General Role Research Articles

Impact of perioperative high-protein nutritional support on the quality of life of patients with primary lung cancer: a Russian prospective multicenter comparative study (NUTRILUNC study)

BACKGROUND: Individuals over the age of 70 comprise over half of operable patients with stage 0–IIIA lung cancer. In the early postoperative period of this cohort, pain, fatigue, insomnia, and/or mood disturbances are the four most common symptoms, which can significantly diminish quality of life and functional status. Perioperative nutritional support in such patients, which enhances exercise tolerance, can have a positive impact on their quality of life and socialization. AIM: To assess the effect of perioperative nutritional support using high-protein oral nutrition supplements on the general health and quality of life of non-small cell lung cancer patients during the postoperative period. MATERIALS AND METHODS: Patients with primary non-small cell lung cancer (n=112, 69 males), aged 57.2±8.2, who were awaiting lung surgery and at risk of malnutrition (Nutritional Risk Screening Assessment 2002 score ≥3) were randomly assigned into two groups. Oral nutritional support (Nutridrink Compact Protein, Nutricia LLC) was administered to the study group (n=55) at a rate of 250 ml/d (36 g of protein, 612 kcal) for 14 days prior to and 14 days following the surgery, in addition to the standard diet. Control group patients (n=57) were provided a standard diet. The quality of life was assessed using the Quality of Life Questionnaire Core-30. Results are presented as mean ± standard deviation. Differences were considered significant at p ≤0.05. RESULTS: Throughout the entire observation period, the study group exhibited superior growth indicators in terms of general health status, physical, and role functioning than the control group (p 0.05). The study group patients exhibited a propensity toward improved emotional functioning, and by the end of the study, weakness and insomnia were less pronounced (p 0.05). Other indicators did not exhibit any significant variations. CONCLUSION: Нigh-protein perioperative oral nutrition supplements exert a positive impact on the quality of life of non-small cell lung cancer patients.

A Decade of Experience Between Open and Minimally Invasive Hepatectomies for Hepatocellular Carcinoma

Background and Objectives: Hepatic resection offers promising outcomes for patients with hepatocellular carcinoma (HCC) but can be constrained by factors like patient suitability. Continuous advancements in laparoscopic and robotic technologies have made minimally invasive hepatectomies (MIHs) a viable alternative to open hepatectomies with benefits in terms of recovery and complications. Materials and Methods: We completed a retrospective review on 138 HCC patients who underwent OH or MIH between 2010 and 2020 at the Hume-Lee Transplant Center. Univariate and multivariate analyses were completed on demographic, clinical, and tumor-specific data to assess the impact of these variables on overall and disease-free survival at 1, 3, and 5 years. Preoperative metrics like length of hospital stay (LOS) and operation duration were also evaluated. Results: Of the 109 OH and 29 MIH patients, MIH patients demonstrated shorter LOS and operative times. However, overall survival (OS) and disease-free survival (DFS) were similar between groups, with no significant variations in 1-, 3-, and 5-year survival rates. Age > 60 years and a lack of preoperative transcatheter arterial chemoembolization (TACE) were significant predictors of inferior OS and DFS in multivariate analyses. Conclusions: MIH is an efficient substitute for OH with comparable survival, even in older patients. The reduced LOS and operation time enhance its feasibility, and older patients previously denied for curative resection may qualify for MIH. Preoperative TACE also enhances survival outcomes, emphasizing its general role in managing resectable HCCs. Both robotic and laparoscopic hepatectomies offer acceptable short- and long-term clinical outcomes, highlighting MIH as the standard choice for HCC patients.

Massively parallel binding assay (MPBA) reveals limited transcription factor binding cooperativity, challenging models of specificity.

DNA-binding domains (DBDs) within transcription factors (TFs) recognize short sequence motifs that are highly abundant in genomes. In vivo, TFs bind only a small subset of motif occurrences, which is often attributed to the cooperative binding of interacting TFs at proximal motifs. However, large-scale testing of this model is still lacking. Here, we describe a novel method allowing parallel measurement of TF binding to thousands of designed sequences within yeast cells and apply it to quantify the binding of dozens of TFs to libraries of regulatory regions containing clusters of binding motifs, systematically mutating all motif combinations. With few exceptions, TF occupancies were well explained by independent binding to individual motifs, with motif cooperation being of only limited effects. Our results challenge the general role of motif combinatorics in directing TF genomic binding and open new avenues for exploring the basis of protein-DNA interactions within cells.

An in vivo screen for proteolytic switch domains that can mediate Notch activation by force.

Notch proteins are single pass transmembrane receptors activated by sequential extracellular and intramembrane cleavages that release their cytosolic domains to function as transcription factors in the nucleus. Upon binding, Delta/Serrate/LAG-2 (DSL) ligands activate Notch by exerting a "pulling" force across the intercellular ligand/receptor bridge. This pulling force is generated by Epsin-mediated endocytosis of ligand into the signal-sending cell, and results in the extracellular cleavage of the force-sensing Negative Regulatory Region (NRR) of the receptor by an ADAM10 protease [Kuzbanian (Kuz) in Drosophila ]. Here, we have used chimeric Notch and DSL proteins to screen for other domains that can function as ligand-dependent proteolytic switches in place of the NRR in the developing Drosophila wing. While many of the tested domains are either refractory to cleavage or constitutively cleaved, we identify several that mediate Notch activation in response to ligand. These NRR analogues derive from widely divergent source proteins and have strikingly different predicted structures. Yet, almost all depend on force exerted by Epsin-mediated ligand endocytosis and cleavage catalyzed by Kuz. We posit that the sequence space of protein domains that can serve as force-sensing proteolytic switches in Notch activation is unexpectedly large, a conclusion that has implications for the mechanism of target recognition by Kuz/ADAM10 proteases and is consistent with a more general role for force dependent ADAM10 proteolysis in other cell contact-dependent signaling mechanisms. Our results also validate the screen for increasing the repertoire of proteolytic switches available for synthetic Notch (synNotch) therapies and tissue engineering.

The transcription elongation factors Spt4 and Spt5 control neural progenitor proliferation and are implicated in neuronal remodeling during Drosophila mushroom body development.

Spt4 and Spt5 form the DRB sensitivity inducing factor (DSIF) complex that regulates transcription elongation at multiple steps including promotor-proximal pausing, processivity and termination. Although this implicated a general role in transcription, several studies pointed to smaller sets of target genes and indicated a more specific requirement in certain cellular contexts. To unravel common or distinct functions of Spt4 and Spt5 in vivo, we generated knock-out alleles for both genes in Drosophila melanogaster. Using the development of the mushroom bodies as a model, we provided evidence for two common functions of Spt4 and Spt5 during mushroom body development, namely control of cell proliferation of neural progenitor cells and remodeling of axonal projections of certain mushroom body neurons. This latter function is not due to a general requirement of Spt4 and Spt5 for axon pathfinding of mushroom body neurons, but due to distinct effects on the expression of genes controlling remodeling.

Revealing antibiotic resistance's ancient roots: insights from pristine ecosystems.

The prevailing belief that antibiotic resistance mechanisms emerged with human antibiotic use has been challenged. Evidence indicates that some antibiotic resistance genes (ARGs) have a long evolutionary history, predating the advent of antibiotics in human medicine, thereby demonstrating that resistance is an ancient phenomenon. Despite extensive surveys of resistance elements in environments impacted by human activity, limited data are available from remote and pristine habitats. This minireview aims to compile the most relevant research on the origins and evolution of ARGs in these habitats, which function as reservoirs for ancient resistance mechanisms. These studies indicate that ancient ARGs functionally similar to modern resistance genes, highlighting the general role of natural antimicrobial substances in fostering the evolution and exchange of diverse resistance mechanisms through horizontal gene transfer over time. This minireview underscores that antibiotic resistance was present in ancestral microbial communities and emphasizes the ecological role of antibiotics and resistance determinants. Understanding ancient ARGs is crucial for predicting and managing the evolution of antibiotic resistance. Thus, these insights provide a foundational basis for developing new antibiotics and strategies for microbial resistance management.

An ERP-based comparison of gender representations elicited by generic masculine role nouns and the German gender star form

There is an ongoing debate about the linguistic gender forms that should be used to elicit fair mental representations of all genders. While most languages with grammatical gender traditionally use the masculine form to refer to people in a gender-independent way, numerous empirical studies have demonstrated that this form leads to a male bias in mental representations. In German, the so-called gender star form has been proposed as an alternative to the masculine form, aimed at better representing persons with nonmale gender identities. To provide empirical data on this claim, we compared the neural processing mechanisms elicited by the gender star form with those elicited by the generically intended masculine form during reference resolution. Participants in the present ERP study read sentence pairs in which a group of people was introduced with a role noun in one of the two gender forms and then revealed to be partly comprised of men or women. Following the masculine form, anaphoric references to women (vs. men) resulted in an increased ERP amplitude in the P600 range. In contrast, following the gender star form, the P600 amplitude was increased for references to men (vs. women), albeit in a slightly different spatio-temporal range. The present data thus indicate that the gender star form and the generically intended masculine form impose partially different demands on the syntactic operations performed by the brain during reference resolution but that, in the end, neither form elicits gender-balanced mental representations of men and women in German.

BMP2 and BMP7 cooperate with H3.3K27M to promote quiescence and invasiveness in pediatric diffuse midline gliomas.

Pediatric diffuse midline gliomas (pDMG) are an aggressive type of childhood cancer with a fatal outcome. Their major epigenetic determinism has become clear, notably with the identification of K27M mutations in histone H3. However, the synergistic oncogenic mechanisms that induce and maintain tumor cell phenotype have yet to be deciphered. In 20 to 30% of cases, these tumors have an altered BMP signaling pathway with an oncogenic mutation on the BMP type I receptor ALK2, encoded by ACVR1. However, the potential impact of the BMP pathway in tumors non-mutated for ACVR1 is less clear. By integrating bulk, single-cell, and spatial transcriptomic data, we show here that the BMP signaling pathway is activated at similar levels between ACVR1 wild-type and mutant tumors and identify BMP2 and BMP7 as putative activators of the pathway in a specific subpopulation of cells. By using both pediatric isogenic glioma lines genetically modified to overexpress H3.3K27M and patients-derived DIPG cell lines, we demonstrate that BMP2/7 synergizes with H3.3K27M to induce a transcriptomic rewiring associated with a quiescent but invasive cell state. These data suggest a generic oncogenic role for the BMP pathway in gliomagenesis of pDMG and pave the way for specific targeting of downstream effectors mediating the K27M/BMP crosstalk.

BMP2 and BMP7 cooperate with H3.3K27M to promote quiescence and invasiveness in pediatric diffuse midline gliomas

Pediatric diffuse midline gliomas (pDMG) are an aggressive type of childhood cancer with a fatal outcome. Their major epigenetic determinism has become clear, notably with the identification of K27M mutations in histone H3. However, the synergistic oncogenic mechanisms that induce and maintain tumor cell phenotype have yet to be deciphered. In 20 to 30% of cases, these tumors have an altered BMP signaling pathway with an oncogenic mutation on the BMP type I receptor ALK2, encoded by ACVR1. However, the potential impact of the BMP pathway in tumors non-mutated for ACVR1 is less clear. By integrating bulk, single-cell, and spatial transcriptomic data, we show here that the BMP signaling pathway is activated at similar levels between ACVR1 wild-type and mutant tumors and identify BMP2 and BMP7 as putative activators of the pathway in a specific subpopulation of cells. By using both pediatric isogenic glioma lines genetically modified to overexpress H3.3K27M and patients-derived DIPG cell lines, we demonstrate that BMP2/7 synergizes with H3.3K27M to induce a transcriptomic rewiring associated with a quiescent but invasive cell state. These data suggest a generic oncogenic role for the BMP pathway in gliomagenesis of pDMG and pave the way for specific targeting of downstream effectors mediating the K27M/BMP crosstalk.

Kernels of Motor Memory Formation: Temporal Generalization in Bimanual Adaptation.

In daily life, we coordinate both simultaneous and sequential bimanual movements to manipulate objects. Our ability to rapidly account for different object dynamics suggests there are neural mechanisms to quickly deal with them. Here we investigate how actions of one arm can serve as a contextual cue for the other arm, and facilitate adaptation. Specifically, we examine the temporal characteristics that underlie motor memory formation and recall, by testing the contextual effects of prior, simultaneous, and post contralateral arm movements in both male and female human participants. To do so, we measure their temporal generalization in three bimanual interference tasks. Importantly, the timing context of the learned action plays a pivotal role in the temporal generalization. While motor memories trained with post adaptation contextual movements generalize broadly, motor memories trained with prior contextual movements exhibit limited generalization, and motor memories trained with simultaneous contextual movements do not generalize to prior or post contextual timings. This highlights temporal tuning in sensorimotor plasticity: different training conditions yield substantially different temporal generalization characteristics. Since these generalizations extend far beyond any variability in training times, we suggest that the observed differences may stem from inherent differences in the use of prior, current and post-adaptation contextual information in the generation of natural behavior. This would imply differences in the underlying neural circuitry involved in learning and executing the corresponding coordinated bimanual movements.Significance Statement This study addresses a fundamental question in the field of sensorimotor neuroscience of how multiple movements are temporally linked within a single motor memory. We examine the temporal generalization of motor memory formation by varying the timing of contextual movements associated with a learned motor memory across a range of prior, current, and post adaptation movement times using a bimanual motor learning task. We observed distinct patterns of temporal generalization based on whether the contextual movements occurred prior to, simultaneously with, or after the adaptation movement. For the first time, our findings reveal that the timing of contextual movements is crucial in the formation and generalization of motor memories.

Long Noncoding VIM-AS1: Biomarker of Breast Fibrosis Susceptibility After Radiation Therapy and Promoter of Transforming Growth Factor Beta1–Driven Fibrosis

Fibrosis is a common late complication of radiation therapy. Molecular dysregulations leading to fibrosis have been characterized for the coding part of the genome, notably those involving the TGFB1 gene network. However, because a large part of the human genome encodes RNA transcripts that are not translated into proteins, exploring the involvement of the noncoding part of the genome in fibrosis susceptibility and development was the aim of this work. Breast cancer patients having or not having developed severe breast fibrosis after radiation therapy were retrospectively selected from the COPERNIC collection. Exome sequencing and RNA-seq transcriptomic profiling were performed on 19 primary dermal fibroblast strains isolated from the patients' nonirradiated skin. Functional experiments were based on fibrogenic induction by transforming growth factor-Beta1 (TGFB1) and gene knockdown in healthy donor fibroblasts. Coding and noncoding transcriptomes discriminated fibrosis from nonfibrosis conditions, and a signature of breast fibrosis susceptibility comprising 15 long noncoding RNAs (lncRNAs) was identified. A hazard ratio validation showed that the lncRNA vimentin antisense long noncoding RNA 1 (VIM-AS1) was the best biomarker associated with fibrosis risk. This lncRNA has not been previously associated with any fibrotic disorder, but we found it upregulated in data sets from cardiac fibrosis and scleroderma, suggesting a general role in tissue fibrosis. Functional experiments demonstrated a profibrotic action of VIM-AS1 because its knockdown reduced myofibroblast activation, collagen matrix production, and dermal organoid contraction. RNA-seq data analysis after VIM-AS1 silencing also pointed out the regulation of replication, cell cycle, and DNA repair. Mechanistically, because VIM-AS1 was found coregulated with the vimentin gene, these data support a profibrotic function of the TGFB1/VIM-AS1/vimentin axis, targeting the dynamics of fibroblast-myofibroblast transition. Noncoding RNA analysis can provide specific biomarkers relevant to the prediction of normal tissue responses after radiation therapy, which opens perspectives of next-generation approaches for treatment, in the frame of the recent developments of RNA-based technologies.

The deformation mechanisms responsible for strain localization in nanotwinned nickel alloys

Nanotwinned Ni-Mo-W alloys possess a combination of unique mechanical and thermal properties, such as ultrahigh strength and microstructural stability, which are correlated with the presence of densely packed growth twins. In a previous study, the ultrahigh compressive strength of Ni84Mo11W5 (atomic percent) micropillars was associated with the formation of highly localized shear bands, but the trigger for such localized plasticity was not identified. Here, Ni86Mo3W11 (atomic percent) micropillars were carefully compressed to various levels to uncover the nanoscale deformation mechanisms that trigger the strain localization. Post-mortem transmission electron microscopy investigations of pillars after the first measurable strain burst revealed ∼50 nm thick shear bands consisting of reoriented and twin-free grains, while the columnar grains adjacent to the shear bands were partly detwinned. More importantly, unlike the Mo-rich pillars, the W-rich pillars showed discernible plasticity before the first strain burst. Close inspection made before the formation of a mature shear band revealed a detwinning region of ∼30 nm thickness that aligned more parallel to the coherent twin boundaries, and multiple nanotwins truncated with incoherent twin boundaries were resolved between the detwinning band and the nanotwinned grains. These observations strongly suggest detwinning, facilitated by migration of incoherent twin boundaries, to be the precursor to strain localization and the intensive shear banding observed in nanotwinned Ni-Mo-W alloys. Comparing the present results with the literature further highlights the general role of detwinning in governing the plastic behavior of nanotwinned alloys with a wide range of stacking fault energy.

Health-Related Quality of Life of Adolescents With Non-transfusion-Dependent Thalassemia in Basrah, Iraq.

Thalassemia is a chronic inherited disease with the potential for serious clinical and psychological effects. In the case of thalassemia, a cure is not currently accessible, and lifelong treatment is required. Health-related quality of life (HRQoL) is considered a crucial health outcome. This study aims to assess the HRQoL of children and adolescents with non-transfusion-dependent thalassemia (NTDT) and compare it with that of beta-thalassemia major (β-TM) and healthy subjects. This case-control study included 88 patients with NTDT and 153 age- and gender-matched healthy children and adolescents. In addition, we included 70 registered patients with β-TM. We used the short-form health survey questionnaire to assess HRQoL. Of the 88 patients, 41 were diagnosed with alpha-thalassemia intermedia (α-TI; hemoglobin H disease), and 47 were with beta-thalassemia intermedia (β-TI). HRQoL domains were significantly higher in healthy children and adolescents compared to NTDT patients (P<0.001); the role emotion domain was the most affected in NTDT patients (51.92 ± 3.37), followed by general health (52.72 ± 3.05) and role physical (53.59 ± 3.13). α-TI patients had significantly higher HRQoL domains than patients with β-TI. The study also indicated that NTDT patients had significantly better QoL scores compared to β-TM patients (P<0.001) across all domains. NTDT patients have a lower HRQoL compared to healthy controls. However, their HRQoL scores are significantly better than those of patients with β-TM. Among NTDT patients, those with α-TI have significantly better HRQoL scores compared to patients with β-TI.

Abstract B061: Bridging the gap in inequality in timely cancer diagnosis: GLORIA network Colombia

Abstract Introduction: In Latin American countries, survival rates for highly malignant tumors show disparities in access to diagnosis and treatment between small and big cities. Colombia is an example where the rate of pathologists is 0.88 per 100,000 inhabitants. Oncopathologists are predominantly situated in major cities, being a minimal percentage of this specialty. Whole slide imaging (WSI) technology can be used to mitigate disparities by facilitating diagnostic support for less-experienced pathologists in distant locations from expert centers. Telepathology brings a solution in bridging these gaps, enabling connectivity and facilitating timely diagnoses and treatments. To achieve this goal, a Colombian research group developed the GLORIA Colombia Network, which will provide WSI scanners and a telepathology network in small cities connecting them to an expert central laboratory. This will facilitate decision-making for oncopathological diagnoses. We aim to show a preliminary phase of the project; knowledge, attitudes, and practices of general pathologists operating the scanners are explored to delve into fears and expectations so that an introduction of this technology can be made. Methods:Introductory phase consisted of a semi-structured survey piloted by the research group and conducted via Google Forms for general pathology laboratories in Colombia, through the network ASOCOLPAT (Colombian pathologist association). There were 23 close questions related to context recognition, and an open question to explore qualitative aspects related to telepathology. ResultsA total of 51 responses from general pathologists were obtained, 100% stated they had needed assistance of a subspecialist in high complexity cases; 47% noted soft tissue tumors were challenging diagnoses, 35.2% affirmed hematological tumors were also challenging. The 25.5% reported stress high levels in complex diagnoses. 64% reported 1-10 complex cases/month in capital cities. The most frequently requested type of tumor for consultation was lymph nodes (21.3%), followed by melanocytic tumors (23.5%). Furthermore, 27.4% stated the response time for interconsultation ranged from one week to one month. Additionally, 79.2% of pathologists attempt to diagnose the case themselves, but if unable to do so, they refer it to a specialist. The open question revealed doubts about general pathologists' roles, and their feeling of undervalue compared to subspecialists. This question highlighted the need for training, and telepathology emerged as an alternative to facilitate communication between general pathologists and subspecialists. Emphasizing the importance lies in improving diagnostic times, which affects patients’ quality of life. Conclusion GLORIA network, bridges healthcare gaps by connecting general pathologists with specialists, enabling faster and accurate diagnoses. This initiative reduces stress, offers training, and improves diagnostic reliability, benefiting patients in remote areas with complex malignant tumors. Citation Format: Gabriela Guerron-Gomez, Maria C. Restrepo-Guarnizo, Andres Mosquera-Zamudio, Oscar Mendoza, John J. Sprockel, Arley Gomez, Laura D. Olarte Suarez, Merideidy Plazas Vargas, Rafael Parra-Medina, Marcela Gomez-Suarez. Bridging the gap in inequality in timely cancer diagnosis: GLORIA network Colombia [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr B061.

Biochemical and neurophysiological effects of deficiency of the mitochondrial import protein TIMM50.

TIMM50, an essential TIM23 complex subunit, is suggested to facilitate the import of ∼60% of the mitochondrial proteome. In this study, we characterized a TIMM50 disease causing mutation in human fibroblasts and noted significant decreases in TIM23 core protein levels (TIMM50, TIMM17A/B, and TIMM23). Strikingly, TIMM50 deficiency had no impact on the steady state levels of most of its putative substrates, suggesting that even low levels of a functional TIM23 complex are sufficient to maintain the majority of TIM23 complex-dependent mitochondrial proteome. As TIMM50 mutations have been linked to severe neurological phenotypes, we aimed to characterize TIMM50 defects in manipulated mammalian neurons. TIMM50 knockdown in mouse neurons had a minor effect on the steady state level of most of the mitochondrial proteome, supporting the results observed in patient fibroblasts. Amongst the few affected TIM23 substrates, a decrease in the steady state level of components of the intricate oxidative phosphorylation and mitochondrial ribosome complexes was evident. This led to declined respiration rates in fibroblasts and neurons, reduced cellular ATP levels and defective mitochondrial trafficking in neuronal processes, possibly contributing to the developmental defects observed in patients with TIMM50 disease. Finally, increased electrical activity was observed in TIMM50 deficient mice neuronal cells, which correlated with reduced levels of KCNJ10 and KCNA2 plasma membrane potassium channels, likely underlying the patients' epileptic phenotype.

Retinopathy and vision-related quality of life in blood dyscrasias.

To study the association of retinopathy with vision-related quality of life in patients with blood dyscrasias. A cross-sectional observational study was conducted at a university-based hospital. Two hundred patients with blood dyscrasias underwent comprehensive ocular examination, including dilated fundus examination. Vision-related quality of life was assessed using the National Eye Institute Visual Functioning Questionnaire-25 (NEI-VFQ-25). Retinopathy was observed in 99 out of 200 patients (49.50%) with blood dyscrasias. The most common retinal findings were venous tortuosity with dilation (31.70%), intraretinal hemorrhages (27.88%), soft exudates (12.50%), white-centered hemorrhages (12.50%), and arteriolar attenuation (12.50%). A significant association was found between retinopathy in blood dyscrasias and NEI-VFQ subscales of general vision (P value: 0.01**), near activities (P value: 0.04*), distance activities (P value: 0.01**), mental health (P value: 0.01**), color vision (P value: 0.01**), peripheral vision (P value: 0.01**), role difficulties (P value: 0.01**), and social functioning (P value: 0.01**). The study highlights the prevalence of retinopathy in blood dyscrasia patients and its detrimental impact on vision-related quality of life. Regular fundus examinations are imperative for early detection and management of retinopathy to prevent significant visual impairment. Further research is warranted to elucidate underlying mechanisms and improve clinical management strategies.

Pelvic Organ Prolapse Surgery: Postoperative Quality of Life in Ethiopian Women.

Pelvic organ prolapse (POP) has a profound influence on a woman's quality of life (QoL). Assessment of QoL using patient-reported outcome (PRO) measures in pelvic organ prolapse surgery is common practice in developed countries, but despite the burden of POP in developing countries, such as Ethiopia, the use of PROs to record preoperative and postoperative QoL scores is limited. This study is aimed at assessing the QoL among Ethiopian women with POP before and after surgery using the validated Pelvic Organ Quality of Life (P-QoL) questionnaire.Additionally, we will compare postoperative QoL measurements of reconstructive procedures with those of obliterative procedures. This is a prospective observational study conducted at a single hospital in Ethiopia on women who were scheduled for surgery for symptomatic POP. Patients' QoL was assessed preoperatively using the P-QoL questionnaire and at each subsequent follow-up visit for 1 year (3, 6, 9, and 12months). Patients undergoing an obliterative procedure were evaluated and compared with those having reconstructive procedures. The mean score for general health perceptions, prolapse impact, role limitations, physical limitations, social limitations, and emotions was 0 at 12 months postoperatively. Despite significant improvements from baseline, personal relationships, sleep or energy disturbance, and symptom severity measures continued to negatively impact QoL at 12 months postoperatively. Quality of life among Ethiopian women with POP is poor across all domains. Native tissue repair employing either reconstructive or obliterative methods significantly improves QoL across all domains up to 12months postoperatively. The use of validated tools to assess PROs is essential to provide evidence-based care that improves QoL in ways that are meaningful to patients.

Antisense transcription from stress-responsive transcription factors fine-tunes the cold response in Arabidopsis.

Transcription of antisense long noncoding RNAs (lncRNAs) occurs pervasively across eukaryotic genomes. Only a few antisense lncRNAs have been characterized and shown to control biological processes, albeit with idiosyncratic regulatory mechanisms. Thus, we largely lack knowledge about the general role of antisense transcription in eukaryotic organisms. Here, we characterized genes with antisense transcription initiating close to the poly(A) signal of genes (PAS genes) in Arabidopsis (Arabidopsis thaliana). We compared plant native elongation transcript sequencing (plaNET-seq) with RNA sequencing during short-term cold exposure and detected massive differences between the response in active transcription and steady-state levels of PAS gene-derived mRNAs. The cold-induced expression of transcription factors B-BOX DOMAIN PROTEIN28 (BBX28) and C2H2-TYPE ZINC FINGER FAMILY PROTEIN5 (ZAT5) was detected by plaNET-seq, while their steady-state level was only slightly altered due to high mRNA turnover. Knockdown of BBX28 and ZAT5 or of their respective antisense transcripts severely compromised plant freezing tolerance. Decreased antisense transcript expression levels resulted in a reduced cold response of BBX28 and ZAT5, revealing a positive regulatory role of both antisense transcripts. This study expands the known repertoire of noncoding transcripts. It highlights that native transcription approaches can complement steady-state RNA techniques to identify biologically relevant players in stress responses.

Mechanosensitive Piezo channels and their potential roles in peripheral auditory perception

AbstractHearing sound and responding to external and internal mechanical stimuli requires specific proteins as mechanotransducers that convert mechanical forces into biological signals. However, our understanding of the mechanotransduction process in the inner ear is still incomplete. Mechanically activated ion channels, PIEZO1 and PIEZO2, are widely distributed throughout the body and play essential roles. Recent studies have discovered that Piezo channels are expressed in inner ear hair cells, suggesting their potential involvement in auditory perception. This review summarizes the existing discoveries about the Piezo channels, including their structure, mechanogating mechanisms, and general physiological roles, explicitly focusing on Piezo channels in the auditory systems. Piezo channels play roles in ultrasound perception, generation of anomalous current, hair cell development, and potentially in the normal mechanoelectrical transduction process of hair cells. Collectively, this review aims to provide a new perspective on the Piezo channel and its potential roles in auditory perception.

A Humanized Yeast Model for Studying TRAPP Complex Mutations; Proof-of-Concept Using Variants from an Individual with a TRAPPC1-Associated Neurodevelopmental Syndrome.

Variants in membrane trafficking proteins are known to cause rare disorders with severe symptoms. The highly conserved transport protein particle (TRAPP) complexes are key membrane trafficking regulators that are also involved in autophagy. Pathogenic genetic variants in specific TRAPP subunits are linked to neurological disorders, muscular dystrophies, and skeletal dysplasias. Characterizing these variants and their phenotypes is important for understanding the general and specialized roles of TRAPP subunits as well as for patient diagnosis. Patient-derived cells are not always available, which poses a limitation for the study of these diseases. Therefore, other systems, like the yeast Saccharomyces cerevisiae, can be used to dissect the mechanisms at the intracellular level underlying these disorders. The development of CRISPR/Cas9 technology in yeast has enabled a scar-less editing method that creates an efficient humanized yeast model. In this study, core yeast subunits were humanized by replacing them with their human orthologs, and TRAPPC1, TRAPPC2, TRAPPC2L, TRAPPC6A, and TRAPPC6B were found to successfully replace their yeast counterparts. This system was used for studying the first reported individual with an autosomal recessive disorder caused by biallelic TRAPPC1 variants, a girl with a severe neurodevelopmental disorder and myopathy. We show that the maternal variant (TRAPPC1 p.(Val121Alafs*3)) is non-functional while the paternal variant (TRAPPC1 p.(His22_Lys24del)) is conditional-lethal and affects secretion and non-selective autophagy in yeast. This parallels defects seen in fibroblasts derived from this individual which also showed membrane trafficking defects and altered Golgi morphology, all of which were rescued in the human system by wild-type TRAPPC1. This study suggests that humanized yeast can be an efficient means to study TRAPP subunit variants in the absence of human cells and can assign significance to variants of unknown significance (VUS). This study lays the foundation for characterizing further TRAPP variants through this system, rapidly contributing to disease diagnosis.