In vivo PIWI slicing in mouse testes deviates from rules established in vitro [LETTER TO THE EDITOR]

AlexandrosSfakianakis shared this article with you from Inoreader In vivo PIWI slicing in mouse testes deviates from rules established in vitro [LETTER TO THE EDITOR] via RNA current issue Argonautes are small RNA-binding proteins, with some having small RNA-guided endonuclease (slicer) activity that cleaves target nucleic acids. One cardinal rule that is structurally defined is the inability of slicers to cleave target RNAs when nucleotide mismatches exist between the paired small RNA and the target at the cleavage site. Animal-specific PIWI clade Argonautes associate with PIWI-interacting RNAs (piRNAs) to silence transposable elements in the gonads, and this is essential for fertility. We previously demonstrated that purified endogenous mouse MIWI fails to cleave mismatched targets in vitro. Surprisingly, here we find using knock-in mouse models that target sites with cleavage-site mismatches at the 10th and 11th piRNA nucleotides are precisely sliced in vivo. This is identical to the slicing outcome in knock-in mice where targets are base-paired perfectly with the piRNA. Additionally, we find that pachytene piRNA-guided slicing in both these situations failed to initiate phased piRNA production from the specific target mRNA we studied. Instead, the two slicer cleavage fragments were retained in PIWI proteins as pre-piRNA and 17–19 nt by-product fragments. Our results indicate that PIWI slicing rules established in vitro are not respected in vivo, and that all targets of PIWI slicing are not substrates for piRNA biogenesis. View on Web

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Designing a Prolonged Method of Therapeutic Delivery to Support Rehabilitation From Ototoxic Damage in a Schwann Cell Model

AlexandrosSfakianakis shared this article with you from Inoreader Designing a Prolonged Method of Therapeutic Delivery to Support Rehabilitation From Ototoxic Damage in a Schwann Cell Model via Otology & Neurotology - Published Ahead-of-Print Hypothesis The ototoxicity of gentamicin and cisplatin can be evaluated with a Schwann cell model to screen for otoprotective agents that can be encapsulated into poly (lactic-co-glycolic acid) (PLGA) microparticles for drug delivery to the inner ear. Background Aminoglycosides and cisplatin are widely prescribed but known to cause ototoxicity. There is strong evidence that compromise to Schwann cells ensheathing inner ear afferent neurons results in inner ear dysfunction mimicking drug-induced ototoxicity. There is a need for a model for ototoxic demyelination to screen medications for protective potential and to subsequently target and tune the delivery of any promising agents. Methods RT4-D6P2T rat schwannoma cells were used as a Schwann cell model to assess gentamicin and cisplatin toxicity and to screen for protective agents. Cell viability was evaluated with the MTT cell proliferation assay. N-acetylcysteine (NAC) was encapsulated into a PLGA microparticle, and its elution profile was determined. Results The estimated 50% lethal concentration dose for gentamicin was 805.6 μM, which was 46-fold higher than that for cisplatin (17.5 μM). In several trials, cells dosed with NAC and cisplatin demonstrated a 22.6% (p View on Web

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Looking for Synergies in Healthy Upper Limb Motion: A Focus on the Wrist

AlexandrosSfakianakis shared this article with you from Inoreader Looking for Synergies in Healthy Upper Limb Motion: A Focus on the Wrist via Neural Systems and Rehabilitation Engineering, IEEE Transactions on - new TOC Recent studies on human upper limb motion highlighted the benefit of dimensionality reduction techniques to extrapolate informative joint patterns. These techniques can simplify the description of upper limb kinematics in physiological conditions, serving as a baseline for the objective assessment of movement alterations, or to be imple mented in a robotic joint. However, the successful description of kinematic data requires a proper alignment of the acquisitions to correctly estimate kinematic patterns and their motion variability. Here, we propose a structured methodology to process and analyze upper limb kinematic data, considering time warping and task segmentation to register task execution on a common normalized completion time axis. Functional principal component analysis (fPCA) was used to extract patterns of motion of the wrist joint from the data collected by healthy participants performing activities of daily living. Our results suggest that wrist trajectories can be described as a linear combination of few functional principal components (fPCs). In fact, three fPCs explained more than 85% of the variance of any task. Wrist trajectories in the reaching phase of movement were highly correlated among participants and significantly more than trajectories in the manipulation phase ( $text{p}< 0.01$ ). The se findings may be useful in simplifying the control and design of robotic wrists, and could aid the development of therapies for the early detection of pathological conditions. View on Web

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Surface Electromyography-Based Analysis of the Lower Limb Muscle Network and Muscle Synergies at Various Gait Speeds

AlexandrosSfakianakis shared this article with you from Inoreader Surface Electromyography-Based Analysis of the Lower Limb Muscle Network and Muscle Synergies at Various Gait Speeds via Neural Systems and Rehabilitation Engineering, IEEE Transactions on - new TOC Gait movement is an important activity in daily human life. The coordination of gait movement is directly affected by the cooperation and functional connectivity between muscles. However, the mechanisms of muscle operation at different gait speeds remain unclear. Therefore, this study addressed the gait speed effect on the changes in co operative modules and functional connectivity between muscles. To this end, surface electromyography (sEMG) signals were collected from eight key lower extremity muscles of twelve healthy subjects walking on a treadmill at high, middle, and low motion speeds. Nonnegative matrix factorization (NNMF) was applied to the sEMG envelope and intermuscular coherence matrix, yielding five muscle synergies. Muscle functional networks were constructed by decomposing the intermuscular coherence matrix, revealing different layers of functional muscle networks across frequencies. In addition, the coupling strength between cooperative muscles grew with gait speed. Different coordination patterns among muscles with changes in gait speed related to the neuromuscular system regulation were identified. View on Web

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Fasting Plasma Glucose Increase and Neutrophil-to-Lymphocyte Ratio as Risk Predictors of Clinical Outcome of COVID-19 Pneumonia in Type 2 Diabetes Mellitus

AlexandrosSfakianakis shared this article with you from Inoreader Fasting Plasma Glucose Increase and Neutrophil-to-Lymphocyte Ratio as Risk Predictors of Clinical Outcome of COVID-19 Pneumonia in Type 2 Diabetes Mellitus via Experimental and Clinical Endocrinology & Diabetes Exp Clin Endocrinol Diabetes DOI: 10.1055/a-2009-6937 Aim of the study To evaluate fasting plasma glucose (FPG) increase and neutrophil-to-lymphocyte ratio (NLR) as risk predictors of severe clinical outcome of COVID-19 pneumonia in type 2 diabetes mellitus (T2DM) hospitalised patients. Patients and methods Type 2 diabetes mellitus (T2DM) patients hospitalised between March 2020 and February 2021 were studied retrospectively. The NLR ratio at admission and FPG increase (day 7, day with maximal FPG) were evaluated in association with the clinical progression of SARS-CoV-2 infection. Results Three hundred patients (165 men, 135 women) were included in the study. The mean age was 67.17±8.65 years. Severe COVID-19 pneumonia was diagnosed in 170 patients (56.7%). Fifty-four patients (18%) were intubated and 49 (16.3%) died. Greater increase in FPG (79.5 vs. 44.5 mg/dL for day 1–7, p<0.001; and 113.5 vs. 75 mg/dL for day 1-day with maximum glucose value, p<0.001) and higher NLR at admission (10.65 vs. 6.85) were seen in patients with need of high-flow oxygen compared to those without need, and they were associated with a higher probability of intubation and death. Conclusion FPG increase and NLR could be significant risk predictors of severe COVID-19 pneumonia in T2DM hospitalised patients. [...] Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany Article in Thieme eJournals: Table of contents  |  Abstract  |  Full text View on Web

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Analysis of Imaging Results for Semisitting Compared with Supine Positioning in the Retrosigmoid Approach for Resection of Cerebellopontine Angle Vestibular Schwannomas

AlexandrosSfakianakis shared this article with you from Inoreader Analysis of Imaging Results for Semisitting Compared with Supine Positioning in the Retrosigmoid Approach for Resection of Cerebellopontine Angle Vestibular Schwannomas via Otology & Neurotology Current Issue Objective To compare the completeness of resection of vestibular schwannomas using three-dimensional segmented volumetric analysis of pre- and postoperative magnetic resonance imaging (MRI) of patients undergoing supine and semisitting positioning for the retrosigmoid approach. Study Design Retrospective chart review. Setting Tertiary medical center. Patients Patients with vestibular schwannomas undergoing surgical resection via the retrosigmoid approach. Intervention(s) Tumor resection via the retrosigmoid approach with different patient positioning: standard supine versus semisitting. Main Outcome Measure(s) Preoperative versus postoperative three-dimensional segmented volumetric MRI analysis of vestibular schwannomas. Results A total of 43 patients (15 supine and 28 semisitting) underwent retrosigmoid craniotomy for resection of vestibular schwannomas. For the conventional supine and semisitting positioning, mean preoperative tumor volumes were 12.65 and 8.73 cm3 (p = 0.15), respectively. Postoperative mean tumor volumes for the supine and semisitting positions were 2.09 and 0.48 cm3 (p = 0.13), respectively. There were 11 cases of postoperative sigmoid sinus thrombosis, 3 in the conventional supine group and 8 in the semisitting groups, and there were 6 cases of postoperative cerebrospinal fluid leaks, all in the semisitting group. The mean House–Brackmann scores for the supine and semisitting groups were 2.9 and 2.3, respectively. There was no statistically significant difference between groups in the rates of these or any other postoperative complications. Conclusions The semisitting position for the suboccipital retrosigmoid approach for vestibular schwannoma resection does not compromise the ability to adequately resect the tumor as seen by volumetric MRI results. Further studies are needed to establish the safety of this position compared with the traditional supine approach. View on Web

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Esophageal Glomus Tumors: Rare Neoplasms with Aggressive Clinical Behavior

AlexandrosSfakianakis shared this article with you from Inoreader Esophageal Glomus Tumors: Rare Neoplasms with Aggressive Clinical Behavior via Histopathology Aims Glomus tumors are neoplasms with perivascular smooth muscle differentiation, which rarely occur in the esophagus and may behave aggressively in this site based upon prior case reports. This study describes the clinicopathologic features of 3 esophageal glomus tumors diagnosed at 2 large academic institutions between 1984 and 2022. Methods and Results Three cases of esophageal glomus tumors were identified. Patients included 2 females and 1 male, with an age range of 19-65 years. All 3 tumors behaved in a malignant fashion, with metastases to various sites (lymph nodes, lung, pericardium, pleura, diaphragm, scalp). One patient developed an aorto-esophageal fistula, resulting in a fatal hemorrhage. Tumors ranged in size from 4.5 to 8.1 cm. Histologically, all tumors had a multinodular, perivascular growth pattern. The neoplasms showed varying degrees of cytologic atypia and spindling, elevated mitotic activity (2-12 mitotic figures per 10 high-power fields), and necrosis was seen in in 2 cases. All tumors expressed smooth muscle actin by immunohistochemistry, and harbored NOTCH gene alterations (MIR143::NOTCH2 fusion in 2 cases; NOTCH3 rearrangement and NOTCH1 point mutation in 1 case). An ATRX splicing mutation in exon 10 was also identified in 1 case. Conclusions Esophageal glomus tumors pose diagnostic challenges given their rarity at this site but can be recognized by their characteristic perivascular growth pattern, round central nuclei, and supportive ancillary studies. Given the propensity for aggressive behavior in this location, we recommend management by a multidisciplinary sarcoma team for optimal outcome. View on Web

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STAT3 regulates 5‐Fu resistance in human colorectal cancer cells by promoting Mcl‐1‐dependent cytoprotective autophagy

AlexandrosSfakianakis shared this article with you from Inoreader STAT3 regulates 5‐Fu resistance in human colorectal cancer cells by promoting Mcl‐1‐dependent cytoprotective autophagy via Cancer Science Abstract Chemoresistance to 5-Fluorouracil (5-Fu)-based chemotherapy is one of the primary reasons for the failure of colorectal cancer (CRC) management. STAT3 can mediate tumor drug resistance through a variety of diverse mechanisms. Nonetheless, the underlying mechanisms of STAT3-induced 5-Fu resistance in CRC are still poorly understood. Here, we aimed to investigate the potential mechanism(s) of STAT3-induced 5-Fu resistance in CRC. Quantitative RT-PCR and Western blot were used to test the expression of STAT3 and Mcl-1 in chemosensitive and chemoresistant CRC tissues and cell lines. After overexpression or knockdown of STAT3 or Mcl-1, and/or treated with or without 5-Fu or chloroquine (CQ), we tested cell viability, inhibitory concentration 50% (IC50) value of 5-FU, cell apoptosis, proliferation, migration, and autophagy. STAT3 and Mcl-1 were significantly upregulated in the chemoresistant CRC tissues and cell lines, and STAT3 positively regulated Mcl-1. Functional studies demonstrated that STAT3 promoted 5-Fu resistance in CRC. Mechanistically, STAT3 triggered autophagy via Mcl-1 to induce cancer chemoresistance. Our results show that STAT3 regulates 5-Fu resistance in CRC by promoting Mcl-1-dependent cytoprotective autophagy. Our results provide a novel role of STAT3 and may offer a new approach for managing CRC 5-Fu resistance. View on Web

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Investigation of Shared Genetic Risk Factors Between Parkinson's Disease and Cancers

AlexandrosSfakianakis shared this article with you from Inoreader Investigation of Shared Genetic Risk Factors Between Parkinson's Disease and Cancers via Movement Disorders Abstract Background Epidemiological studies that examined the association between Parkinson's disease (PD) and cancers led to inconsistent results, but they face a number of methodological difficulties. Objective We used results from genome-wide association studies (GWASs) to study the genetic correlation between PD and different cancers to identify common genetic risk factors. Methods We used individual data for participants of European ancestry from the Courage-PD (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease; PD, N = 16,519) and EPITHYR (differentiated thyroid cancer, N = 3527) consortia and summary statistics of GWASs from iPDGC (International Parkinson Disease Genomics Consortium; PD, N = 482,730), Melanoma Meta-Analysis Consortium (MMAC), Breast Cancer Association Consortium (breast cancer), the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (prostate cancer), International Lung Cancer Consortium (lung cancer), and Ovarian Cancer Association Consortium (ovarian cancer) (N comprised between 36,017 and 228,951 for cancer GWASs). We estimated the genetic correlation between PD and cancers using linkage disequilibrium score regression. We studied the association between PD and polymorphisms associated with cancers, and vice versa, using cross-phenotypes polygenic risk score (PRS) analyses. Results We confirmed a previously reported positive genetic correlation of PD with melanoma (Gcorr = 0.16 [0.04; 0.28]) and reported an additional significant positive correlation of PD with prostate cancer (Gcorr = 0.11 [0.03; 0.19]). There was a significant inverse association between the PRS for ovarian cancer and PD (odds ratio [OR] = 0.89 [0.84; 0.94]). Conversely, the PRS of PD was positively associated with breast cancer (OR = 1.08 [1.06; 1.10]) and inversely associated with ovarian cancer (OR = 0.95 [0.91; 0.99]). The association between PD and ovarian cancer was mostly driven by rs183211 located in an intron of the NSF gene (17q21.31). Conclusions We show evidence in favor of a contribution of pleiotropic genes to the association between PD and specific cancers. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA. View on Web

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Exposure to Particulate Matter and Respirable Crystalline Silica in Tunnel Construction Workers Using Tunnel Boring Machines

AlexandrosSfakianakis shared this article with you from Inoreader Exposure to Particulate Matter and Respirable Crystalline Silica in Tunnel Construction Workers Using Tunnel Boring Machines via Annals of Work Exposures and Health Advance Access Abstract Objectives This study aimed to assess the exposure to a selection of aerosols and gases in the work environment for workers performing tunnel construction using tunnel boring machines (TBMs), to identify determinants of exposure based on the information available and to calculate robust estimates of exposure using a statistical model. The focus was particulate matter (PM) and respirable crystalline silica (RCS). In addition, concentrations of nitrogen dioxide (NO2), elemental carbon (EC), and oil mist were assessed. Methods Personal sampling was conducted from February 2017 to February 2019. PM in the thoracic and the respirable aerosol fractions was collected, and RCS was determined in the respirable aerosol fraction. Context information was collected on questionnaires. Because the workers could participate in the sampling more than once and multiple measurements were performed on the same date a mixed model was use d in the analysis. Concentrations of PM and RCS are presented as estimated and measured geometric means (GMest and GMmea) and estimated arithmetic mean (AMest) in addition to the median. Measured concentrations of NO2, EC, and oil mist are presented as geometric means. Results A total of 290 and 289 personal samples of PM in the thoracic and respirable aerosol fractions were available for analysis, respectively. Work title/work location, type of work (production, maintenance, or a combination of the two), and date of sampling were identified as determinants of exposure. Workers in the front of the TBMs had the highest exposure to PM and RCS. The GMest of RCS exposure varied from 35 to 413 μg m–3 depending on the work title. The geometric standard deviations for measured RCS concentrations by work title ranged from 1.6 to 3.5. A total of 16 samples of NO2 and EC and 12 samples of oil mist were co llected. Maximum values of NO2 and EC were 54 µg m–3 and 23 µg m–3, respectively. The maximum measured value of oil mist was 0.08 mg m–3. Conclusions All TBM workers were exposed to PM and RCS. Exposure to RCS may be substantial, and workers in front of the TBM were exposed to the highest concentrations of both PM and RCS. A day-to-day variation was found, probably caused by differences in drilling activities. Preventive measures are warranted to keep the exposure to PM and consequently the exposure to RCS as low as possible to protect the health of workers in tunnel construction. View on Web

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