , Lu Chao
Published: January 2024

Background

There are many predictions about the progression of natural collapse course of osteonecrosis of the femoral head. Here, we aimed to combine the three classical prediction methods to explore the progression of the natural collapse course.

Methods

This retrospective study included 127 patients admitted to our hospital from October 2016 to October 2017, in whom the femoral head had not collapsed. Logistic regression analysis was performed to determine the collapse risk factors, and Kaplan–Meier survival curves were used for femoral head survival analysis. The collapse rate of the femoral head was recorded within 5 years based on the matrix model. The specificity of the matrix model was analyzed using the receiver operating characteristic curve.

Results

A total of 127 patients with a total of 202 hips were included in this study, and 98 hips collapsed during the follow-up period. Multivariate logistics regression analysis showed that the predictive ability of the matrix model was stronger than Association Research Circulation Osseous staging, Japanese Investigation Committee classification, and area (P < 0.05). Kaplan–Meier survival curve showed that the median survival time of femoral head in patients was 3 years. The result of the receiver operating characteristic curve analysis showed that the area under the curve (AUC) of the matrix model had better predictive value (AUC = 0.771, log-rank test: P < 0.001).

Conclusion

We creatively combined the three classical prediction methods for evaluating the progression of the natural collapse course based on the matrix model and found that the higher the score of the matrix model, the higher the femoral head collapse rate. Specifically, the matrix model has a potential value in predicting femoral head collapse and guiding treatment selection.
Age-dependent genes in adipose stem and precursor cells affect regulation of fat cell differentiation and link aging to obesity via cellular and genetic interactions
Authors: Kar Asha , Alvarez Marcus , Garske Kristina M. , Huang Huiling , Lee Seung Hyuk T. , Deal Milena , Das Sankha Subhra , Koka Amogha , Jamal Zoeb , Mohlke Karen L. , Laakso Markku , Heinonen Sini , Pietiläinen Kirsi H. , Pajukanta Päivi
Published: January 2024

Background

Age and obesity are dominant risk factors for several common cardiometabolic disorders, and both are known to impair adipose tissue function. However, the underlying cellular and genetic factors linking aging and obesity on adipose tissue function have remained elusive. Adipose stem and precursor cells (ASPCs) are an understudied, yet crucial adipose cell type due to their deterministic adipocyte differentiation potential, which impacts the capacity to store fat in a metabolically healthy manner.

Methods

We integrated subcutaneous adipose tissue (SAT) bulk (n=435) and large single-nucleus RNA sequencing (n=105) data with the UK Biobank (UKB) (n=391,701) data to study age-obesity interactions originating from ASPCs by performing cell-type decomposition, differential expression testing, cell-cell communication analyses, and construction of polygenic risk scores for body mass index (BMI).

Results

We found that the SAT ASPC proportions significantly decrease with age in an obesity-dependent way consistently in two independent cohorts, both showing that the age dependency of ASPC proportions is abolished by obesity. We further identified 76 genes (72 SAT ASPC marker genes and 4 transcription factors regulating ASPC marker genes) that are differentially expressed by age in SAT and functionally enriched for developmental processes and adipocyte differentiation (i.e., adipogenesis). The 76 age-perturbed ASPC genes include multiple negative regulators of adipogenesis, such as RORA, SMAD3, TWIST2, and ZNF521, form tight clusters of longitudinally co-expressed genes during human adipogenesis, and show age-based differences in cellular interactions between ASPCs and adipose cell types. Finally, our genetic data demonstrate that cis-regional variants of these genes interact with age as predictors of BMI in an obesity-dependent way in the large UKB, while no such gene-age interaction on BMI is observed with non-age-dependent ASPC marker genes, thus independently confirming our cellular ASPC results at the biobank level.

Conclusions

Overall, we discover that obesity prematurely induces a decrease in ASPC proportions and identify 76 developmentally important ASPC genes that implicate altered negative regulation of fat cell differentiation as a mechanism for aging and directly link aging to obesity via significant cellular and genetic interactions.
Induction of cervical disc degeneration and discogenic pain by low concentration Propionibacterium acnes infection: an in vivo animal study
Authors: Li Jie , Li Hui , Chen Yilei , Bei Dikai , Huang Bao , Gan Kaifeng , Sang Peiming , Liu Junhui , Shan Zhi , Chen Jian , Zhao Fengdong , Chen Binhui
Published: January 2024

Background

Although cervical intervertebral disc (IVD) degeneration is closely associated with neck pain, its cause remains unclear. In this study, an animal model of cervical disc degeneration and discogenic neck pain induced by a low concentration of Propionibacterium acnes (P. acnes-L) is investigated to explore the possible mechanisms of cervical discogenic pain.

Methods

Cervical IVD degeneration and discitis was induced in 8-week-old male rats in C3–C6 IVDs through the anterior intervertebral puncture with intradiscal injections of low and high concentrations of P. acnes (P. acnes-L, n = 20 and P. acnes-H, n = 15) or Staphylococcus aureus (S. aureus, n = 15), compared to control (injection with PBS, n = 20). The structural changes in the cervical IVD using micro-CT, histological evaluation, and gene expression assays after MRI scans at 2 and 6 weeks post-modeling. The P. acnes-L induced IVD degeneration model was assessed for cervical spine MRI, histological degeneration, pain-like behaviors (guarding behavior and forepaw von Frey), nerve fiber growth in the IVD endplate region, and DRG TNF-α and CGRP.

Results

IVD injection with P. acnes-L induced IVD degeneration with decreased IVD height and MRI T2 values. IVD injection with P. acnes-H and S. aureus both lead to discitis-like changes on T2-weighted MRI, trabecular bone remodeling on micro-CT, and osseous fusion after damage in the cartilage endplate adjacent to the injected IVD. Eventually, rats in the P. acnes-L group exhibited significant nociceptive hypersensitivity, nerve fiber ingrowth was observed in the IVD endplate region, inflammatory activity in the DRG was significantly increased compared to the control group, and the expression of the pain neurotransmitter CGRP was significantly upregulated.

Conclusion

P. acnes-L was validated to induce cervical IVD degeneration and discogenic pain phenotype, while P. acnes-H induced was identified to resemble septic discitis comparable to those caused by S. aureus infection.
Impaired synaptic function and hyperexcitability of the pyramidal neurons in the prefrontal cortex of autism-associated Shank3 mutant dogs
Authors: Zhu Feipeng , Shi Qi , Jiang Yong-hui , Zhang Yong Q. , Zhao Hui
Published: January 2024

Background

SHANK3 gene is a highly replicated causative gene for autism spectrum disorder and has been well characterized in multiple Shank3 mutant rodent models. When compared to rodents, domestic dogs are excellent animal models in which to study social cognition as they closely interact with humans and exhibit similar social behaviors. Using CRISPR/Cas9 editing, we recently generated a dog model carrying Shank3 mutations, which displayed a spectrum of autism-like behaviors, such as social impairment and heightened anxiety. However, the neural mechanism underlying these abnormal behaviors remains to be identified.

Methods

We used Shank3 mutant dog models to examine possible relationships between Shank3 mutations and neuronal dysfunction. We studied electrophysiological properties and the synaptic transmission of pyramidal neurons from acute brain slices of the prefrontal cortex (PFC). We also examined dendrite elaboration and dendritic spine morphology in the PFC using biocytin staining and Golgi staining. We analyzed the postsynaptic density using electron microscopy.

Results

We established a protocol for the electrophysiological recording of canine brain slices and revealed that excitatory synaptic transmission onto PFC layer 2/3 pyramidal neurons in Shank3 heterozygote dogs was impaired, and this was accompanied by reduced dendrite complexity and spine density when compared to wild-type dogs. Postsynaptic density structures were also impaired in Shank3 mutants; however, pyramidal neurons exhibited hyperexcitability.

Limitations

Causal links between impaired PFC pyramidal neuron function and behavioral alterations remain unclear. Further experiments such as manipulating PFC neuronal activity or restoring synaptic transmission in Shank3 mutant dogs are required to assess PFC roles in altered social behaviors.

Conclusions

Our study demonstrated the feasibility of using canine brain slices as a model system to study neuronal circuitry and disease. Shank3 haploinsufficiency causes morphological and functional abnormalities in PFC pyramidal neurons, supporting the notion that Shank3 mutant dogs are new and valid animal models for autism research.
Naturally occurring low sociality in female rhesus monkeys: A tractable model for autism or not?
Authors: Oztan Ozge , Del Rosso Laura A. , Simmons Sierra M. , Nguyen Duyen K. K. , Talbot Catherine F. , Capitanio John P. , Garner Joseph P. , Parker Karen J.
Published: January 2024

Background

Autism spectrum disorder (ASD) is characterized by persistent social interaction impairments and is male-biased in prevalence. We have established naturally occurring low sociality in male rhesus monkeys as a model for the social features of ASD. Low-social male monkeys exhibit reduced social interactions and increased autistic-like trait burden, with both measures highly correlated and strongly linked to low cerebrospinal fluid (CSF) arginine vasopressin (AVP) concentration. Little is known, however, about the behavioral and neurochemical profiles of female rhesus monkeys, and whether low sociality in females is a tractable model for ASD.

Methods

Social behavior assessments (ethological observations; a reverse-translated autistic trait measurement scale, the macaque Social Responsiveness Scale-Revised [mSRS-R]) were completed on N = 88 outdoor-housed female rhesus monkeys during the non-breeding season. CSF and blood samples were collected from a subset of N = 16 monkeys across the frequency distribution of non-social behavior, and AVP and oxytocin (OXT) concentrations were quantified. Data were analyzed using general linear models.

Results

Non-social behavior frequency and mSRS-R scores were continuously distributed across the general female monkey population, as previously found for male monkeys. However, dominance rank significantly predicted mSRS-R scores in females, with higher-ranking individuals showing fewer autistic-like traits, a relationship not previously observed in males from this colony. Females differed from males in several other respects: Social behavior frequencies were unrelated to mSRS-R scores, and AVP concentration was unrelated to any social behavior measure. Blood and CSF concentrations of AVP were positively correlated in females; no significant relationship involving any OXT measure was found.

Limitations

This study sample was small, and did not consider genetic, environmental, or other neurochemical measures that may be related to female mSRS-R scores.

Conclusions

Dominance rank is the most significant predictor of autistic-like traits in female rhesus monkeys, and CSF neuropeptide concentrations are unrelated to measures of female social functioning (in contrast to prior CSF AVP findings in male rhesus monkeys and male and female autistic children). Although preliminary, this evidence suggests that the strong matrilineal organization of this species may limit the usefulness of low sociality in female rhesus monkeys as a tractable model for ASD.
Repeatability of [15O]H2O PET imaging for lower extremity skeletal muscle perfusion: a test–retest study
Authors: Christensen Nana Louise , Sørensen Jens , Bouchelouche Kirsten , Madsen Michael Alle , Buhl Christian Selmer , Tolbod Lars Poulsen
Published: January 2024

Background

[15O]H2O PET/CT allows noninvasive quantification of tissue perfusion and can potentially play a future role in the diagnosis and treatment of peripheral artery disease. We aimed to evaluate the reliability of dynamic [15O]H2O PET imaging for measuring lower extremity skeletal muscle perfusion. Ten healthy participants underwent same-day test–retest study with six dynamic [15O]H2O PET scans of lower legs and feet. Manual volume-of-interests were drawn in skeletal muscles, and PET time activity curves were extracted. K1 values (mL/min/100 mL) were estimated using a single-tissue compartment model (1TCM), autoradiography (ARG), and parametric imaging with blood input functions obtained from separate heart scans.

Results

Resting perfusion values in the muscle groups of the lower legs ranged from 1.18 to 5.38 mL/min/100 mL (ARG method). In the muscle groups of the feet, perfusion values ranged from 0.41 to 3.41 mL/min/100 mL (ARG method). Test–retest scans demonstrated a strong correlation and good repeatability for skeletal muscle perfusion with an intraclass correlation coefficient (ICC) of 0.88 and 0.87 and a repeatability coefficient of 34% and 53% for lower legs and feet, respectively. An excellent correlation was demonstrated when comparing volume-of-interest-based methods (1TCM and ARG) (lower legs: ICC = 0.96, feet: ICC = 0.99). Parametric images were in excellent agreement with the volume-of-interest-based ARG method (lower legs: ICC = 0.97, feet: ICC = 0.98).

Conclusion

Parametric images and volume-of-interest-based methods demonstrated comparable resting perfusion values in the lower legs and feet of healthy individuals. The largest variation was seen between individuals, whereas a smaller variation was seen between muscle groups. Repeated measurements of resting blood flow yielded a strong overall correlation for all methods.
Features and outcomes of patients admitted to the ICU for chimeric antigen receptor T cell-related toxicity: a French multicentre cohort
Authors: Le Cacheux Corentin , Couturier Audrey , Sortais Clara , Houot Roch , Péré Morgane , Gastinne Thomas , Seguin Amélie , Reignier Jean , Lascarrou Jean-Baptiste , Tadié Jean-Marc , Quelven Quentin , Canet Emmanuel
Published: January 2024

Background

Chimeric antigen receptor T-cell (CAR-T) therapy is increasingly used in patients with refractory haematological malignancies but can induce severe adverse events. We aimed to describe the clinical features and outcomes of patients admitted to the intensive care unit (ICU) after CAR-T therapy.

Methods

This retrospective observational cohort study included consecutive adults admitted to either of two French ICUs in 2018–2022 within 3 months after CAR-T therapy.

Results

Among 238 patients given CAR-T therapy, 84 (35.3%) required ICU admission and were included in the study, a median of 5 [0–7] days after CAR-T infusion. Median SOFA and SAPSII scores were 3 [2–6] and 39 [30–48], respectively. Criteria for cytokine release syndrome were met in 80/84 (95.2%) patients, including 18/80 (22.5%) with grade 3–4 toxicity. Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 46/84 (54.8%) patients, including 29/46 (63%) with grade 3–4 toxicity. Haemophagocytic lymphohistiocytosis was diagnosed in 15/84 (17.9%) patients. Tocilizumab was used in 73/84 (86.9%) patients, with a median of 2 [1–4] doses. Steroids were given to 55/84 (65.5%) patients, including 21/55 (38.2%) given high-dose pulse therapy. Overall, 23/84 (27.4%) patients had bacterial infections, 3/84 (3.6%) had fungal infections (1 invasive pulmonary aspergillosis and 2 Mucorales), and 2 (2.4%) had cytomegalovirus infection. Vasopressors were required in 23/84 (27.4%), invasive mechanical ventilation in 12/84 (14.3%), and dialysis in 4/84 (4.8%) patients. Four patients died in the ICU (including 2 after ICU readmission, i.e., overall mortality was 4.8% of patients). One year after CAR-T therapy, 41/84 (48.9%) patients were alive and in complete remission, 14/84 (16.7%) were alive and in relapse, and 29/84 (34.5%) had died. These outcomes were similar to those of patients never admitted to the ICU.

Conclusion

ICU admission is common after CAR-T therapy and is usually performed to manage specific toxicities. Our experience is encouraging, with low ICU mortality despite a high rate of grade 3–4 toxicities, and half of patients being alive and in complete remission at one year.
Mitochondrial-to-nuclear communications through multiple routes regulate cardiomyocyte proliferation
Authors: Li Xinhang , Zhu Yalin , Ruiz-Lozano Pilar , Wei Ke
Published: January 2024

The regenerative capacity of the adult mammalian heart remains a formidable challenge in biological research. Despite extensive investigations into the loss of regenerative potential during evolution and development, unlocking the mechanisms governing cardiomyocyte proliferation remains elusive. Two recent groundbreaking studies have provided fresh perspectives on mitochondrial-to-nuclear communication, shedding light on novel factors that regulate cardiomyocyte proliferation. The studies identified two mitochondrial processes, fatty acid oxidation and protein translation, as key players in restricting cardiomyocyte proliferation. Inhibition of these processes led to increased cell cycle activity in cardiomyocytes, mediated by reduction in H3k4me3 levels through accumulated α-ketoglutarate (αKG), and activation of the mitochondrial unfolded protein response (UPRmt), respectively. In this research highlight, we discuss the novel insights into mitochondrial-to-nuclear communication presented in these studies, the broad implications in cardiomyocyte biology and cardiovascular diseases, as well as the intriguing scientific questions inspired by the studies that may facilitate future investigations into the detailed molecular mechanisms of cardiomyocyte metabolism, proliferation, and mitochondrial-to-nuclear communications.
A regularization method for solving the G-variational inequality problem and fixed-point problems in Hilbert spaces endowed with graphs
Authors: Khuangsatung Wongvisarut , Singta Akarate , Kangtunyakarn Atid
Published: January 2024

This article considers and investigates a variational inequality problem and fixed-point problems in real Hilbert spaces endowed with graphs. A regularization method is proposed for solving a G-variational inequality problem and a common fixed-point problem of a finite family of G-nonexpansive mappings in the framework of Hilbert spaces endowed with graphs, which extends the work of Tiammee et al. (Fixed Point Theory Appl. 187, 2015) and Kangtunyakarn, A. (Rev. R. Acad. Cienc. Exactas Fís. Nat., Ser. A Mat. 112:437–448, 2018). Under certain conditions, a strong convergence theorem of the proposed method is proved. Finally, we provide numerical examples to support our main theorem. The numerical examples show that the speed of the proposed method is better than some recent existing methods in the literature.
The effectiveness of expanded carrier screening based on next-generation sequencing for severe monogenic genetic diseases
Authors: Zhang Xue , Chen Qian , Li Junnan , Luo Xin , Luo Jianyun , Li Jian , Zeng Ziye , Wu Yan , Zhang Hua , Dong Yanling
Published: January 2024

Expanded carrier screening (ECS) based on next-generation sequencing has been the subject of few studies to estimate the effectiveness of ECS in the Chinese population. A total of 3737 individuals from Southwest China or the general Chinese population, including 1048 pairs and 1641 individuals, were analysed by ECS for 155 monogenetic diseases. An ECS panel was used to detect 147 genes and 10,449 variants in 145 autosomal recessive and 10 X-linked recessive disorders. A total of 43.27% (1617/3737) were found to be carriers of at least one of the 155 monogenetic diseases. The average number of carriers of these recessive mutations was 0.54 and ranged from 0 to 4. Of the 1048 couples, 74.81% (n = 784) were found to have at least one partner carrying more than one disease. In addition, 5.34% of the couples at risk (n = 56) were heterozygous for the same autosomal recessive disease, and 0.37% of the women (9/2440) were carriers of X-linked diseases. Our study demonstrated the clinical significance of ECS in Chinese populations and the need for a programme of familial screening for the prevention of severe recessive monogenetic diseases.
Effects of input text genre on Chinese young EFL learners’ performance on continuation tasks
Authors: Li Xueping , Wang Yiru
Published: January 2024

This study examines how the genre of input text influences Chinese young EFL learners’ performance on continuation tasks. Participants were 30 students in Grade 9 and repeated-measures design was adopted to compare their performance on narrative and argumentative continuation tasks, in terms of writing quality, CAF indicators as well as alignment. Results showed that (i) genre had no significant influence on students’ scores on the two continuation tasks; (ii) argumentative continuation task brought about more complex sentences and words, as reflected by most indicators, but narrative continuation task led to relatively longer writing, and no significant difference was found for accuracy; (iii) students’ writings on argumentative task contained more 4-word phrases that were drawn from the input text, while the writings on narrative task were semantically more related to the reading input. This study provides another piece of validity evidence for employing continuation tasks in different genres in language tests and has implications for the writing teaching of Chinese young EFL learners.
Thermochromic phantoms and paint to characterize and model image-guided thermal ablation and ablation devices: a review
Authors: Negussie Ayele H. , Morhard Robert , Rivera Jocelyne , Delgado Jose F. , Xu Sheng , Wood Bradford J.
Published: January 2024

Heat-based local ablation techniques are effective treatments for specific oligometastatic and localized cancers and are being studied for their potential to induce immunogenic cell death and augment systemic immune responses to immunotherapies. The diverse technologies associated with thermal therapy have an unmet need for method development to enable device-specific experimentation, optimization, calibration and refinement of the parameter space to optimize therapeutic intent while minimizing side effects or risk to the patient. Quality assurance, training, or comparing thermal dose among different modalities or techniques using animal models is time and resource intensive. Therefore, the application and use of tissue mimicking thermosensitive, thermochromic liquid crystal and thermochromic paint phantom models may reduce costs and hurdles associated with animal use. Further, their homogenous composition may enable more precise assessment of ablative techniques. This review utilized SciFinder, Web of Science, PubMed and EMBASE to systematically evaluate the literature describing the background and applications of thermochromic liquid crystal, thermochromic paint and tissue-mimicking thermochromic phantoms used to characterize the thermal effects of ablation devices with a focus on facilitating their use across the medical device development life cycle.

Graphical Abstract
Evaluation of computed tomography (CT) findings in patients with symptomatic deviated nasal septum and their correlation with intraoperative findings
Authors: Rehman Ayaz , Deva Faiza Ashfah , Malik Bashir Ahmad , Wani Asif A. , Masoodi Majid ul Islam
Published: January 2024

Aim

To evaluate the computed tomography (CT) findings in patients having a symptomatic deviated nasal septum (DNS) and their comparison with intraoperative findings.

Methods

Cross-sectional, observational study done in the department of ENT and HNS at a tertiary care center, over a period of 16 months. Patients presenting with nasal obstruction as the chief complaint and findings of deviated nasal septum on anterior rhinoscopy without clinical features of chronic rhinosinusitis (CRS) were included in the present study. All patients underwent CT scans of paranasal sinuses (PNS) as per the govt. scheme for approval of surgery. Surgery was planned as per the indication based on history, clinical examination, and non-contrast CT scan PNS findings. The average duration from CT scan to surgery was 4.5 weeks.

Results

All 200 (100%) patients had DNS with inferior turbinate hypertrophy in 103 (52.5%), concha bullosa in 22 (11.0%), pneumatized superior turbinate in 6 (3.0%), and PMT (paradoxical middle turbinate) in 22 (11.0%). On comparing CT scan findings with intraoperative findings, it was found that maxillary sinus involvement had been seen in 28 (14.0%) patients on CT scan and only 8 (4.0%) patients intraoperatively. Similarly, CT scan involvement compared to and intraoperative involvement of anterior ethmoidal sinus was seen in 20 (10.0%) compared to 6 (3.0%) patients intraoperatively, posterior ethmoid in 12 (6.0%) compared to 3 (1.5%) frontal sinus in 4 (2.0%) compared to 1 (0.5%), sphenoid in 11 (5.5%) compared to 2 (1.0%), and osteomeatal complex (OMC) in 27 (13.5%) compared to 6 (3.0%) patients intraoperatively. Involvement of PMT, enlarged inferior, and concha bullosa was similar on CT scan and intraoperatively.

Conclusion

From this study, we concluded that a preoperative CT scan is a poor tool in predicting sinus disease in patients without clinical features of sinus disease and has a limited role in patients with symptomatic DNS. Insurance companies and government agencies should review their policies of ordering CT scans for approving septal surgeries.
Feasibility and Clinical Utility of Reporting Hereditary Cancer Predisposition Pathogenic Variants Identified in Research Germline Sequencing: A Prospective Interventional Study
Authors: Hutchcraft Megan L. , Zhang Shulin , Lin Nan , Pickarski Justine C. , Belcher Elizabeth A. , Wei Sainan , Bocklage Thèrése , Miller Rachel W. , Villano John L. , Cavnar Michael J. , Kim Joseph , Arnold Susanne M. , Ueland Frederick R. , Kolesar Jill M.
Published: January 2024

PURPOSE

Patients with cancer frequently undergo research-grade germline sequencing but clinically actionable results are not routinely disclosed. The objective of this study is to evaluate the feasibility of reporting clinically relevant secondary findings (SF) identified in germline research sequencing using the institutional molecular tumor board (MTB) and the treating oncology physician.

METHODS

This prospective, interventional cohort study enrolled Total Cancer Care participants with any cancer diagnosis at a single institution. Patients underwent research-grade germline whole-exome sequencing, with bioinformatic analysis in a Clinical Laboratory Improvement Amendments–certified laboratory to verify pathogenic/likely pathogenic germline variants (PGVs) in any American College of Medical Genomics and Genetics SF v2.0 genes. After a protocol modification in consenting patients, the MTB reported PGVs to treating oncology physicians with recommendations for referral to a licensed genetic counselor and clinical confirmatory testing.

RESULTS

Of the 781 enrolled participants, 32 (4.1%) harbored cancer predisposition PGVs, 24 (3.1%) were heterozygous carriers of an autosomal recessive cancer predisposition syndrome, and 14 (1.8%) had other hereditary disease PGVs. Guideline-directed testing would have missed 37.5% (12/32) of the inherited cancer predisposition PGVs, which included BRCA1, BRCA2, MSH6, SDHAF2, SDHB, and TP53 variants. Three hundred fifteen participants consented to reporting results; results for all living patients were reported to the clinical team with half referred to a licensed genetic counselor. There was concordance between all research variants identified in patients (n = 9) who underwent clinical confirmatory sequencing.

CONCLUSION

MTB reporting of research-grade germline sequencing to the clinical oncology team is feasible. Over a third of PGVs identified using a universal testing strategy would have been missed by guideline-based approach, suggesting a role for expanding germline testing.
The Association of Guideline-Directed Prophylaxis With Postoperative Nausea and Vomiting in Adult Patients: A Single-Center, Retrospective Cohort Study
Authors: Andrew Benjamin Y. , Holmes Romel , Taicher Brad M. , Habib Ashraf S.
Published: January 2024

BACKGROUND:

Consensus guidelines for postoperative nausea and vomiting (PONV) prophylaxis recommend a risk-based approach in which the number of antiemetics administered is based on a preoperative estimate of PONV risk. These guidelines have been adapted by the Multicenter Perioperative Outcomes Group (MPOG) to serve as measures of clinician and hospital compliance with guideline-recommended care. However, the impact of this approach on clinical outcomes is not known.

METHODS:

We performed a single-center, retrospective study of adult patients undergoing general anesthesia from 2018 to 2021. Risk factors for PONV were defined using MPOG definitions: female sex, history of PONV or motion sickness, nonsmoker, inhaled anesthesia >60 minutes, high-risk procedure (cholecystectomy, laparoscopic, gynecologic), and age <50 years. Adequate prophylaxis was defined using the MPOG PONV-05 metric: at least 2 agents for patients with 1 to 2 risk factors and at least 3 agents for patients with 3+ risk factors. PONV was defined as documented PONV or receipt of rescue antiemetics. To estimate the association between adequate prophylaxis and PONV, we used Bayesian binomial models with overlap propensity score weighting.

RESULTS:

We included 76,703 cases (43% receiving adequate prophylaxis) with PONV occurring in 19%. In unadjusted and unweighted comparison, adequate prophylaxis was associated with increased incidence of PONV: median odds ratio 1.21 (95% credible interval [1.16–1.25]). However, after propensity score weighting and multivariable adjustment, adequate prophylaxis was associated with reduced relative and absolute risk for PONV: weighted marginal median odds ratio 0.90 [0.84–0.98] and absolute risk reduction (ARR) 1.6% [0.6%–2.6%]. There was evidence for a differential effect of adequate prophylaxis across the guideline-defined risk spectrum, with benefit seen in patients with 1 to 5 risk factors (conditional probabilities of benefit >0.81), but not in those at high predicted risk. Patient-specific, covariate-adjusted ARR was heterogeneous, with a median patient-specific conditional probability of benefit of 0.84 (95% credible interval, 0.73–0.90).

CONCLUSIONS:

Guideline-directed PONV prophylaxis is associated with a modest reduction in PONV, although this effect is small and heterogeneous on the absolute scale. We found evidence for a differential association between adequate prophylaxis and PONV across the guideline-defined risk spectrum, with diminution in patients at very high predicted preoperative risk. While patient-specific benefit was heterogenous, most patients had reasonably high predicted probabilities of absolute benefit from a guideline-directed strategy. Further assessment of these associations in a multicenter setting, with more robust investigation of risk prediction methods will allow for better understanding of the optimal approach to PONV prophylaxis.
Palpation Versus Ultrasonography for Identifying the Cricothyroid Membrane in Case of a Laterally Deviated Larynx: A Randomized Trial
Authors: Lohse Robin , Wagner Nanna , Kristensen Michael Seltz
Published: January 2024

BACKGROUND:

Large neck circumference and displacement of the trachea due to pathology increase the risk of failed identification of the cricothyroid membrane and cricothyroidotomy. We investigated whether ultrasound aids in the successful identification of the cricothyroid membrane in a model of an obese neck with midline deviation of the trachea.

METHODS:

We developed silicone neck models that were suitable for both palpation and ultrasonography and where the trachea deviated laterally from the midline to either side. After reading a book chapter and participating in a 25-minute lecture and a 15- to 23-minute hands-on demonstration and rehearsal of ultrasonography for identification of the cricothyroid membrane, anesthesiologists and anesthesiology residents randomly performed identification with either ultrasound or palpation on 1 of 2 neck models.

RESULTS:

We included 57 participants, of whom 29 and 28 were randomized to palpation and ultrasound, respectively. Correct identification of the cricothyroid membrane was achieved by 21 (75.0%) vs 1 (3.5%) of participants in the ultrasound versus palpation groups (risk ratio [RR], 21.8 [95% confidence interval {CI}, 3.1–151.0]). The tracheal midline position in the sagittal plane was identified correctly by 24 (85.7%) vs 16 (55.2%) of participants in the ultrasound versus palpation groups (RR, 1.6 [95% CI, 1.1–2.2]).

CONCLUSIONS:

Identification of the cricothyroid membrane in a model of an obese neck with midline deviation of the trachea was more often successful with ultrasound compared to palpation. Our study supports the potential use of ultrasound before induction of anesthesia and airway management in this group of patients, and it may even be applied in emergency situations when ultrasound is readily available. Further studies in human subjects should be conducted.
Analgesic Effect of Exercise on Neuropathic Pain via Regulating the Complement Component 3 of Reactive Astrocytes
Authors: Wang Chenghao , He Hui , Gao Tianchi , Sun Xinzheng , Du Lixia , Yang Yayue , Zhu Jianyu , Yang Yachen , Wang Yanqing , Mi Wenli
Published: January 2024

BACKGROUND:

Exercise has been proven to be an efficient intervention in attenuating neuropathic pain. However, the underlying mechanisms that drive exercise analgesia remain unknown. In this study, we aimed to examine the role of complement component 3 (C3) in neuropathic pain and whether antinociceptive effects are produced by exercise via regulating C3 in mice.

METHODS:

In this study, using a spared nerve injury (SNI)-induced neuropathic pain mice model, C57BL/6J mice were divided into 3 groups: Sham mice, SNI mice, and SNI + Exercise (Ex) mice with 30-minute low-intensity aerobic treadmill running (10 m/min, no inclination). Paw withdrawal threshold; thermal withdrawal latency; and glial fibrillary acidic protein, C3, tumor necrosis factor-α, and interlukin-1β expression in the spinal cord were monitored. C3 knockout (KO) mice were further used to verify the role of C3 in neuropathic pain.

RESULTS:

von Frey test, acetone test, and CatWalk gait analysis revealed that treadmill exercise for 4 weeks reversed pain behaviors. In addition, exercise reduced astrocyte reactivity (SNI mean = 14.5, 95% confidence interval [CI], 12.7–16.3; SNI + Ex mean = 10.3, 95% CI, 8.77–11.9, P = .0003 SNI + Ex versus SNI) and inflammatory responses in the spinal cord after SNI. Moreover, it suppressed the SNI-induced upregulation of C3 expression in the spinal cord (SNI mean = 5.46, 95% CI, 3.39–7.53; SNI + Ex mean = 2.41, 95% CI, 1.42–3.41, P = .0054 SNI + Ex versus SNI in Western blot). C3 deficiency reduced SNI-induced pain and spinal astrocyte reactivity (wild type mean = 7.96, 95% CI, 6.80–9.13; C3 KO mean = 5.98, 95% CI, 5.14–6.82, P = .0052 C3 KO versus wild type). Intrathecal injection of recombinant C3 (rC3) was sufficient to produce mechanical (rC3-Ex mean = 0.77, 95% CI, 0.15–1.39; rC3 mean = 0.18, 95% CI, −0.04 to 0.41, P = .0168 rC3-Ex versus rC3) and cold (rC3-Ex mean = 1.08, 95% CI, 0.40–1.77; rC3 mean = 3.46, 95% CI, 1.45–5.47, P = .0025 rC3-Ex versus rC3) allodynia in mice. Importantly, exercise training relieved C3-induced mechanical and cold allodynia, and the analgesic effect of exercise was attenuated by a subeffective dose of intrathecal injection of C3.

CONCLUSIONS:

Overall, these results suggest that exercise suppresses neuropathic pain by regulating astroglial C3 expression and function, thereby providing a rationale for the analgesic effect of exercise as an acceptable alternative approach for treating neuropathic pain.
Exploring the ATG9A interactome uncovers interaction with VPS13A
Authors: van Vliet Alexander R. , Jefferies Harold B. J. , Faull Peter A. , Chadwick Jessica , Ibrahim Fairouz , Skehel Mark J. , Tooze Sharon A.
Published: January 2024

ATG9A, a transmembrane protein of the core autophagy pathway, cycles between the Golgi, endosomes and a vesicular compartment. ATG9A was recently shown to act as a lipid scramblase, and this function is thought to require its interaction with another core autophagy protein, ATG2A, which acts as a lipid transfer protein. Together, ATG9A and ATG2A are proposed to function to expand the growing autophagosome. However, ATG9A is implicated in other pathways including membrane repair and lipid droplet homeostasis. To elucidate other ATG9A interactors within the autophagy pathway, or interactors beyond autophagy, we performed an interactome analysis through mass spectrometry. This analysis revealed a host of proteins involved in lipid synthesis and trafficking, including ACSL3, VPS13A and VPS13C. Furthermore, we show that ATG9A directly interacts with VPS13A and forms a complex that is distinct from the ATG9A–ATG2A complex.