Search

In this paper, we study quotients of a numerical semigroups with RF (Row-Factorization) matrices. We prove a formula for the Frobenious number of quotients of some families of numerical semigroups. Moreover, we examine half of the numerical semigroups, pseudo-symmetric numerical semigroups.

The Sorting and Assembly Machinery (SAM) Complex functions in the assembly of β-barrel in the mitochondrial membrane. The SAM complex is made up of three subunits, Sam35, Sam37, and Sam50. While both Sam35 and Sam37 are peripheral membrane proteins that are not required for survival, Sam50 interacts with the MICOS complex to connect the inner and outer mitochondrial membranes and forms the mitochondrial intermembrane space bridging (MIB) complex. Specifically, Sam50 stabilizes the MIB complex for protein transport, respiratory chain complex assembly, and cristae integrity regulation. To structurally form and sustain the cristae, the MICOS complex assembles at the cristae junction and binds directly to Sam50. However, the role of Sam50 in overall mitochondrial structure and metabolism in skeletal muscle remains unclear. Here, we use SBF-SEM and Amira software perform 3D renderings of mitochondria and autophagosomes in human myotubes. Beyond this, Gas Chromatography-Mass Spectrometry-based metabolomics was utilized to interrogate differential changes of the metabolites in wild-type (WT) andSam50deficient myotubes. Ablation ofSam50, revealed increases in ß-Alanine, propanoate, and phenylalanine, and tyrosine metabolism. Additionally, we observed that mitochondrial fragmentation and autophagosome formation was increased inSam50-deficient myotubes compared to control myotubes. Beyond this, the metabolomic analysis revealed an increase in amino acid metabolism and fatty acid metabolism. XF24 Seahorse Analyzer shows that oxidative capacity is further impaired upon ablation ofSam50in both murine and human myotubes. Together, these data suggest Sam50 is critical for establishing and maintaining mitochondria, mitochondrial cristae structure, and mitochondrial metabolism.

SummaryOPA1 is a dynamin-related GTPase that modulates various mitochondrial functions and is involved in mitochondrial morphology. There are eight different isoforms of OPA1 in humans that are expressed as short or long-form isoforms. These isoforms contribute to OPA1’s ability to control mitochondrial functions. However, isolating OPA1 isoforms through western blot has been a difficult task. To address this issue, we outline an optimized western blot protocol to isolate different isoforms of OPA1 on the basis of different antibodies. This protocol can be used to study changes in mitochondrial structure and function.Tweetable AbstractWestern blot protocol optimization to visualize OPA1 isoforms.HighlightsProtocol for isolating OPA1 isoforms in skeletal muscle tissueSteps for running isolated skeletal muscle cells from muscle tissue on a gelHow to collect samples in preparation for western blottingDetection of OPA1 isoformsGraphical AbstractKey Resources TableMethod SummarySamples for western blot analysis are isolated from lysed cells, loaded onto a gel, and ran using optimized conditions to better isolate OPA1 isoforms. Samples are transferred to a membrane to for incubation and protein detection using OPA1 antibodies.

Isolation of skeletal muscles allows for the exploration of many complex diseases. Fibroblasts and myoblast play important roles in skeletal muscle morphology and function. However, skeletal muscles are complex and made up of many cellular populations and validation of these populations is highly important. Therefore, in this article, we discuss a comprehensive method to isolate mice skeletal muscle, create satellite cells for tissue culture, and use immunofluorescence to validate our approach.Novel imaging technology is increasing our ability to visualize and analyze cellular organelles and compartments.Tweetable AbstractProper antibody validation of cellular populations within isolated skeletal muscle can lead to better elucidation of skeletal muscle structure and function, and their roles in complex diseases.Graphical AbstractMethod SummaryMyoblasts are isolated from mouse limb muscles. They are plated for immunofluorescence-based validation using confocal microscopy. This method demonstrates the need for reliable antibodies to correctly determine and differentiate between cellular populations within isolated skeletal muscles.

SummaryProximity ligation assays (PLA) use specific antibodies to detect endogenous protein-protein interactions. PLA is a highly useful biochemical technique that allows two proteins within close proximity to be visualized with fluorescent probes amplified by PCR. While this technique has gained prominence, the use of PLA in mouse skeletal muscle (SkM) is novel. In this article, we discuss how the PLA method can be used in SkM to study the protein-protein interactions within mitochondria-endoplasmic reticulum contact sites (MERCs).Tweetable AbstractProximity Ligation Assays can be used in skeletal muscle tissue and myoblasts to explore the protein-protein interactions involved in MERC sites.HighlightsSkeletal muscle tissue and cells are plated on glass coverslips for evaluation by proximity ligation assay (PLA).Following fixation, cells are probed and stained for Mfn1, Mfn2, mitochondria, and ER and imaged using fluorescence confocal microscopy.This method shows that PLA can be used in mouse SkM and is adaptable to other models.Protocol for detection of protein-protein interactions using PLA.Graphical AbstractKey Resources Table

Metabolic water, the water that is produced from O2 during respiration, carries an isotopic signature that can be different from that of the water the cell is growing in. It has been well known that for large land organisms, like birds and mammals, metabolic water contributes significantly to the water balance and has an important control on the signature of the oxygen-stable-isotopes of the water inside the organism. This isotopic signature is then carried over through isotopic equilibrium to other oxygen-bearing species like phosphate. However, for small organisms like bacteria, it has been widely assumed for decades, that the large surface area to volume ratio enables a fast exchange of the cell water with the ambient water. As a result, the isotopic signature of the metabolic water will be heavily diluted and erased. In contrast, a recent work reported indirect evidence of significant control of metabolic water on the oxygen isotopes inside microbial cells. This indirect evidence is based on deviations of oxygen isotopes in phosphate from the expected equilibrium with the ambient water. Here we report the results of experiments that directly tested the possible contribution of metabolic water to phosphate oxygen isotopes in bacteria. We found that ambient water did control the oxygen isotopes in the phosphate. However, there were large deviations from the expected equilibrium. Nevertheless, we found that these deviations were not correlated with the isotopic composition of metabolic water. Hence, other mechanisms, which will be discussed, are responsible for these deviations.

Mitochondria are required for energy production and even give brown adipose tissue (BAT) its characteristic color due to their high iron content and abundance The physiological function and bioenergetic capacity of mitochondria are connected to the structure, folding, and organization of its inner-membrane cristae. During the aging process, mitochondrial dysfunction is observed, and the regulatory balance of mitochondrial dynamics is often disrupted, leading to increased mitochondrial fragmentation in aging cells. Therefore, we hypothesized that the morphological changes in BAT mitochondria and cristae observed across aging would reflect alterations to energy dynamics. We developed a quantitative three-dimensional (3D) electron microscopy approach to map cristae network organization in mouse BAT to test this hypothesis. Using this methodology, we investigated the 3D morphology of mitochondrial cristae in adult (3-month) and aged (2-year) murine BAT tissue via serial block face-scanning electron microscopy (SBF-SEM) and3D reconstruction software for manual segmentation, analysis, and quantification. Upon investigation, we found increases in mitochondrial volume, surface area, and complexity and decreased sphericity in aged BAT. Cristae examination revealed decreased cristae volume, perimeter, and complexity, with cristate appearing more heterogeneous. Overall, these data define the nature of the mitochondrial structure in BAT, showing loss of cristae definition across aging, suggesting alterations in functionality and bioactivity.Graphical AbstractWorkflow overview of serial block facing-scanning electron microscopy (SBF-SEM), data segmentation, and 3D analysis of mitochondria using Amira software in murine BAT.

Choosing a mentor requires a certain level of introspection for both the mentor and the mentee. The dynamics of mentorship may change depending on the academic status of the mentee. Regardless, mentors should help their trainees grow both academically and professionally. The success of an individual in the fields of science, technology, engineering, mathematics, and medicine (STEMM) depends on more than intellectual capacity; a holistic view encompassing all factors that contribute to scientific achievement is all-important. Specifically, one new method scientists can adopt is quotients, which are scales and techniques that can be used to measure aptitude in a specific area. In this paper, we focus on these factors and how to grow one's adversity quotient (AQ), social quotient (SQ), and Personal Growth Initiative Scale (PGIS). We also look at how mentors can better understand the biases of their trainees. In addressing this, mentors can help trainees become more visible and encourage other trainees to become allies while increasing the visibility of their peers.

Introduction There is scarce data regarding the incidence of venous thromboembolism (VTE) and arterial thromboembolism (ATE) in the molecular subtypes of non-small cell lung cancer (NSCLC). We aimed to investigate the association between Anaplastic Lymphoma Kinase (ALK)-positive NSCLC and thromboembolic events. Methods A retrospective population-based cohort study of the Clalit Health Services database, included patients with NSCLC diagnosed between 2012 and 2019. Patients exposed to ALK-tyrosine-kinase inhibitors (TKIs) were defined as ALK-positive. The outcome was VTE (at any site) or ATE (stroke or myocardial infarction) 6 months prior to the diagnosis of cancer, until 5 years post-diagnosis. The cumulative incidence of VTE and ATE and hazard-ratios (HR) with 95% CIs were calculated (at 6- 12- 24 and 60-months), using death as a competing risk. Cox proportional hazards multivariate regression was performed, with the Fine and Gray correction for competing risks. Results The study included 4762 patients, of which 155 (3.2%) were ALK-positive. The overall 5-year VTE incidence was 15.7% (95% CI, 14.7-16.6%). ALK-positive patients had a higher VTE risk compared to ALK-negative patients (HR 1.87 [95% CI, 1.31-2.68]) and a 12-month VTE incidence of 17.7% (13.9-22.7%) compared to 9.9% (9.1-10.9%) in ALK-negative patients. The overall 5-year ATE incidence was 7.6% [6.8-8.6%]. ALK positivity was not associated with ATE incidence (HR 1.24 [0.62-2.47]). Conclusions In this study, we observed a higher VTE risk, but not ATE risk, in patients with ALK-rearranged NSCLC relative to those without ALK rearrangement. Prospective studies are warranted to evaluate thromboprophylaxis in ALK-positive NSCLC.

Drugs Approved by the U.S. Food and Drug Administration by April 30, 2014, That Were Included in the Analysis

Purpose: Evaluate the association between the use of phase I expansion cohorts (ECs) and drug performance in phase II as well as time to approval by the FDA.Experimental Design: We performed a systematic search of MEDLINE for single-agent dose-finding adult oncology phase I trials published in 2006 to 2011 and subsequent phase II trials. Successful phase II trials were those that met their primary endpoints. Dates of approval were obtained from the Drugs@FDA website in April 2014. A logistic regression model was used to determine the associations between variables and success in phase II.Results: We identified 533 phase I trials evaluating 381 drugs; 112 drugs had at least one phase I trial with an expansion cohort. Phase I trials with expansion cohorts of two to 20 patients were associated with a higher rate of successful phase II trials than those with no expansion cohort [48% vs. 27%; OR, 2.1; 95% confidence interval (CI), 1.1–4.0; P = 0.037]. Phase II success rates were the same for expansion cohort with two to 20 and more than 20 patients (48% vs. 52%). Other positive associations were disease-specific trials (OR, 1.7; 95% CI, 1.0–2.9; P = 0.037), industry sponsorship (OR, 2.9; 95% CI, 1.5–5.7; P = 0.0024), and response rate of 6% to 20% (OR, 2.89; 95% CI, 1.6–5.2; P = 0.0007). Drugs tested in phase I trials with expansion cohorts had a higher rate of 5-year approval (19% vs. 5%; HR, 4.4; 95% CI, 2.2–8.8; P < 0.001).Conclusions: The use of expansion cohorts in phase I trials was associated with success of subsequent phase II trials. However, confounders may play a role in this association. Clin Cancer Res; 23(15); 4020–6. ©2017 AACR.

Partially charged chiral molecules act as spin filters, with preference for electron transport toward one type of spin ("up" or "down"), depending on their handedness. This effect is named the chiral induced spin selectivity (CISS) effect. A consequence of this phenomenon is spin polarization concomitant with electric polarization in chiral molecules. These findings were shown by adsorbing chiral molecules on magnetic surfaces and investigating the spin-exchange interaction between the surface and the chiral molecule. This field of study was developed using artificial chiral molecules. Here we used such magnetic surfaces to explore the importance of the intrinsic chiral properties of proteins in determining their stability. First, proteins were adsorbed on paramagnetic and ferromagnetic nanoparticles in a solution, and subsequently urea was gradually added to induce unfolding. The structural stability of proteins was assessed using two methods: bioluminescence measurements used to monitor the activity of the Luciferase enzyme, and fast spectroscopy detecting the distance between two chromophores implanted at the termini of a Barnase core. We found that interactions with magnetic materials altered the structural and functional resilience of the natively folded proteins, affecting their behavior under varying mild denaturing conditions. Minor structural disturbances at low urea concentrations were impeded in association with paramagnetic nanoparticles, whereas at higher urea concentrations, major structural deformation was hindered in association with ferromagnetic nanoparticles. These effects were attributed to spin exchange interactions due to differences in the magnetic imprinting properties of each type of nanoparticle. Additional measurements of proteins on macroscopic magnetic surfaces support this conclusion. The results imply a link between internal spin exchange interactions in a folded protein and its structural and functional integrity on magnetic surfaces. Together with the accumulating knowledge on CISS, our findings suggest that chirality and spin exchange interactions should be considered as additional factors governing protein structures.

Introduction: The purpose of the present study was to assess nasal mucociliary clearance (NMC) and sinonasal symptoms of healthcare professionals wearing filtering facepiece-3 (FFP3) respirators. Methods: This prospective cross-sectional study was conducted at a large tertiary care academic center. Thirty-four healthcare professionals working at a coronavirus disease-19 patient care unit were included in the study. Visual analog scale (VAS) scores of sinonasal symptoms (nasal discharge, postnasal discharge, nasal blockage, hyposmia, facial pain/pressure, facial fullness, headache, fatigue, halitosis, cough) and the NMC times of the participants were assessed immediately before wearing FFP3 respirators and after 4 h of work with FFP3 respirators. Results: The mean age of the participants was 28.82 ± 4.95 (range, 26–31) years. Twenty participants were female and 14 were male. After wearing the FFP3 respirators for 4 h, a statistically significant increase was observed in total VAS scores for all sinonasal symptoms and NMC times (p < 0.001). When the VAS score of each sinonasal symptom was evaluated separately, a statistically significant increase was found for VAS scores of nasal discharge, postnasal discharge, nasal blockage, hyposmia, facial pain/pressure, and facial fullness (p < 0.05). Conclusion: The present study shows that nasal mucosal functions might be affected significantly after 4 h of using FFP3 respirators. The long-term effects and clinical significance of these short-term changes should be investigated on healthcare professionals in further studies.

Mitochondria and peroxisomes are dynamic signaling organelles that constantly undergo fission, driven by the large GTPase dynamin-related protein 1 (DRP1; encoded by DNM1L). Patients with de novo heterozygous missense mutations in DNM1L present with encephalopathy due to defective mitochondrial and peroxisomal fission (EMPF1) – a devastating neurodevelopmental disease with no effective treatment. To interrogate the mechanisms by which DRP1 mutations cause cellular dysfunction, we used human-derived fibroblasts from patients who present with EMPF1. In addition to elongated mitochondrial morphology and lack of fission, patient cells display lower coupling efficiency, increased proton leak and upregulation of glycolysis. Mitochondrial hyperfusion also results in aberrant cristae structure and hyperpolarized mitochondrial membrane potential. Peroxisomes show a severely elongated morphology in patient cells, which is associated with reduced respiration when cells are reliant on fatty acid oxidation. Metabolomic analyses revealed impaired methionine cycle and synthesis of pyrimidine nucleotides. Our study provides insight into the role of mitochondrial dynamics in cristae maintenance and the metabolic capacity of the cell, as well as the disease mechanism underlying EMPF1.

To evaluate the serotype distribution and antibiotic resistance in pneumococcal infections in adults and to provide a perspective regarding serotype coverage of both current and future pneumococcal vaccines.This passive surveillance study was conducted with theIn the whole study group (410 samples from adults aged ≥18 years), the most frequent serotypes were 3 (14.1%), 19 F (12%) and 1 (9.3%). The vaccine coverage for PCV13, PCV15, PCV20 and PPV23 was 63.9%, 66.6%, 74.1% and 75.9%, respectively, in all isolates. Penicillin non-susceptibility in invasive pneumococcal disease (IPD) was 70.8% and 57.1% in the patients aged65 and ≥65 years, respectively. About 21.1% and 4.3% of the patients with and without IPD had cefotaxime resistance. Non-susceptibility to erythromycin and moxifloxacin was 38.2% and 1.2%, respectively.The results revealed that novel PCV vaccines may provide improved coverage as compared with the currently available vaccine, PCV13. The significant antibiotic resistance rates imply the need to extend the serotype coverage of the vaccines. Continuing the surveillance in pneumococcal diseases is critical to explore the serotype distribution and incidence changes of IPD cases in the population and to inform policy makers to make necessary improvements in the national immunization programmes.Key messagesThis multicentre study demonstrated the most recent serotype distribution and antibiotic resistance in adult population in Turkey.Shifting from PCV13 to novel conjugated vaccines will significantly increase the coverage.Continuing the surveillance in pneumococcal diseases is critical to explore the serotype distribution changes and the incidence of cases with invasive pneumococcal disease in the population.

We investigate the effects of risk cycles on business cycles, using a panel spanning 150 years and 74 countries. We capture risk cycles by identifying periods when agents’ perception of financial risk is high and low. A long- lasting low-risk environment encourages risky investments that ultimately augment growth but at the cost of building up of vulnerabilities in the economy and thus, has a boom-to-bust effect on growth: an initial increase followed by a reversal in two years. Such an effect is particularly stronger for countries with excessive credit growth. Global risk cycles have a more pronounced effect on growth than local risk cycles, highlighting the relative importance of the global environment. Low-risk affects growth amid its notable impact on capital flows, investment, and lending quality.

ImportanceAdvanced stage non-small cell lung cancer (NSCLC) patients with no driver mutations are typically treated with immune checkpoint inhibitor (ICI)-based therapy, either in the form of monotherapy or concurrently with chemotherapy, while treatment modality selection is based mainly on programmed death ligand 1 (PD-L1) expression levels in the tumor. However, PD-L1 assays are only moderately predictive of therapeutic benefit.ObjectiveTo develop a novel decision-making tool for physicians treating NSCLC patients on whether to administer immune checkpoint inhibitor (ICI) therapy alone or in combination with chemotherapy.Design, setting, and participantsThis multicenter observational study includes patients from an ongoing clinical trial (PROPHETIC;NCT04056247). Patients were recruited from 13 different centers (total n=425; 58 patients were excluded) from June 2016 and June 2021. Plasma samples were obtained prior to treatment initiation, and deep proteomic profiling was conducted. PROphet® computational model for predicting clinical benefit (CB) probability at 12 months was developed based on the plasma proteomic profile. The model performance was validated in a blinded manner. Following validation, training and prediction was performed over the entire cohort using cross-validation methodology. The patients were divided into four groups based on their PD-L1 expression level combined with their CB probability, and the survival outcome was examined for each group. The data were analyzed from July to October 2022.Main outcome and measuresClinical benefit from ICI-based treatment, overall survival (OS) and progression-free survival (PFS).ResultsThe model displayed strong predictive capability with an AUC of 0.78 (p-value = 5.00e-05), outperforming a PD-L1-based predictive model (AUC = 0.62; p-value 2.76e-01), and exhibited a significant difference in OS and PFS between patients with low and high CB probabilities. When combining CB probability with PD-L1 expression levels, four patient subgroups were identified; (i) patients with PD-L1≥50% and a negative PROphet result who significantly benefit from ICI-chemotherapy combination therapy compared to ICI monotherapy; (ii) patients with PD-L1≥50% and a positive PROphet result who benefit similarly from either treatment modalities; (iii) patients with PD-L1Conclusions and relevanceThe PROphet® model displayed good performance for prediction of CB at 12 months based on a plasma sample obtained prior to treatment. Our findings further demonstrate a potential clinical utility for informing treatment decisions for NSCLC patients treated with ICIs by adding resolution to the PD-L1 biomarker currently used to guide treatment selection, thereby enabling to select the most suitable treatment modality for each patient.