Differential impact of sex on regulation of skeletal muscle mitochondrial function and protein homeostasis by hypoxia-inducible factor-1α in normoxia.

Hypoxia-inducible factor (HIF)-1α is continuously synthesized and degraded in normoxia. During hypoxia, HIF1α stabilization restricts cellular/mitochondrial oxygen utilization. Cellular stressors can stabilize HIF1α even during normoxia. However, less is known about HIF1α function(s) and sex-specific effects during normoxia in the basal state. Since skeletal muscle is the largest protein store in mammals and protein homeostasis has high energy demands, we determined HIF1α function at baseline during normoxia in skeletal muscle. Untargeted multiomics data analyses were followed by experimental validation in differentiated murine myotubes with loss/gain of function and skeletal muscle from mice without/with post-natal muscle-specific Hif1a deletion (Hif1amsd). Mitochondrial oxygen consumption studies using substrate, uncoupler, inhibitor, titration protocols; targeted metabolite quantification by gas chromatography-mass spectrometry; and post-mitotic senescence markers using biochemical assays were performed. Multiomics analyses showed enrichment in mitochondrial and cell cycle regulatory pathways in Hif1a deleted cells/tissue. Experimentally, mitochondrial oxidative functions and ATP content were higher with less mitochondrial free radical generation with Hif1a deletion. Deletion of Hif1a also resulted in higher concentrations of TCA cycle intermediates and HIF2α proteins in myotubes. Overall responses to Hif1amsd were similar in male and female mice, but changes in complex II function, maximum respiration, Sirt3 and HIF1ß protein expression and muscle fibre diameter were sex-dependent. Adaptive responses to hypoxia are mediated by stabilization of constantly synthesized HIF1α. Despite rapid degradation, the presence of HIF1α during normoxia contributes to lower mitochondrial oxidative efficiency and greater post-mitotic senescence in skeletal muscle. In vivo responses to HIF1α in skeletal muscle were differentially impacted by sex. KEY POINTS: Hypoxia-inducible factor -1α (HIF1α), a critical transcription factor, undergoes continuous synthesis and proteolysis, enabling rapid adaptive responses to hypoxia by reducing mitochondrial oxygen consumption. In mammals, skeletal muscle is the largest protein store which is determined by a balance between protein synthesis and breakdown and is sensitive to mitochondrial oxidative function. To investigate the functional consequences of transient HIF1α expression during normoxia in the basal state, myotubes and skeletal muscle from male and female mice with HIF1α knockout were studied using complementary multiomics, biochemical and metabolite assays. HIF1α knockout altered the electron transport chain, mitochondrial oxidative function, signalling molecules for protein homeostasis, and post-mitotic senescence markers, some of which were differentially impacted by sex. The cost of rapid adaptive responses mediated by HIF1α is lower mitochondrial oxidative efficiency and post-mitotic senescence during normoxia.

Metabolomics-based pharmaceutical evaluation of different parts of Swertia chirayita (Roxb.) Buch.-Ham. ex C.B. Clarke from the western Himalayas.

Swertia species are common ingredients in numerous herbal remedies. It is also used to treat a wide range of illnesses and possess diverse therapeutic activities. The aim of the study is to elucidate the comprehensive metabolomics profile of Swertia chirayita and the role of various extraction methods in the phytochemical compositions of the extracts of S. chirayita, and their antioxidant and enzyme inhibitory activities. Extraction of the stems, leaves, and flowering tops of S. chirayita was performed by maceration, infusion, and soxhlation using methanol and water as solvent. Extracts were subjected to phytochemical profiling by a liquid-chromatographic system. Antioxidant and enzyme inhibitory activity was carried out. The metabolomics profiling showed that a diverse range of specialized metabolites were present in the stems and leaves & flowering tops of the plant. All the extracts showed substantial antioxidant and enzyme inhibitory activities further confirmed by molecular docking studies. This study appraised the use of S. chirayita aerial parts as a potential antioxidant and its therapeutic application in various chronic illnesses including Alzheimer's disease, diabetes, and other skin-related disorders.

Ensuring carbon neutrality via algae-based wastewater treatment systems: Progress and future perspectives.

The emergence of algal biorefineries has garnered considerable attention to researchers owing to their potential to ensure carbon neutrality via mitigation of atmospheric greenhouse gases. Algae-derived biofuels, characterized by their carbon-neutral nature, stand poised to play a pivotal role in advancing sustainable development initiatives aimed at enhancing environmental and societal well-being. In this context, algae-based wastewater treatment systems are greatly appreciated for their efficacy in nutrient removal and simultaneous bioenergy generation. These systems leverage the growth of algae species on wastewater nutrients-including carbon, nitrogen, and phosphorus-alongside carbon dioxide, thus facilitating a multifaceted approach to pollution remediation. This review seeks to delve into the realization of carbon neutrality through algae-mediated wastewater treatment approaches. Through a comprehensive analysis, this review scrutinizes the trajectory of algae-based wastewater treatment via bibliometric analysis. It subsequently examines the case studies and empirical insights pertaining to algae cultivation, treatment performance analysis, cost and life cycle analyses, and the implementation of optimization methodologies rooted in artificial intelligence and machine learning algorithms for algae-based wastewater treatment systems. By synthesizing these diverse perspectives, this study aims to offer valuable insights for the development of future engineering applications predicated on an in-depth understanding of carbon neutrality within the framework of circular economy paradigms.

Adaptive exhaustion during prolonged intermittent hypoxia causes dysregulated skeletal muscle protein homeostasis.

Nocturnal hypoxaemia, which is common in chronic obstructive pulmonary disease (COPD) patients, is associated with skeletal muscle loss or sarcopenia, which contributes to adverse clinical outcomes. In COPD, we have defined this as prolonged intermittent hypoxia (PIH) because the duration of hypoxia in skeletal muscle occurs through the duration of sleep followed by normoxia during the day, in contrast to recurrent brief hypoxic episodes during obstructive sleep apnoea (OSA). Adaptive cellular responses to PIH are not known. Responses to PIH induced by three cycles of 8 h hypoxia followed by 16 h normoxia were compared to those during chronic hypoxia (CH) or normoxia for 72 h in murine C2C12 and human inducible pluripotent stem cell-derived differentiated myotubes. RNA sequencing followed by downstream analyses were complemented by experimental validation of responses that included both unique and shared perturbations in ribosomal and mitochondrial function during PIH and CH. A sarcopenic phenotype characterized by decreased myotube diameter and protein synthesis, and increased phosphorylation of eIF2α (Ser51) by eIF2α kinase, and of GCN-2 (general controlled non-derepressed-2), occurred during both PIH and CH. Mitochondrial oxidative dysfunction, disrupted supercomplex assembly, lower activity of Complexes I, III, IV and V, and reduced intermediary metabolite concentrations occurred during PIH and CH. Decreased mitochondrial fission occurred during CH. Physiological relevance was established in skeletal muscle of mice with COPD that had increased phosphorylation of eIF2α, lower protein synthesis and mitochondrial oxidative dysfunction. Molecular and metabolic responses with PIH suggest an adaptive exhaustion with failure to restore homeostasis during normoxia. KEY POINTS: Sarcopenia or skeletal muscle loss is one of the most frequent complications that contributes to mortality and morbidity in patients with chronic obstructive pulmonary disease (COPD). Unlike chronic hypoxia, prolonged intermittent hypoxia is a frequent, underappreciated and clinically relevant model of hypoxia in patients with COPD. We developed a novel, in vitro myotube model of prolonged intermittent hypoxia with molecular and metabolic perturbations, mitochondrial oxidative dysfunction, and consequent sarcopenic phenotype. In vivo studies in skeletal muscle from a mouse model of COPD shared responses with our myotube model, establishing the pathophysiological relevance of our studies. These data lay the foundation for translational studies in human COPD to target prolonged, nocturnal hypoxaemia to prevent sarcopenia in these patients.

Machine learning can guide suitability of consultation and patient referral through telemedicine for hepatobiliary diseases.

BACKGROUND AND AIM: Telemedicine is an evolving tool to provide health-care services. We evaluated the suitability of telemedicine to deliver effective consultation for hepatobiliary disorders. METHODS: In this prospective study spanning over a year, we interviewed hepatologists delivering the teleconsultations through a pre-validated questionnaire. A consult was deemed suitable based on the physician's judgment in the absence of unplanned hospitalization. We evaluated factors determining the suitability through inferential statistics and machine learning models, namely, extreme gradient boosting (XGB) and decision tree (DT). RESULTS: Of 1118 consultations, 917 (82.0%) were deemed suitable. On univariable analysis, patients with skilled occupation, higher education, out-of-pocket expenses, and diseases such as chronic hepatitis B, C, and non-alcoholic fatty liver disease (NAFLD) without cirrhosis were associated with suitability (P < 0.05). Patients with cirrhosis (compensated or decompensated), acute-on-chronic liver failure (ACLF), and biliary obstruction were likely unsuitable (P < 0.05). XGB and DT models predicted suitability with an area under the receiver operating curve of 0.808 and 0.780, respectively. DT demonstrated that compensated cirrhosis with higher education or skilled occupation with age < 55 years had 78% chance of suitability whereas hepatocellular carcinoma, decompensated cirrhosis, and ACLF patients were unsuitable with a 60-95% probability. In non-cirrhotic liver diseases, hepatitis B, C, and NAFLD were suitable, with a probability of 89.7%. Biliary obstruction and previous failure of teleconsultation were unsuitable, with a probability of 70%. Non-cirrhotic portal fibrosis, dyspepsia, and dysphagia not requiring intervention were suitable (probability: 88%). CONCLUSION: A simple decision tree can guide the referral of unsuitable and the management of suitable patients with hepatobiliary diseases through telemedicine.

Occurrence of antibiotics in wastewater: Potential ecological risk and removal through anaerobic-aerobic systems.

Antibiotics are intensively used to improve public health, prevent diseases and enhance productivity in animal farms. Contrarily, when released, the antibiotics laden wastewater produced from pharmaceutical industries and their application sources poses a potential ecological risk to the environment. This study provides a discussion on the occurrence of various antibiotics in wastewater and their potential ecological risk in the environment. Further, a critical review of anaerobic-aerobic processes based on three major systems (such as constructed wetland, high-rate bioreactor, and integrated treatment technologies) applied for antibiotics removal from wastewater is performed. The review also explores microbial dynamics responsible for antibiotic biodegradation in anaerobic-aerobic systems and its economic feasibility at wider-scale applications. The operational problems and prospective modifications are discussed to define key future research directions. The appropriate selection of treatment processes, sources control, understanding of antibiotic fate, and adopting precise monitoring strategies could eliminate the potential ecological risks of antibiotics. Integrated bio-electrochemical systems exhibit antibiotics removal ≥95% by dominant Geobacter sp. at short HRT ∼4-10 h. Major process factors like organic loading rate, hydraulic loading rate (HRT), and solid retention time significantly affect the system performance. This review will be beneficial to the researchers by providing in-depth understanding of antibiotic pollution and its abatement via anaerobic-aerobic processes to develop sustainable wastewater treatment technology in the future.

Anaerobic-aerobic treatment of wastewater and leachate: A review of process integration, system design, performance and associated energy revenue.

Hybrid anaerobic-aerobic biological systems are an environmentally sustainable way of recovering bioenergy during the treatment of high-strength wastewaters and landfill leachate. This study provides a critical review of three major categories of anaerobic-aerobic processes such as conventional wetland, high-rate and integrated bioreactor systems applied for treatment of wastewaters and leachate. A comparative assessment of treatment mechanisms, critical operating parameters, bioreactor configurations, process control strategies, efficacies, and microbial dynamics of anaerobic-aerobic systems is provided. The review also explores the influence of wastewater composition on treatment performance, ammonium nitrogen removal efficacy, impact of mixing leachate, energy consumption, coupled bioenergy production and economic aspects of anaerobic-aerobic systems. Furthermore, the operational challenges, prospective modifications, and key future research directions are discussed. This review will provide in-depth understanding to develop sustainable engineering applications of anaerobic-aerobic processes for effective co-treatment of wastewaters and leachate.

Franchising structure changes and shareholder value: Evidence from store buybacks and refranchising.

Drawing on agency theory and transaction cost analysis, this study investigates the impact of refranchising and buybacks of downstream retail units by franchising firms on shareholder value (i.e., stock returns). It further evaluates the contingency role of firm and industry factors in shaping this impact. An event study analysis over the years 2001-2020 confirms that both refranchising and buybacks positively affect stock returns. However, notable impact differences emerge between the two types of strategic decisions. For refranchising, firms with lower royalty rates, smaller returns-on-assets (ROA), and higher trade credit provided generate higher stock returns. Whereas, for buybacks, firms with higher royalty rates derive more value in stock markets. Analysis further shows that investors judge refranchising (buybacks) less (more) favorably in munificent industries, but industry dynamism has no effect on the stock returns generated from these moves. Together, the study offers important implications for franchising theory and retail practice in marketing. Supplementary Information: The online version contains supplementary material available at 10.1007/s11747-022-00921-3.

Integrated multiomics analysis identifies molecular landscape perturbations during hyperammonemia in skeletal muscle and myotubes.

Ammonia is a cytotoxic molecule generated during normal cellular functions. Dysregulated ammonia metabolism, which is evident in many chronic diseases such as liver cirrhosis, heart failure, and chronic obstructive pulmonary disease, initiates a hyperammonemic stress response in tissues including skeletal muscle and in myotubes. Perturbations in levels of specific regulatory molecules have been reported, but the global responses to hyperammonemia are unclear. In this study, we used a multiomics approach to vertically integrate unbiased data generated using an assay for transposase-accessible chromatin with high-throughput sequencing, RNA-Seq, and proteomics. We then horizontally integrated these data across different models of hyperammonemia, including myotubes and mouse and human muscle tissues. Changes in chromatin accessibility and/or expression of genes resulted in distinct clusters of temporal molecular changes including transient, persistent, and delayed responses during hyperammonemia in myotubes. Known responses to hyperammonemia, including mitochondrial and oxidative dysfunction, protein homeostasis disruption, and oxidative stress pathway activation, were enriched in our datasets. During hyperammonemia, pathways that impact skeletal muscle structure and function that were consistently enriched were those that contribute to mitochondrial dysfunction, oxidative stress, and senescence. We made several novel observations, including an enrichment in antiapoptotic B-cell leukemia/lymphoma 2 family protein expression, increased calcium flux, and increased protein glycosylation in myotubes and muscle tissue upon hyperammonemia. Critical molecules in these pathways were validated experimentally. Human skeletal muscle from patients with cirrhosis displayed similar responses, establishing translational relevance. These data demonstrate complex molecular interactions during adaptive and maladaptive responses during the cellular stress response to hyperammonemia.

Improvement of chronic HCV infection-related depression, anxiety, and neurocognitive performance in persons achieving SVR-12: A real-world cohort study.

Chronic hepatitis C virus (HCV) infection is associated with neuropsychiatric changes. Also, patients with cirrhosis may develop overt or minimal hepatic encephalopathy. Sustained virological response (SVR) with direct-acting antiviral agents (DAAs) may improve the neuropsychiatric manifestations and quality of life (QoL). Consecutive patients (with and without cirrhosis, all genders and aged 18-65 years) with hepatitis C were assessed at enrolment and at 12 weeks after therapy completion for mood (Beck's Depression Inventory [BDI]), anxiety (generalized anxiety disorder [GAD-7]), QoL (SF-36 ver.2) and computer-based tests for number connection (NCT), visual memory, Stroop test and reaction times. We recruited 385 viraemic chronic HCV patients (76.1% male, 21.0% cirrhotic, mean age 39.4 ± 14.2 years, 59.3% genotype 3, mean HCV RNA load 5.8 log). Overall SVR-12 rates were 90.6%, with cure rates 87.6% and 91.4% in patients with and without cirrhosis, respectively. Patients who achieved SVR-12 had mean percentage reduction in BDI (11.3%, p = .000), GAD (8.6%, p = .001) and Stroop test (58.4%, p = .001), with improved NCT (1.7%, p = .001), visual memory (13.7%, p = .001) and digit span (23.8%, p = .002). On multivariate logistic regression, adherence (OR, 17.5 [95% CI 2.80-110.50], p = .000), high ALT (OR 1.02 [95% CI 1.00-1.05]), and BDI score (OR 1.73 [95% CI 1.42-3.26] p = .039) predicted cure. SVR-12 was associated with improved visual memory ≥5.5 (AUC-0.708; sensitivity 62.5%, specificity 63%, p = .000) and % correct Stroop test responses >26.6% (AUC-0.918, sensitivity 94.4% specificity 80.4%, p = .000). In conclusion, given the cumulative evidence of the safety of DAAs and efficacy of improving cognitive and neuropsychological and quality-of-life outcomes irrespective of age and gender, as shown in our study, future recommendations should focus on integrated universal HCV care to enable HCV elimination.

Combined PEG3350 Plus Lactulose Results in Early Resolution of Hepatic Encephalopathy and Improved 28-Day Survival in Acute-on-Chronic Liver Failure.

BACKGROUND AND AIMS: Acute-on-chronic liver failure (ACLF) is associated with high short-term mortality in those with hepatic encephalopathy (HE). Polyethylene glycol (PEG) 3350 electrolyte solution can ensure rapid gut catharsis, which may resolve HE more effectively than lactulose. In this open-label-randomized trial, we compared PEG+lactulose versus lactulose alone in ACLF with HE grade ≥2 for efficacy and outcome. PATIENTS AND METHODS: Patients were randomized to receive PEG (2 L q12 h) followed by lactulose (30 mL q8 h) or standard medical treatment [SMT, lactulose (titrated 30 mL q8 h)]. Endpoints were HE grade improvement at 24 hours, 48 hours, and 7 days using hepatic encephalopathy scoring algorithm (HESA), ammonia reduction, HE resolution, and survival benefit. RESULTS: Of 60 patients, 29 were randomized to PEG+lactulose arm and 31 to SMT. In the PEG arm, early reduction in HESA score was noted in more persons [18 (62.1%) vs. 10 (32.2%); P=0.021] with a shorter median time to HE resolution [4.5 (3 to 9) d vs. 9 (8 to 11) d; P=0.023]. On multivariate analysis, age [hazard ratio (HR),1.06 (1.00 to 1.13); P=0.03], HESA score [HR, 6.01 (1.27 to 28.5); P=0.024], and model for end-stage liver disease [HR, 1.26 (1.01 to 1.53); P=0.022] were predictors of mortality at 28 days. Ammonia level or reduction did not correlate with HE grades. Adverse events included excessive diarrhea (20.6% vs. 9.6%) in the PEG and SMT arms, albeit without dyselectrolytemia or worsened renal function. In the PEG versus SMT arm, survival at 28 days were 93.1% versus 67.7% (P=0.010) and at 90 days was 68.9% versus 48.3% (P=0.940), respectively, with fewer persons relapsing with HE in the PEG arm. CONCLUSIONS: PEG resulted in early and sustained HE resolution with improved short-term survival making, it a suitable and safe drug in patients with acute HE in ACLF.

Sofosbuvir plus velpatasvir combination for the treatment of chronic hepatitis C in patients with end stage renal disease on renal replacement therapy: A systematic review and meta-analysis.

INTRODUCTION: Sofosbuvir (SOF) and velpatasvir (VEL) is a pan-genotypic regimen for the treatment of Hepatitis C virus (HCV) infection. The data on the efficacy and safety of this regimen is end-stage renal disease (ESRD) is scanty. This systematic review and meta-analysis was done to ascertain the efficacy and safety of SOF and VEL in patients with chronic Hepatitis C (CHC) and ESRD on renal replacement therapy (RRT). METHODS: Systematic search of Pubmed, Embase, Scopus, and Google Scholar was conducted using the search term (end-stage renal disease OR renal replacement therapy OR chronic kidney failure OR severe renal impairment OR chronic kidney disease OR haemodialysis OR dialysis OR peritoneal dialysis) AND (sofosbuvir OR velpatasvir OR NS5A inhibitors OR directly acting antivirals). Pooled sustained virologic response (SVR) and adverse event rates with 95% confidence intervals were estimated. RESULTS: Seven studies (410 patients with CHC and ESRD on RRT) fulfilled our eligibility criteria. The overall pooled SVR rate of SOF and VEL in patients with HCV on RRT was 97.69% (95% CI: 95.71 to 98.92). There was no significant heterogeneity (I2 : 39.3%, p-value of Cochran's Q = 0.13) among the studies. The pooled estimate of efficacy of SOF-VEL combination among patients with cirrhosis was 91.94% (95% CI 77.03-98.52). Pooled SVR rates in genotype 3 infection [94.6%, (95%: CI 81.3-99.4)] was comparable to that in those with documented non-genotype 3 infection [94.63%, (95% CI 87.12-98.44)]. No serious adverse event attributable to SOF and VEL was reported in the included studies. CONCLUSION: The fixed-dose combination of SOF and VEL is effective and safe in CHC patients with ESRD on RRT.

Characterization of Differentially Detectable Mycobacterium tuberculosis in the Sputum of Subjects with Drug-Sensitive or Drug-Resistant Tuberculosis before and after Two Months of Therapy.

Standard methods for enumerating Mycobacterium tuberculosis in patient sputum can miss large populations of viable M. tuberculosis cells that are unable to grow either on solid medium or in liquid medium unless the medium has been extensively diluted. Because these bacteria can be detected in liquid medium after limiting dilution, they have been termed differentially culturable or differentially detectable M. tuberculosis (DD-Mtb). Treatment with isoniazid (H), rifampin (R), pyrazinamide (Z), and ethambutol (E) (HRZE) for 1 to 2 weeks has been shown to increase the representation of DD-Mtb in the sputum of drug-sensitive (DS) tuberculosis (TB) patients. However, little is known about DD-Mtb after longer periods of treatment with HRZE or in patients with drug-resistant (DR) TB who receive second-line therapies. Here, we measured the proportion of DD-Mtb cells in the sputum of 47 subjects, 29 with DS TB and 18 with DR TB, before initiation of treatment and at 2 weeks and 2 months thereafter. Prior to treatment, DD-Mtb cells represented the majority of M. tuberculosis cells in the sputum of 21% of subjects with DS TB, and this proportion rose to 65% after 2 weeks of treatment with first-line drugs. In subjects with DR TB, DD-Mtb cells were found in the sputum of 29% of subjects prior to treatment initiation, and this proportion remained steady at 31% after 2 weeks of treatment with second-line drugs. By 2 months, DD-Mtb cells were detected in the sputum of only 2/15 (13.3%) subjects with DS TB and in 0/15 of subjects with DR TB. One of the DS subjects whose sputum was positive for DD-Mtb at month 2 later experienced treatment failure.

Multiomics-Identified Intervention to Restore Ethanol-Induced Dysregulated Proteostasis and Secondary Sarcopenia in Alcoholic Liver Disease.

BACKGROUND/AIMS: Signaling and metabolic perturbations contribute to dysregulated skeletal muscle protein homeostasis and secondary sarcopenia in response to a number of cellular stressors including ethanol exposure. Using an innovative multiomics-based curating of unbiased data, we identified molecular and metabolic therapeutic targets and experimentally validated restoration of protein homeostasis in an ethanol-fed mouse model of liver disease. METHODS: Studies were performed in ethanol-treated differentiated C2C12 myotubes and physiological relevance established in an ethanol-fed mouse model of alcohol-related liver disease (mALD) or pair-fed control C57BL/6 mice. Transcriptome and proteome from ethanol treated-myotubes and gastrocnemius muscle from mALD and pair-fed mice were analyzed to identify target pathways and molecules. Readouts including signaling responses and autophagy markers by immunoblots, mitochondrial oxidative function and free radical generation, and metabolic studies by gas chromatography-mass spectrometry and sarcopenic phenotype by imaging. RESULTS: Multiomics analyses showed that ethanol impaired skeletal muscle mTORC1 signaling, mitochondrial oxidative pathways, including intermediary metabolite regulatory genes, interleukin-6, and amino acid degradation pathways are ß-hydroxymethyl-butyrate targets. Ethanol decreased mTORC1 signaling, increased autophagy flux, impaired mitochondrial oxidative function with decreased tricarboxylic acid cycle intermediary metabolites, ATP synthesis, protein synthesis and myotube diameter that were reversed by HMB. Consistently, skeletal muscle from mALD had decreased mTORC1 signaling, reduced fractional and total muscle protein synthesis rates, increased autophagy markers, lower intermediary metabolite concentrations, and lower muscle mass and fiber diameter that were reversed by ß-hydroxymethyl-butyrate treatment. CONCLUSION: An innovative multiomics approach followed by experimental validation showed that ß-hydroxymethyl-butyrate restores muscle protein homeostasis in liver disease.

Understanding Fermi resonances in the complex vibrational spectra of the methyl groups in methylamines.

Vibrational spectra of the methyl groups in mono-methylamine (MMA), dimethylamine (DMA), and trimethylamine (TMA) monomers and their clusters were measured in three experimental set-ups to capture their complex spectral features as a result of bend/umbrella-stretch Fermi resonance (FR). Multiple bands were observed between 2800 and 3000 cm-1 corresponding to the methyl groups for MMA and DMA. On the other hand, the corresponding spectrum of TMA is relatively simple, exhibiting only four prominent bands in the same frequency window, even though TMA has a larger number of methyl groups. The discrete variable representation (DVR) based ab initio anharmonic algorithm with potential energy surface (PES) at CCSD/aug-cc-pVDZ quality is able to capture all the experimentally observed spectral features across all three amines, and the constructed vibrational Hamiltonian was used to analyze the couplings that give rise to the observed FR patterns. It was observed that the vibrational coupling among CH stretch modes on different methyl groups is weak (less than 2 cm-1) and stronger vibrational coupling is found to localize within a methyl group. In MMA and DMA, the complex feature between 2850 and 2950 cm-1 is a consequence of closely packed overtone states that gain intensities by mixing with the stretching modes. The simplification of the spectral pattern of TMA can be understood by the red-shift of the symmetric CH3 stretching modes by about 80 cm-1 relative to MMA, which causes the symmetric CH3 stretch to shift outside the FR window.

RNA polymerase III subunits C37/53 modulate rU:dA hybrid 3' end dynamics during transcription termination.

RNA polymerase (RNAP) III synthesizes tRNAs and other transcripts, and mutations to its subunits cause human disorders. The RNAP III subunit-heterodimer C37/53 functions in initiation, elongation and in termination-associated reinitiation with subunit C11. C37/53 is related to heterodimers associated with RNAPs I and II, and C11 is related to TFIIS and Rpa12.2, the active site RNA 3' cleavage factors for RNAPs II and I. Critical to termination is stability of the RNA:DNA hybrid bound in the active center, which is loose for RNAP III relative to other RNAPs. Here, we examined RNAP III lacking C37/53/C11 and various reconstituted forms during termination. First, we established a minimal terminator as 5T and 3A on the non-template and template DNA strands, respectively. We demonstrate that C11 stimulates termination, and does so independently of its RNA cleavage activity. We found that C37/53 sensitizes RNAP III termination to RNA:DNA hybrid strength and promotes RNA 3' end pairing/annealing with the template. The latter counteracts C11-insensitive arrest in the proximal part of the oligo(T)-tract, promoting oligo(rU:dA) extension toward greater hybrid instability and RNA release. The data also indicate that RNA 3' end engagement with the active site is a determinant of termination. Broader implications are also discussed.

Vibrational spectroscopic signatures of hydrogen bond induced NH stretch-bend Fermi-resonance in amines: The methylamine clusters and other N-H⋯N hydrogen-bonded complexes.

The appearance of multiple bands in the N-H stretching region of the infrared spectra of the neutral methylamine dimer and trimer is a sign of NH bend-stretch anharmonic coupling. Ab initio anharmonic calculations were carried out in a step-wise manner to reveal the origin of various bands observed in the spectrum of the methylamine dimer. A seven-dimensional potential energy surface involving symmetric and asymmetric stretching and bending vibrations of both the hydrogen bond donor and the acceptor along intermolecular-translational modes was constructed using the discrete variable representation approach. The resulting spectrum of the dimer shows five bands that can be attributed to the symmetric stretching (νsym D), asymmetric stretchin (νasym D), and bending overtone (2νbend D) of the donor moiety. These appear along with the combination band arising out of bending vibrations of the donor and acceptor (νbend D + νbend A) and with the combination of the intermolecular translational mode over the donor bending overtone (νtrans + 2νbend D). The spectrum of the trimer essentially consists of all the features seen in the dimer with marginal changes in band positions. The analysis of the experimental spectra based on the two-state deperturbation model and ab initio anharmonic calculations yield a matrix element of about 40 cm-1 for the N-H bend-stretch Fermi resonance coupling. In general, the IR spectra of the hydrogen-bonded amino group depict three sets of bands that arise due to bend-stretch Fermi resonance coupling.

A liquid crucible model for aggregation of phenylacetylene in the gas phase.

The aggregation of phenylacetylene in the gas phase was investigated by selectively recording the IR spectra of clusters consisting of up to six monomer units. Analysis of the IR spectra with the aid of B97-D3/aug-cc-pVDZ level calculations reveals the formation of an anti-parallel π-stacked structure of the dimer and a hitherto unknown assembly of clusters incorporating exclusively aromatic C-Hπ interactions between various units of the trimer and higher clusters. The aggregation behaviour of phenylacetylene in the gas phase is fundamentally different from benzene, phenol and aniline vis-à-vis their crystal structures. The structures of the three known polymorphic crystals can be reconciled by the formation of supramolecular synthons with acetylenic C-Hπ interactions, which is preferred over energetically favored aromatic C-Hπ interactions. Furthermore, the small (phenylacetylene)n [n = 3-6] clusters, the structures incorporating aromatic C-Hπ interactions, can be envisaged as liquid-like aggregates which under varied conditions lead to the formation of multiple polymorphs during in situ cryo-crystallization.

Shannon Entropy for Quantifying Uncertainty and Risk in Economic Disparity.

The rise in economic disparity presents significant risks to global social order and the resilience of local communities. However, existing measurement science for economic disparity (e.g., the Gini coefficient) does not explicitly consider a probability distribution with information, deficiencies, and uncertainties associated with the underlying income distribution. This article introduces the quantification of Shannon entropy for income inequality across scales, including national-, subnational-, and city-level data. The probabilistic principles of Shannon entropy provide a new interpretation for uncertainty and risk related to economic disparity. Entropy and information-based conflict rise as world incomes converge. High-entropy instances can resemble both happy and prosperous societies as well as a socialist-communist social structure. Low entropy signals high-risk tipping points for anomaly and conflict detection with higher confidence. Finally, spatial-temporal entropy maps for U.S. cities offer a city risk profiling framework. The results show polarization of household incomes within and across Baltimore, Washington, DC, and San Francisco. Entropy produces reliable results at significantly reduced computational costs than Gini coefficients.

Mechanics of tablet formation: a comparative evaluation of percolation theory with classical concepts.

The present study is based on the fundamentals of percolation theory and its application in understanding compression and compaction of powder materials. Four materials, i.e. carbamazepine, microcrystalline cellulose, crospovidone and croscarmellose sodium, with dissimilar deformation and compaction behavior were selected to validate the hypotheses of percolation phenomenon. The values of two percolation thresholds, i.e. bond and site, corresponding to the lower and intermediate compression pressures, were determined using Heckel equation. The compactibility of powder materials was evaluated using classical models as well as the power law equation. The values of percolation thresholds were found to better assess the deformation behavior of powder materials compared to the values of mean yield pressure. The power law equation demonstrated better prediction of compactibility of powder materials compared to the classical models. The value of the critical exponent, q, determined using power law equation by plotting tensile strength vs. normalized relative density of powder compacts was found to be closer to the theoretical value of 2.70. Furthermore, the theoretical knowledge of percolation thresholds of individual powder components in the binary mixture was found to be helpful in improving compaction properties of the poorly compactible material, i.e. carbamazepine. Thus percolation theory can be helpful in predicting compression and compaction behavior of powder materials and serve as a potent tool for the successful design of tablet formulations.