Functional Implications Research Articles

Hyperreflective material evolution patterns during long term anti-VEGF therapy in neovascular age-related macular degeneration.

This retrospective, real-life cohort was analyzed to detect the frequency of different HRM evolution patterns and their correlation with MNV types, morphological and functional changes in exudative nAMD under long-term anti-VEGF therapy.We evaluated optical coherence tomography (OCT) volume scans in 143 eyes of 94 nAMD patients (start of anti-VEGF therapy 2009-2018, therapy until the last visit) and recorded the VA at all visits. HRM evolution patterns were differentiated: pattern 1 = no HRM, pattern 2 = subretinal HRM resolved during follow-up, pattern 3 = persistent subretinal HRM with new HRM-boundary remodeling [BR], pattern 4 = persistent subretinal HRM without HRM-BR. Pattern 1 was observed in 58 eyes (40.6%), 33 eyes (23.1%) showed pattern 2, 39 eyes (27.3%) pattern 3 and 13 eyes (9.1%) pattern 4. HRM pattern correlated with type 1-3 MNV (p = 0.02), especially pattern 1 with type 1 MNV and pattern 3 with type 2 MNV. Over time, a change of MNV types could be observed only from type 2 into type 1 MNV (p = 0.0001). Some eyes with HRM pattern 3 changed during follow-up into pattern 4, which was often associated with the presence of macular atrophy (p = 0.0001) and demonstrated a reduced mean VA compared to pattern 1-3 at baseline (p = 0.0001), year 1 (p = 0.0001) and final visit (p = 0.02).In this study, we characterized different HRM evolution patterns in a real-world dataset and demonstrated their associations with MNV transformation during long term anti-VEGF therapy. The HRM patterns may provide prognostic value with morphological and functional implications.

Prognostic factors and impact of management strategies for status epilepticus: The STEPPER study in the Emilia-Romagna region, Italy.

The STEPPER (Status Epilepticus in Emilia-Romagna) study aimed to investigate the clinical characteristics, prognostic factors, and treatment approaches of status epilepticus (SE) in adults of the Emilia-Romagna region (ERR), Northern Italy. STEPPER, an observational, prospective, multicentric cohort study, was conducted across neurology units, emergency departments, and intensive care units of the ERR over 24 months (October 2019-October 2021), encompassing incident cases of SE. Patients were followed up for 30 days. A total of 578 cases were recruited (56% female, mean age = 70 years, 32% with previous diagnosis of epilepsy, 43% with in-hospital onset, 35% stuporous/comatose, 46% with nonconvulsive SE). Etiology was known in 87% (acute 43%, remote 24%, progressive 17%, definite epileptic syndrome 3%). The mean pre-SE Rankin Scale score was 2, the Status Epilepticus Severity Score was ≥4 in 33%, the Epidemiology-Based Mortality Score in Status Epilepticus score was ≥64 in 61%, and 34% were refractory. The sequence of treatments followed current clinical practice guidelines in 63%. Benzodiazepines (BDZs) were underused as first-line therapy (71%), especially in in-hospital onset cases; 15% were treated with continuous intravenous anesthetic drugs. Mortality was 24%; 63% of survivors had functional worsening. At the two-step multivariable analysis, incorrect versus correct treatment sequence with correct BDZ dose was the strongest predictor of failure to resolve SE in the in-hospital group (odds ratio [OR] = 4.42, 95% confidence interval [CI] = 1.86-10.5), with a similar trend in the out-of-hospital group (OR = 2.22, 95% CI = .98-5.02). In turn, failure to resolve was the strongest predictor of 30-day mortality (OR = 11.3, 95% CI = 4.16-30.9, out-of-hospital SE; OR = 6.42, 95% CI = 2.79-14.8, in-hospital SE) and functional worsening (OR = 5.83, 95% CI = 2.05-16.6, out-of-hospital SE; OR = 9.30, 95% CI 2.22-32.3, in-hospital SE). The STEPPER study offers insights into real-world SE management, highlighting its significant morbidity and functional decline implications. Although nonmodifiable clinical factors contribute to SE severity, modifiable factors such as optimized first-line therapies and adherence to guidelines can potentially influence prognosis.

Free Fasciocutaneous versus Muscle Flaps in Lower Extremity Reconstruction: Implications for Functionality and Quality of Life.

Free tissue transplantations are commonly used to treat complex lower extremity defects caused by trauma, vascular disease, or malignancy, particularly when vital structures are exposed. This study aimed to expand the knowledge on patient-reported outcomes by comparing fasciocutaneous and muscle flaps, with the goal of facilitating patient counseling. Additionally, patient-level risk factors associated with decreased functioning and health-related quality of life were identified. This retrospective, cross-sectional, multicenter study included patients who underwent microsurgical lower extremity reconstruction using free fasciocutaneous or muscle flaps between 2003 and 2021, with a minimum follow-up of 12 months. Data were collected from medical records, pain scores, Short-Form 36 (SF-36), and Lower Extremity Functional Scale (LEFS). Mean scores were compared between flap types and predictors of LEFS, SF-36 mental component summary (MCS), and SF-36 physical component summary (PCS) scores were determined using a backward stepwise regression model. Of the 206 patients eligible, 100 (49%) were included in the retrospective part. A total of 89 (43%) responded to the questionnaires, with 62 treated using a fasciocutaneous flap and 27 with a muscle flap. No significant differences in total LEFS, SF-36 PCS, or MCS scores were found between the two flap type. Pain was a significant predictor of decreased functional outcomes for both flap types and was also linked to poorer mental health in patients treated with fasciocutaneous flaps. Other predictors of low patient-reported outcome scores included obesity, diabetes, poorer mental health, and a follow-up of less than 2 years. Patients treated with fasciocutaneous and muscle flaps experience comparable levels of functionality and quality of life after surgery. Flap selection should be based on defect characteristics, along with the surgeon's individual skills and preferences. A comprehensive approach that considers physical comorbidities, pain, and mental health is essential, as these factors significantly impact patient functionality and quality of life.

Underutilized Mexican crop, runner bean (Phaseolus coccineus): A comprehensive review of nutritional and functional implications

Introduction. The scarlet runner bean (Phaseolus coccineus L.), also known as the runner or ayocote bean, is one of five Phaseolus species domesticated in Mesoamerica. It holds considerable economic importance, ranking third after P. vulgaris and P. lunatus. Despite its relevance, research on its bioactive compounds and potential health benefits still needs to be conducted. Objective: This review explores the nutritional composition, anti-nutritional factors, and bioactive compound levels of P. coccineus, emphasizing their implications for consumer health. Methodology: A comprehensive literature review, following PRISMA 2020 guidelines, was conducted across electronic databases, identifying 163 relevant studies. After applying inclusion and exclusion criteria, 13 studies were selected for analysis. Results: These studies highlighted P. coccineus as a potential source of nutraceutical properties and innovative food products aimed at enhancing nutritional quality. The bioactive compounds, including antioxidants and peptides, suggest benefits in preventing chronic diseases and promoting food security. Conclusions: However, further research is required to fully understand the composition of phenolic compounds, bioactive peptides, and anti-nutritional factors in P. coccineus, promoting its consumption as a functional food and novel dietary ingredient. Expanding its use in novel food formulations could enhance its dietary value and positively impact public health.

DisorderUnetLM: Validating ProteinUnet for efficient protein intrinsic disorder prediction.

The prediction of intrinsic disorder regions has significant implications for understanding protein functions and dynamics. It can help to discover novel protein-protein interactions essential for designing new drugs and enzymes. Recently, a new generation of predictors based on protein language models (pLMs) is emerging. These algorithms reach state-of-the-art accuracy without calculating time-consuming multiple sequence alignments (MSAs). This article introduces the new DisorderUnetLM disorder predictor, which builds upon the idea of ProteinUnet. It uses the Attention U-Net convolutional network and incorporates features from the ProtTrans pLM. DisorderUnetLM achieves top results in the direct comparison with recent predictors exploiting MSAs and pLMs. Moreover, among 43 predictors on the latest CAID-2 benchmark, it ranks 1st for the NOX subset in terms of the ROC-AUC metric (0.844) and 2nd for the AP metric (0.596). For the CAID-2 PDB subset, it ranks in the top 10 (ROC-AUC of 0.924 and AP of 0.862). The code and model are publicly available and fully reproducible at doi.org/10.24433/CO.7350682.v1.

NcRNA Editing: Functional Characterization and Computational Resources.

Non-coding RNAs (ncRNAs) play crucial roles in gene expression regulation, translation, and disease development, including cancer. They are classified by size in short and long non-coding RNAs. This chapter focuses on the functional implications of adenosine-to-inosine (A-to-I) RNA editing in both short (e.g., miRNAs) and long ncRNAs. RNA editing dynamically alters the sequence and structure of primary transcripts, impacting ncRNA biogenesis and function. Notable findings include the role of miRNA editing in promoting glioblastoma invasiveness, characterizing RNA editing hotspots across cancers, and its implications in thyroid cancer and ischemia. This chapter also highlights bioinformatics resources and next-generation sequencing (NGS) technologies that enable comprehensive ncRNAome studies and genome-wide RNA editing detection. Dysregulation of RNA editing machinery has been linked to various human diseases, emphasizing the potential of RNA editing as a biomarker and therapeutic target. This overview integrates current knowledge and computational tools for studying ncRNA editing, providing insights into its biological significance and clinical applications.

Connectome-based prediction of functional impairment in experimental stroke models.

Experimental rat models of stroke and hemorrhage are important tools to investigate cerebrovascular disease pathophysiology mechanisms, yet how significant patterns of functional impairment induced in various models of stroke are related to changes in connectivity at the level of neuronal populations and mesoscopic parcellations of rat brains remain unresolved. To address this gap in knowledge, we employed two middle cerebral artery occlusion models and one intracerebral hemorrhage model with variant extent and location of neuronal dysfunction. Motor and spatial memory function was assessed and the level of hippocampal activation via Fos immunohistochemistry. Contribution of connectivity change to functional impairment was analyzed for connection similarities, graph distances and spatial distances as well as the importance of regions in terms of network architecture based on the neuroVIISAS rat connectome. We found that functional impairment correlated with not only the extent but also the locations of the injury among the models. In addition, via coactivation analysis in dynamic rat brain models, we found that lesioned regions led to stronger coactivations with motor function and spatial learning regions than with other unaffected regions of the connectome. Dynamic modeling with the weighted bilateral connectome detected changes in signal propagation in the remote hippocampus in all 3 stroke types, predicting the extent of hippocampal hypoactivation and impairment in spatial learning and memory function. Our study provides a comprehensive analytical framework in predictive identification of remote regions not directly altered by stroke events and their functional implication.

Comprehensive annotation of mutations in hallmark genes insights into structural and functional implications.

Understanding the multifaceted role of hallmark gene mutations in cancer progression is critical for developing targeted therapies. This study comprehensively analyses 344 hallmark gene mutations by mapping them to their three-dimensional protein structures using PDB data and AlphaFold models. Mutations were classified based on their locations, such as protein interfaces, ligand-binding sites, dimer interfaces, protein-DNA interfaces, and core regions. The results reveal that highly frequent mutations are located on the ligand-binding site and protein interface, highlighting their significant impact on protein function and interactions. This holistic approach bridges gaps in existing research, offering insights into the structural impacts of genetic alterations in hallmark genes, thereby informing more effective therapeutic strategies.

Dosage compensation of transposable elements in mammals.

In mammals, X-linked dosage compensation involves two processes: X-chromosome inactivation (XCI) to balance X chromosome dosage between males and females, and hyperactivation of the remaining X chromosome (Xa-hyperactivation) to achieve X-autosome balance in both sexes. Studies of both processes have largely focused on coding genes and have not accounted for transposable elements (TEs) which comprise 50% of the X-chromosome, despite TEs being suspected to have numerous epigenetic functions. This oversight is due in part to the technical challenge of capturing repeat RNAs, bioinformatically aligning them, and determining allelic origin. To overcome these challenges, here we develop a new bioinformatic pipeline tailored to repetitive elements with capability for allelic discrimination. We then apply the pipeline to our recent So-Smart-Seq analysis of single embryos to comprehensively interrogate whether X-linked TEs are subject to either XCI or Xa-hyperactivation. With regards to XCI, we observe significant differences in TE silencing in parentally driven "imprinted" XCI versus zygotically driven "random" XCI. Chromosomal positioning and genetic background impact TE silencing. We also find that SINEs may influence 3D organization during XCI. In contrast, TEs do not undergo Xa-hyperactivation. Thus, while coding genes are subject to both forms of dosage compensation, TEs participate only in Xi silencing. Evolutionary and functional implications are discussed.

Exploring Protein Functions of Gut Bacteriome and Mycobiome in Thai Infants Associated with Atopic Dermatitis Through Metaproteomic and Host Interaction Analysis.

Atopic dermatitis (AD), a prevalent allergic skin condition in children, has been closely associated with imbalances in the gut microbiome. To investigate these microbial alterations and their functional implications, we investigated protein expression, functions and interactions of the gut bacteriome and mycobiome as well as the human proteome in Thai infants with AD using integrative metaproteomic and host interaction analysis. As we observed, probiotic species, such as Lactobacillus acidophilus and Bacteroides salyersiae, were reduced in abundance in the AD group while key pathogenic bacteria and fungi, such as Streptococcus constellatus and Penicillium chrysogenum, increased in abundance. Additionally, the functional analysis of expressed proteins was enriched in response to stress and DNA repair in the bacteriome and ribosome biogenesis-related processes in the mycobiome of the AD group, potentially associated to increased reactive oxygen species (ROS), intestinal inflammation, fungal growth and microbial dysbiosis. Further, a protein-protein interactions (PPIs) network analysis incorporating the human proteome revealed 10 signature proteins related to stress and immune system processes associated with AD. Our findings propose the interactions of the key species and signature protein functions between the gut microbes and the human host in response to AD in Thai infants. To our knowledge, this study serves as the first framework for monitoring bacteriome-mycobiome-human gut studies associated with AD and other allergic diseases in infants.

USP21-EGFR signaling axis is functionally implicated in metastatic colorectal cancer

The emerging role of ubiquitin-specific peptidase 21 (USP21) in stabilizing Fra-1 (FOSL1) highlights its involvement in promoting colorectal cancer (CRC) metastasis. Additionally, a reciprocal link between EGFR signaling and Fra-1 activation has been identified, mediated through matrix metalloproteinases (MMPs). However, the functional implications of the USP21-EGFR signaling axis in metastatic CRC (mCRC) are not fully understood. To investigate the clinical correlation between USP21 and EGFR expression, RNA-Seq data from tumor tissues (n = 27) and matched normal tissues (n = 27) of 27 mCRC patients were analyzed. Functional studies were performed, including the use of CRISPR/Cas9 to generate USP21-knockout (USP21-KO) CRC cells, in vitro assays for cancer progression and tumor formation, in vivo xenograft assays in NSG mice. Additionally, the therapeutic effect of the USP21 inhibitor, BAY-805, was evaluated. We found that elevated levels of USP21 and EGFR expression in mCRC patients were associated with poorer survival outcomes. Mechanistically, USP21 was found to enhance EGFR stability by deubiquitinating EGFR, leading to reduced EGFR degradation. USP21-KO colon cancer cells exhibited significantly reduced proliferation, migration, colony formation, and 3D tumor spheroid formation in response to EGF. Furthermore, the tumorigenic activity in vivo was markedly diminished in NSG mice xenografted with USP21-KO colon cancer cells. Importantly, BAY-805 demonstrated a notable inhibitory effect on the formation of 3D tumor spheroids in colorectal cancer cells stimulated with EGF. These findings suggest that USP21 could be a valuable therapeutic target and predictive biomarker for managing mCRC driven by EGF.

Exploring the potential of Braingame Brian for executive function improvement in Spanish-speaking children with ADHD: A pilot study

ABSTRACT Considering the implications of executive function (EF) in the core symptoms of attention deficit hyperactivity disorder (ADHD), further research is required on strategies such as therapies, treatments, and rehabilitation programs focused on improving EF. This study aimed to assess the potential of an EF training program called “Braingame Brian” in improving working memory, inhibition, and cognitive flexibility in children with ADHD. The programme was developed in the Netherlands and has been shown to be effective in pilot studies of ADHD populations conducted in this country. However, it has not been used before in the Spanish-speaking population. A total of 41 children (aged 8–12 years) were assigned to the EF training or waitlist control groups. The intervention consisted of a 25-session training programme of approximately 45 min per day for nine consecutive weeks. Treatment outcomes were assessed using cognitive tasks of the trained EF, as well as evaluations of EF behaviors by parents and teachers. The initial findings suggest that the implementation of the Braingame Brian programme may be associated with improvements in working memory, inhibition, and cognitive flexibility. These preliminary results also indicate the potential for enhancements in parents’ and teachers’ perceptions of EF difficulties in children with ADHD.

Morphological Research Directions at Neuroscience-Related Institutes of the German Max Planck Society, 1948–2002

This article explores the continuation of the pathological morphology research program at neuroscience-related institutes from the Kaiser Wilhelm Society after World War II. It covers the research tradition in the brain sciences, which can be described by an emphasis on gross anatomy, the functional implications of morphological substrates, and the analysis of neurohistological research paths of the human brain in comparative contexts. To enable examination of the assimilation processes of the Kaiser Wilhelm Society’s legacy, the decisions and developments of the newly created Max Planck Society in Germany and its early brain science facilities will be assessed for the time period from 1948 to 2002. Pertaining to these overall developments in the Max Planck Society, a persistence of the “morphological paradigm” (microanatomy, pathology, comparative anatomy, etc.) can be identified as lasting until the 1960s. The newer “functional paradigm” (neurophysiology, electroencephalography, cybernetics, and behavioral studies) only became more visible when the first generations of the scientific leaders left their positions in this national research society. It is of note that many directors and scientific members, including Detlev Ploog (1920–2005), Dieter Lux (1924–1995), Georg W. Kreutzberg (1932–2019), Otto Detlev Creutzfeldt (1927–1992), Hans Thönen (1928–2012), Manfred Eigen (1927–2019), Erwin Neher (b. 1944), Hartmut Wekerle (b. 1944), Albert Hertz (1921–2018), Bert Sakmann (b. 1942), and Wolf Singer (b. 1943) were part of the American Neuroscience Research Program as associates, members, conference chairs, or trainees. Likewise, they joined the Society for Neuroscience early on, after it had emerged from the Neuroscience Research Program’s steering committee in 1969. This article seeks to clarify the context of the reorganization of the brain research-related Max Planck Institutes during the postwar period after World War II. Its trajectory includes the location of the institutes, their previous involvement in applied research, and personal continuities in scientific leadership positions, contributing to debates during the first decades of the Max Planck Society. The lens of pathological brain research emerges here as an important viewpoint to aid the understanding of the continued impact and concerns over the dominant morphological approaches in postwar West German neurology and psychiatry.

Genetic Insights Into Epidermolysis Bullosa: Identification of Novel Variants in Tunisian Patients.

Epidermolysis Bullosa (EB) is a group of genetic skin disorders characterized by extreme skin fragility and blistering. In North African countries, including Tunisia, complex genetic and phenotypic diversity is entangled with a scarcity of scientific research on EB. This lack of knowledge presents a distinct challenge in terms of diagnostic accuracy and patient care. Our study cohort includes 10 Tunisian patients with EB whose genetic profiles were investigated by exome sequencing. In silico analysis was conducted to determine the functional impact of three novel variants. We revealed ten genetic variants, including three novel ones within the COL7A1 and DST genes. The in silico analysis shed light on the potential structural and functional implications of these novel variants. By establishing the correlation between clinical features and genetic alterations, we have expanded the existing database of disease-causing variants associated with EB in Northern Africa. Our study fills a critical knowledge gap in the North African context, where the scarcity of clinical database and genetic testing in addition to the genetic diversity necessitates comprehensive research. Our findings have the potential to improve diagnosis and management strategies for EB patients in low and middle-income countries across the region, especially through the integration of exome sequencing and in silico analysis.

Experimental Myopia Results in Peripapillary Ganglion Cell and Astrocyte Reorganization with No Functional Implications During Early Development.

Myopic eye growth induces mechanical stretch, which can lead to structural and functional retinal alterations. Here, we investigated the effect of lens-induced myopic growth on the distribution of retinal ganglion cells (RGCs), glial fibrillary acidic protein (GFAP) expression and intensity, and peripapillary retinal nerve fiber layer (ppRNFL) thickness in common marmosets (Callithrix jacchus) induced with myopia continuously for six months, using immunohistochemistry and spectral-domain optical coherence tomography. We also explored the relationship between cellular structural parameters and the photopic negative response (PhNR) using full-field electroretinography. Marmosets induced with myopia for six months developed axial myopia, had a thinner ppRNFL, reduced peripapillary ganglion cell (≈20%) and astrocyte density (≈42%), increased panretinal GFAP expression (≈42%) and nasal mid-periphery staining intensity (≈81%) compared to age-matched controls. Greater degrees of myopia and vitreous elongation were associated with reduced peripapillary RGCs and astrocyte density, and increased GFAP expression and intensity. These cellular structural changes did not show a significant relationship with the features of the PhNR, which remained unchanged. The outcomes of this study suggest that myopia induces a reorganization of the peripapillary inner retina at the cellular level that may not result in measurable functional repercussions at this stage of myopia development.

Evaluation of Papain-Urea for Enzymatic Debridement of Coagulation Zones Following Ablative Fractional Laser Treatment.

Ablative fractional CO2 laser (10,600 nm) treatment creates an array of microscopic treatment zones composed of an ablation zone (AZ) surrounded by a denatured coagulation zone (CZ). The CZ is believed to play a functional role in skin tightening, posttreatment inflammation, and laser-assisted drug delivery. This study investigates the viability of enzymatic post-processing to remove the CZ without affecting the surrounding tissue. Ex vivo skin samples were treated with either control, papain, urea, or papain-urea solutions before being covered with occlusive dressing and incubated at 37°C for 1 h. Tissue viability as well as AZ and CZ geometries were assessed histologically. Treatment with all three experimental solutions resulted in a decrease in CZ. The largest average reduction in CZ area was observed in the papain-urea group (44%, p < 0.001), followed by the papain (14%, p < 0.001) and urea (11%, p < 0.001) only groups. Only the papain-urea group showed a significant increase in AZ (14%) and changes in lesion geometry. This exploratory study of enzymatic post-processing with papain-urea highlighted the potential of selectively removing the CZ after treatment with ablative fractional laser therapy. If results can be translated to in vivo studies, these findings could expand the use of high-fluence CO2 laser therapy with functional implications for lowering posttreatment recovery time, providing clinicians more control over skin tightening, and enabling a broader range of laser-assisted drug delivery.

Comparison of the mechanical properties of porcine buccal mucosa and ureter and the clinical implications.

Buccal mucosal grafts have a well-established role in urology regarding the management of ureteric stricture disease. Despite its established use as a graft material there is a lack of data on the mechanical properties of buccal mucosa. We aim to compare the passive mechanical properties of porcine buccal mucosa with the ureter. Buccal mucosa (n = 20) and ureteric specimens (n = 21) were harvested from 19 domestic pigs at the time of euthanasia. Mechanical testing was performed using a uniaxial tensometer to generate stress-strain curves. From these curves, ultimate tensile strength and elastic modulus were calculated. Data was analysed, and one-way ANOVA testing was used to assess for significance variation in mechanical response due to direction of testing, and between tissue types. Porcine ureteric specimens displayed mechanical anisotropy, with a significant difference in the elastic modulus depending on the direction of testing (p = 0.005), and a higher mean ultimate tensile strength in the longitudinal (498.09kPa) compared to the transverse (263.99kPa) direction (p = 0.0005). Buccal mucosa was isotropic with no significant difference in elastic modulus or ultimate tensile strength according to direction of testing. Comparison of tissue types showed a significantly greater mean ultimate tensile strength in the longitudinal direction (p = 0.002) in ureter compared to buccal mucosa. We present the first comparison of the mechanical properties of buccal mucosa with ureter, and demonstrate significant variation in elastic modulus and ultimate tensile strength between the tissue types. These findings have important clinical implications for physiological function and in the design of alternative approaches for reconstruction in buccal mucosa grafted ureters.

Subcellular Localization Guides eNOS Function.

Nitric oxide synthases (NOS) are enzymes responsible for the cellular production of nitric oxide (NO), a highly reactive signaling molecule involved in important physiological and pathological processes. Given its remarkable capacity to diffuse across membranes, NO cannot be stored inside cells and thus requires multiple controlling mechanisms to regulate its biological functions. In particular, the regulation of endothelial nitric oxide synthase (eNOS) activity has been shown to be crucial in vascular homeostasis, primarily affecting cardiovascular disease and other pathophysiological processes of importance for human health. Among other factors, the subcellular localization of eNOS plays an important role in regulating its enzymatic activity and the bioavailability of NO. The aim of this review is to summarize pioneering studies and more recent publications, unveiling some of the factors that influence the subcellular compartmentalization of eNOS and discussing their functional implications in health and disease.

Regulation of volume-regulated anion channels alters sensitivity to platinum chemotherapy.

Cisplatin-based chemotherapy is used across many common tumor types, but resistance reduces the likelihood of long-term survival. We previously found the puromycin-sensitive aminopeptidase, NPEPPS, as a druggable driver of cisplatin resistance in vitro and in vivo and in patient-derived organoids. Here, we present a general mechanism where NPEPPS interacts with the volume-regulated anion channels (VRACs) to control cisplatin import into cells and thus regulate cisplatin response across a range of cancer types. We also find the NPEPPS/VRAC gene expression ratio is a predictive measure of cisplatin response in multiple cancer cohorts, showing the broad applicability of this mechanism. Our work describes a specific mechanism of cisplatin resistance, which, given the characteristics of NPEPPS as a drug target, has the potential to improve cancer patient outcomes. In addition, we describe an intracellular mechanism regulating VRAC activity, which is critical for volume regulation in normal cells - a finding with functional implications beyond cancer.

Methodological Variation Among Studies Evaluating Pain Processing in Tendinopathy: A Scoping Review.

Background/Objectives: Tendinopathy is a condition associated with pain and limited function. While upper and lower extremity tendinopathies may have different functional implications, there have been a number of reports supporting different patterns of dysfunction in pain processing and inhibition. The purpose of this scoping review was to examine the methods across studies examining pain processing in patients with upper and lower extremity tendinopathy. Methods: Five electronic databases (PubMed, Scopus, CINAHL, the Cochrane Library, and SPORTDiscus) and gray literature sources were searched from inception through 15 April 2024, using appropriate keywords and relevant synonyms. Results: In total, 3219 titles were retrieved from the searches, with 43 studies retained for final inclusion. Of the 43 studies, 22 were specific to upper extremity tendinopathies, 19 were specific to lower extremity tendinopathies, and 2 studies included mixed samples. Physical testing to detect nervous system sensitization was most commonly performed using pressure pain thresholds. Although infrequent, questionnaire instruments were used mostly to include the central sensitization inventory. Substantial variation was noted across studies in mode of testing and instruments used, while patient demographics and inclusion criteria were not clearly reported in many instances. Thirty-one studies (72%) reported nervous system sensitization or dysfunction in tendinopathy, while 13 (28%) did not. Conclusions: While the difference between pain processing in tendinopathy is likely multifactorial, the results of this review identified substantial variability in methodology used and reporting in tendon pain research. As inconsistency in evidence can limit clinical guidance, efforts to standardize tendinopathy pain research appear warranted.