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Similarly to humans, healthy, wild-type mice develop osteoarthritis, including of the temporomandibular joint (TMJ), as a result of aging. Pro-inflammatory cytokines, such as IL-1beta, IL-6, and TNFalpha, are known to contribute to the development of osteoarthritis, whereas TGFbeta has been associated with articular regeneration. We hypothesized that a balance between IL-1beta and TGFbeta underlies the development of TMJ osteoarthritis, whereby IL-1beta signaling down-regulates TGFbeta expression as part of disease pathology. Our studies in wild-type mice, as well as the Col1-IL1beta(XAT) mouse model of osteoarthritis, demonstrated an inverse correlation between IL-1beta and TGFbeta expression in the TMJ. IL-1beta etiologically correlated with joint pathology, whereas TGFbeta expression associated with IL-1beta down-regulation and improvement of articular pathology. Better understanding of the underlying inflammatory processes during disease will potentially enable us to harness inflammation for orofacial tissue regeneration. [ABSTRACT FROM AUTHOR]

Objective: Pain from arthritis has been associated with peripheral sensitization of primary sensory afferents and the development of inflammation at the dorsal horns. This study was undertaken to determine whether the role of spinal interleukin-1[beta] (IL-1[beta]) in central processing of pain is important in the development of arthritis.Methods: Col1-IL-1[beta][XAT] mice and GFAP-IL-1[beta][XAT] mice were injected with the feline immunodeficiency virus (FIV) (Cre) vector in the right and left temporomandibular joints (TMJs), or in the cisterna magna, respectively, to induce IL-1[beta] expression in the dorsal horns of the spinal horn. To inhibit intrathecal IL-1 receptor type I (IL-1RI) signaling, FIV(IL-1Ra) vector was injected into the cisterna magna of Col1-IL-1[beta][XAT] mice. The effects of IL-1RI receptor inhibition in GFAP-IL-1[beta][XAT] mice were studied in the GFAP-IL-1[beta][XAT]-IL-1RI-/- compound mouse model. Neuroinflammatory, sensory, and behavioral changes were evaluated in conjunction with arthritic changes in the TMJ, assessed by histopathologic and immunohistochemical analyses.Results: Induction of an osteoarthritis-like condition in the TMJ in the Col1-IL-1[beta][XAT] mouse model resulted in up-regulation of murine IL-1[beta] at the dorsal horns. Moreover, intrathecal inhibition of IL-1RI in Col1-IL-1[beta][XAT] mice with arthritis led to amelioration of joint pathology and attenuation of the attendant joint pain. Overexpression of spinal IL-1[beta] in the recently developed GFAP-IL-1[beta][XAT] somatic mosaic model of neuroinflammation led to development of arthritis-like pathology accompanied by increased pain-like behavior.Conclusion: Our results indicate that joint pathology and pain are dependent on spinal IL-1[beta], and suggest the presence of a bidirectional central nervous system-peripheral joints crosstalk that may contribute to the development, expansion, and exacerbation of arthritis. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To examine the effects of intraarticular induction of interleukin-1beta (IL-1beta) expression in adult mice. METHODS: We used somatic mosaic analysis in a novel transgenic mouse with an inducible IL-1beta transcription unit. Transgene activation was induced by Cre recombinase in the temporomandibular joints (TMJs) of adult transgenic mice (conditional knockin model). The effects of intraarticular IL-1beta induction were subsequently evaluated at the cellular, histopathologic, and behavioral levels. RESULTS: We developed transgenic mice capable of germline transmission of a dormant transcription unit consisting of the mature form of human IL-1beta as well as the reporter gene beta-galactosidase driven by the rat procollagen 1A1 promoter. Transgene activation by a feline immunodeficiency virus Cre vector resulted in histopathologic changes, including articular surface fibrillations, cartilage remodeling, and chondrocyte cloning. We also demonstrated up-regulation of genes implicated in arthritis (cyclooxygenase 2, IL-6, matrix metalloproteinase 9). There was a lack of inflammatory cells in these joints. Behavioral changes, including increased orofacial grooming and decreased resistance to mouth opening, were used as measures of nociception and joint dysfunction, respectively. The significant increase in expression of the pain-related neurotransmitter calcitonin gene-related peptide (CGRP) in the sensory ganglia as well as the auxiliary protein CGRP receptor component protein of the calcitonin-like receptor in the brainstem further substantiated the induction of pain. CONCLUSION: Induction of IL-1beta expression in the TMJs of adult mice led to pathologic development, dysfunction, and related pain in the joints. The somatic mosaic model presented herein may prove useful in the preclinical evaluation of existing and new treatments for the management of joint pathologic changes and pain, such as in osteoarthritis. [ABSTRACT FROM AUTHOR]

Background: The differentiation of bone infarction from acute osteomyelitis in patients with sickle-cell disease is challenging, as the clinical presentations of the two conditions are similar and imaging and laboratory studies are of limited value.Methods: A combination of radionuclide bone-marrow and bone scans was performed sequentially within a twenty-four-hour period (with one exception) to aid in the differentiation between bone infarction and osteomyelitis in seventy-nine consecutive episodes of acute bone pain in children with sickle-cell disease.Results: Seventy cases of bone infarction were diagnosed on the basis of decreased uptake on the bone-marrow scan and abnormal uptake on the bone scan at the site of pain. Antibiotic administration was discontinued in sixty-six of the seventy cases after the imaging results were obtained, and the bone pain resolved. In four of the seventy-nine cases, there was normal uptake on the bone-marrow scan and abnormal uptake on the bone scan at the site of pain, findings that were suggestive of acute osteomyelitis. In three of these cases, osteomyelitis was proven by culture, and the symptoms in all four resolved with antibiotic treatment. In five of the seventy-nine cases, the bone-marrow and bone scans were normal and thought to indicate neither osteomyelitis nor bone infarction; in all of these cases, the symptoms resolved without the use of antibiotics.Conclusions: These findings suggest that osteomyelitis can be differentiated from bone infarction in children with sickle-cell anemia and acute bone pain by a combination of sequential bone-marrow and bone scintigraphy. [ABSTRACT FROM AUTHOR]

We use mathematical and computational models to analyze the ability of federated organizations to solve difficult problems. Federated organizations may have some inherent advantages for solving difficult problems since they can empower multiple subunits to search for policy solutions in parallel and exploit and combine the mutual information discovered by the subunits to reveal even better solutions. We find that the benefits of these methods of experimentation first increase and then decrease as the problem of finding good policies increases in difficulty. [ABSTRACT FROM AUTHOR]

This study tested two forms of alcohol reduction programming for college students. Thirty-seven moderate to heavy drinkers completed measures of quantity/frequency, drinking consequences, and attitude questionnaires. Participants were randomly assigned to one of three groups: 1) a two-hour information and motivation session plus mailed personal feedback on their drinking; 2) mailed feedback only; or 3) no treatment. At a 6-week follow-up session, the feedback-only group decreased drinks per month as compared to control. No other differences were statistically significant, though decreases favored the treatment conditions about equally over control. Implications for research and treatment are discussed. [ABSTRACT FROM AUTHOR]

Dermatomyositis (DM) is an immune mediated inflammatory disease classically associated with muscular and cutaneous involvement. Existing studies have suggested characteristic nailfold findings may be observed in DM, indicating a potential role for nailfold microscopic examination in the diagnosis of DM. To that end, we performed a systematic review of literature pertaining to nailfold microscopic, capillaroscopic, and dermoscopic findings observed in patients with DM, with a secondary review of the association of nailfold microscopic findings with myositis-specific antibody (MSA) and myositis-associated antibody (MAA) status. Thirty-seven papers, representing 346 patients, met inclusion criteria. The most prevalent nailfold findings were evidence of increased vascular diameter (64.5%, n = 223) and decreased vascularity (57.5%, n = 199). Scleroderma-spectrum pattern and microhemorrhage or hemorrhage were both observed in 156 (45.1%) patients. Fifty-one patients had nailfold capillaroscopic findings reported in direct association with antibody positivity and demonstrated a range of nailfold findings, preliminarily suggesting associations between antibody-status and capillaroscopic findings. The results of our study align with existing data indicating the scleroderma-spectrum pattern and the pattern's composite features are prevalent in patients with DM. Our review further demonstrates a variety of nailfold capillaroscopic findings are found in patients positive for MSAs and MAAs., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

We previously reported that certain sub-regions of the thyA gene of Escherichia coli are more mutable than others when many different mutagens and mutators are analyzed (Mashiach et al., Mutation Research Fundamental Molecular Mechansims of Mutagenesis, 821: 111702, 2021). In this study, we focus on a single mutagen, cisplatin and verify that mutations occur preferentially at specific 3 bp sequences, but only when they appear in certain subregions of the gene. Moreover, we show that hotspots for some premutational lesions are camouflaged by the preferential repair effected by the uvrA,B,C-encoded excision repair system, even when they appear on the same strand. We do this by using a novel reporter gene in E. coli, the tdk gene that codes for thymidine deoxykinase, and we describe some of the advantages of utilizing this detection system., (© 2024 The Author(s). Environmental and Molecular Mutagenesis published by Wiley Periodicals LLC on behalf of Environmental Mutagenesis and Genomics Society.)

While multiple factors impact disease, artificial intelligence (AI) studies in medicine often use small, non-diverse patient cohorts due to data sharing and privacy issues. Federated learning (FL) has emerged as a solution, enabling training across hospitals without direct data sharing. Here, we present FL-PedBrain, an FL platform for pediatric posterior fossa brain tumors, and evaluate its performance on a diverse, realistic, multi-center cohort. Pediatric brain tumors were targeted due to the scarcity of such datasets, even in tertiary care hospitals. Our platform orchestrates federated training for joint tumor classification and segmentation across 19 international sites. FL-PedBrain exhibits less than a 1.5% decrease in classification and a 3% reduction in segmentation performance compared to centralized data training. FL boosts segmentation performance by 20 to 30% on three external, out-of-network sites. Finally, we explore the sources of data heterogeneity and examine FL robustness in real-world scenarios with data imbalances., (© 2024. The Author(s).)

As the world population ages, there will be an increasing need for effective therapies for aging-associated neurodegenerative disorders, which remain untreatable. Dementia due to Alzheimer's disease (AD) is one of the leading neurological diseases in the aging population. Current therapeutic approaches to treat this disorder are solely symptomatic, making the need for new molecular entities acting on the causes of the disease extremely urgent. One of the potential solutions is to use compounds that are already in the market. The structures have known pharmacokinetics, pharmacodynamics, toxicity profiles, and patient data available in several countries. Several drugs have been used successfully to treat diseases different from their original purposes, such as autoimmunity and peripheral inflammation. Herein, we divulge the repurposing of drugs in the area of neurodegenerative diseases, focusing on the therapeutic potential of antineoplastics to treat dementia due to AD and dementia. We briefly touch upon the shared pathological mechanism between AD and cancer and drug repurposing strategies, with a focus on artificial intelligence. Next, we bring out the current status of research on the development of drugs, provide supporting evidence from retrospective, clinical, and preclinical studies on antineoplastic use, and bring in new areas, such as repurposing drugs for the prion-like spreading of pathologies in treating AD., (© 2024 The Authors. Medicinal Research Reviews published by Wiley Periodicals LLC.)

Autologous bone marrow mononuclear cells (BMMNCs) infused after severe traumatic brain injury have shown promise for treating the injury. We evaluated their impact in children, particularly their hypothesized ability to preserve the blood-brain barrier and diminish neuroinflammation, leading to structural CNS preservation with improved outcomes. We performed a randomized, double-blind, placebo-sham-controlled Bayesian dose-escalation clinical trial at two children's hospitals in Houston, TX and Phoenix, AZ, USA (NCT01851083). Patients 5-17 years of age with severe traumatic brain injury (Glasgow Coma Scale score ≤ 8) were randomized to BMMNC or placebo (3:2). Bone marrow harvest, cell isolation and infusion were completed by 48 h post-injury. A Bayesian continuous reassessment method was used with cohorts of size 3 in the BMMNC group to choose the safest between two doses. Primary end points were quantitative brain volumes using MRI and microstructural integrity of the corpus callosum (diffusivity and oedema measurements) at 6 months and 12 months. Long-term functional outcomes and ventilator days, intracranial pressure monitoring days, intensive care unit days and therapeutic intensity measures were compared between groups. Forty-seven patients were randomized, with 37 completing 1-year follow-up (23 BMMNC, 14 placebo). BMMNC treatment was associated with an almost 3-day (23%) reduction in ventilator days, 1-day (16%) reduction in intracranial pressure monitoring days and 3-day (14%) reduction in intensive care unit (ICU) days. White matter volume at 1 year in the BMMNC group was significantly preserved compared to placebo [decrease of 19 891 versus 40 491, respectively; mean difference of -20 600, 95% confidence interval (CI): -35 868 to -5332; P = 0.01], and the number of corpus callosum streamlines was reduced more in placebo than BMMNC, supporting evidence of preserved corpus callosum connectivity in the treated groups (-431 streamlines placebo versus -37 streamlines BMMNC; mean difference of -394, 95% CI: -803 to 15; P = 0.055), but this did not reach statistical significance due to high variability. We conclude that autologous BMMNC infusion in children within 48 h after severe traumatic brain injury is safe and feasible. Our data show that BMMNC infusion led to: (i) shorter intensive care duration and decreased ICU intensity; (ii) white matter structural preservation; and (iii) enhanced corpus callosum connectivity and improved microstructural metrics., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The use of bacteriocins has emerged as a propitious strategy in the development of new drugs to combat antibiotic resistance, given their ability to kill bacteria with both broad and narrow natural spectra. Hence, a compelling requirement arises for a precise and efficient computational model that can accurately predict novel bacteriocins. Machine learning's ability to learn patterns and features from bacteriocin sequences that are difficult to capture using sequence matching-based methods makes it a potentially superior choice for accurate prediction. A web application for predicting bacteriocin was created in this study, utilizing a machine learning approach. The feature sets employed in the application were chosen using alternating decision tree (ADTree), genetic algorithm (GA), and linear support vector classifier (linear SVC)-based feature evaluation methods. Initially, potential features were extracted from the physicochemical, structural, and sequence-profile attributes of both bacteriocin and non-bacteriocin protein sequences. We assessed the candidate features first using the Pearson correlation coefficient, followed by separate evaluations with ADTree, GA, and linear SVC to eliminate unnecessary features. Finally, we constructed random forest (RF), support vector machine (SVM), decision tree (DT), logistic regression (LR), k -nearest neighbors (KNN), and Gaussian naïve Bayes (GNB) models using reduced feature sets. We obtained the overall top performing model using SVM with ADTree-reduced features, achieving an accuracy of 99.11% and an AUC value of 0.9984 on the testing dataset. We also assessed the predictive capabilities of our best-performing models for each reduced feature set relative to our previously developed software solution, a sequence alignment-based tool, and a deep-learning approach. A web application, titled BPAGS (Bacteriocin Prediction based on ADTree, GA, and linear SVC), was developed to incorporate the predictive models built using ADTree, GA, and linear SVC-based feature sets. Currently, the web-based tool provides classification results with associated probability values and has options to add new samples in the training data to improve the predictive efficacy. BPAGS is freely accessible at https://shiny.tricities.wsu.edu/bacteriocin-prediction/., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Akhter and Miller.)

Improving the odds and pace of successful biomass and waste carbon utilization technology scale-up is crucial to decarbonizing key industries such as aviation and materials within timelines required to meet global climate goals. In this perspective, we review deficiencies commonly encountered during scale-up to show that many nascent technology developers place too much focus on simply demonstrating that technologies work in progressively larger units ("profit") without expending enough up-front research effort to identify and derisk roadblocks to commercialization (collecting "information") to inform the design of these units. We combine this conclusion with economic and timeline data collected from technology scale-up and piloting operations at the National Renewable Energy Laboratory (NREL) to motivate a more scientific, risk-minimized approach to biomass and waste carbon upgrading scale-up. Our proposed approach emphasizes maximizing information collection in the smallest, most agile, and least expensive experimental setups possible, emulating the mentality embraced by R&D across the petrochemical industry. Key points are supported by examples of successful and unsuccessful scale-up efforts undertaken at NREL and elsewhere. We close by showing that the U.S. national laboratory system is uniquely well equipped to serve as a hub to facilitate effective scale-up of promising biomass and waste carbon upgrading technologies., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Up to 30% of children with cleft palate will develop a severe speech disorder known as velopharyngeal insufficiency. Management of velopharyngeal insufficiency typically involves structural and functional assessment of the velum and pharynx by endoscopy and/or videofluoroscopy. These methods cannot provide direct evaluation of underlying velopharyngeal musculature. MR imaging offers an ideal imaging method, providing noninvasive, high-contrast, high-resolution imaging of soft-tissue anatomy. Furthermore, focused-speech MR imaging techniques can evaluate the function of the velum and pharynx during sustained speech production, providing critical physiologic information that supplements anatomic findings. The use of MR imaging for velopharyngeal evaluation is relatively novel, with limited literature describing its use in clinical radiology. Here we provide a practical approach to perform and interpret velopharyngeal MR imaging examinations. This article discusses the velopharyngeal MR imaging protocol, methods for interpreting velopharyngeal anatomy, and examples illustrating its clinical applications. This knowledge will provide radiologists with a new, noninvasive tool to offer to referring specialists., (© 2024 by American Journal of Neuroradiology.)

A woman in her 50s presented with acute pain and discolouration in the fingertips of both hands, without other features of connective tissue disease. The history was otherwise significant for abdominal bloating, altered bowel habit, urinary urgency and fatigue. Inflammatory markers, antinuclear antibodies, serum protein electrophoresis and complement levels were all normal. The tumour marker CA125 was significantly elevated, prompting a CT abdomen and pelvis, which revealed a large right-sided adnexal mass with multiple enhancing peritoneal and omental nodules and moderate ascites, suggestive of disseminated primary ovarian cancer.Digital ischaemia (DI) can be associated with cancer in up to 15% of cases. An underlying cancer should be suspected in patients presenting with new or worsening symptoms of DI. Prompt treatment with anticancer therapies can achieve complete resolution of DI., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Acne is the most common reason for dermatology consultation in adolescents and young adults. Consultation is often delayed despite unsuccessful self-treatment. Postponing effective treatment places acne sufferers at higher risk for permanent acne scars and post-inflammatory pigment changes., Aim: This review discusses clinical challenges with present therapeutic options for acne treatment and the role of a 1726 nm laser for acne., Methods: Current acne treatment guidelines were reviewed. A literature review was conducted for trials of light-based acne therapy. The selectivity of previous light-based therapies was reviewed., Results: Available acne therapy is effective, but treatment-related side effects are common. Acne treatment guidelines do not include recommendations for light-based treatments. Different types of light-based treatments have been tried but until now no wavelength specifically targeted sebaceous glands., Conclusion: The 1726 nm laser is safe and effective for treating mild to severe acne in all Fitzpatrick skin types. Acne resolution is apparent within the first month and improves for up to 2 years beyond treatment., (© 2023 The Authors. Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

The Saccharomyces species have diverged in their thermal growth profile. Both Saccharomyces cerevisiae and Saccharomyces paradoxus grow at temperatures well above the maximum growth temperature of Saccharomyces kudriavzevii and Saccharomyces uvarum but grow more poorly at lower temperatures. In response to thermal shifts, organisms activate a stress response that includes heat shock proteins involved in protein homeostasis and acquisition of thermal tolerance. To determine whether Saccharomyces species have diverged in their response to temperature, we measured changes in gene expression in response to a 12 °C increase or decrease in temperature for four Saccharomyces species and their six pairwise hybrids. To ensure coverage of subtelomeric gene families, we sequenced, assembled, and annotated a complete S. uvarum genome. In response to heat, the cryophilic species showed a stronger stress response than the thermophilic species, and the hybrids showed a mixture of parental responses that depended on the time point. After an initial strong response indicative of high thermal stress, hybrids with a thermophilic parent resolved their heat shock response to become similar to their thermophilic parent. Within the hybrids, only a small number of temperature-responsive genes showed consistent differences between alleles from the thermophilic and cryophilic species. Our results show that divergence in the heat shock response is mainly a consequence of a strain's thermal tolerance, suggesting that cellular factors that signal heat stress or resolve heat-induced changes are relevant to thermal divergence in the Saccharomyces species., (© The Author(s) 2023. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

Background: Antibiotic resistance is a major public health concern around the globe. As a result, researchers always look for new compounds to develop new antibiotic drugs for combating antibiotic-resistant bacteria. Bacteriocin becomes a promising antimicrobial agent to fight against antibiotic resistance, due to cases of both broad and narrow killing spectra. Sequence matching methods are widely used to identify bacteriocins by comparing them with the known bacteriocin sequences; however, these methods often fail to detect new bacteriocin sequences due to their high diversity. The ability to use a machine learning approach can help find new highly dissimilar bacteriocins for developing highly effective antibiotic drugs. The aim of this work is to develop a machine learning-based software tool called BaPreS (Bacteriocin Prediction Software) using an optimal set of features for detecting bacteriocin protein sequences with high accuracy. We extracted potential features from known bacteriocin and non-bacteriocin sequences by considering the physicochemical and structural properties of the protein sequences. Then we reduced the feature set using statistical justifications and recursive feature elimination technique. Finally, we built support vector machine (SVM) and random forest (RF) models using the selected features and utilized the best machine learning model to implement the software tool., Results: We applied BaPreS to an established dataset and evaluated its prediction performance. Acquired results show that the software tool can achieve a prediction accuracy of 95.54% for testing protein sequences. This tool allows users to add new bacteriocin or non-bacteriocin sequences in the training dataset to further enhance the predictive power of the tool. We compared the prediction performance of the BaPreS with a popular sequence matching-based tool and a deep learning-based method, and our software tool outperformed both., Conclusions: BaPreS is a bacteriocin prediction tool that can be used to discover new highly dissimilar bacteriocins for developing highly effective antibiotic drugs. This software tool can be used with Windows, Linux and macOS operating systems. The open-source software package and its user manual are available at https://github.com/suraiya14/BaPreS ., (© 2023. BioMed Central Ltd., part of Springer Nature.)

In this study, we developed and validated a novel method that allows for the extraction and quantitation of nicotine from a variety of commercially available oral tobacco products including loose and pouched traditional moist smokeless tobacco products, and oral tobacco-derived nicotine (OTDN) lozenges, gums, and pouches. The method employed an extraction technique consisting of salting-out assisted liquid-liquid extraction using sodium hydroxide and acetonitrile in conjunction with ultra-high pressure liquid chromatography coupled to mass spectrometry. Accurate quantitation was obtained using nicotine methyl- d 3 isotopically labeled internal standard. Chromatographic separation of nicotine and nicotine methyl- d 3 internal standard was achieved using a Waters Acquity C18 column (50 mm × 2.1 mm i.d., 2.5 μm) with 10 mM ammonium acetate buffer (pH = 10) and acetonitrile as mobile phase A and B, respectively. Using a gradient elution and a flow rate of 0.4 mL/min for 5 min runtime, nicotine eluted at 1.74 min. The method was validated according to ICH guidelines for all the sample types with an accuracy for nicotine within 89-109%. Repeatability and intermediate precision were both estimated to be ≤7% relative standard deviation (% RSD). This method is applicable for a wide range of traditional moist smokeless and OTDN tobacco products., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

We describe the synthesis and biochemical and cellular profiling of five partially reduced or demethylated analogs of the marine macrolide (-)-zampanolide (ZMP). These analogs were derived from 13-desmethylene-(-)-zampanolide (DM-ZMP), which is an equally potent cancer cell growth inhibitor as ZMP. Key steps in the synthesis of all compounds were the formation of the dioxabicyclo[15.3.1]heneicosane core by an intramolecular HWE reaction (67-95 % yield) and a stereoselective aza-aldol reaction with an (S)-BINOL-derived sorbamide transfer complex, to establish the C(20) stereocenter (24-71 % yield). As the sole exception, for the 5-desmethyl macrocycle, ring-closure relied on macrolactonization; however, elaboration of the macrocyclization product into the corresponding zampanolide analog was unsuccessful. All modifications led to reduced cellular activity and lowered microtubule-binding affinity compared to DM-ZMP, albeit to a different extent. For compounds incorporating the reactive enone moiety of ZMP, IC 50 values for cancer cell growth inhibition varied between 5 and 133 nM, compared to 1-12 nM for DM-ZMP. Reduction of the enone double bond led to a several hundred-fold loss in growth inhibition. The cellular potency of 2,3-dihydro-13-desmethylene zampanolide, as the most potent analog identified, remained within a ninefold range of that of DM-ZMP., (© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Competing Interests: None disclosed.

Background & Aims: Tumor necrosis factor (TNF) superfamily member tumor necrosis factor-like protein 1A (TL1A) has been associated with the susceptibility and severity of inflammatory bowel diseases. However, the function of the tumor necrosis factor-like protein 1A and its receptor death receptor 3 (DR3) in the development of intestinal inflammation is incompletely understood. We investigated the role of DR3 expressed by intestinal epithelial cells (IECs) during intestinal homeostasis, tissue injury, and regeneration., Methods: Clinical phenotype and histologic inflammation were assessed in C57BL/6 (wild-type), Tl1a -/- and Dr3 -/- mice in dextran sulfate sodium (DSS)-induced colitis. We generated mice with an IEC-specific deletion of DR3 (Dr3 ΔIEC ) and assessed intestinal inflammation and epithelial barrier repair. In vivo intestinal permeability was assessed by fluorescein isothiocyanate dextran uptake. Proliferation of IECs was analyzed by bromodeoxyuridine incorporation. Expression of DR3 messenger RNA was assessed by fluorescent in situ hybridization. Small intestinal organoids were used to determine ex vivo regenerative potential., Results: Dr3 -/- mice developed more severe colonic inflammation than wild-type mice in DSS-induced colitis with significantly impaired IEC regeneration. Homeostatic proliferation of IECs was increased in Dr3 -/- mice, but blunted during regeneration. Cellular localization and expression of the tight junction proteins Claudin-1 and zonula occludens-1 were altered, leading to increased homeostatic intestinal permeability. Dr3 ΔIEC mice recapitulated the phenotype observed in Dr3 -/- mice with increased intestinal permeability and IEC proliferation under homeostatic conditions and impaired tissue repair and increased bacterial translocation during DSS-induced colitis. Impaired regenerative potential and altered zonula occludens-1 localization also were observed in Dr3 ΔIEC enteroids., Conclusions: Our findings establish a novel function of DR3 in IEC homeostasis and postinjury regeneration independent of its established role in innate lymphoid cells and T-helper cells., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

A new method was developed and validated for the simultaneous determination of nicotine and tobacco-specific nitrosamines (TSNAs) 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N-nitrosonornicotine (NNN) in two different tests matrices: porcine buccal epithelium tissue and phosphate buffered saline (PBS) extracts of smokeless tobacco products. The novelty of this work is in the development of a liquid chromatography tandem mass spectrometry method that can provide simultaneous quantification of trace levels of TSNAs and high concentrations of nicotine in biological media. Precision, accuracy, and stability were evaluated during method validation to ensure the method was fit for purpose. Several sample preparation and extraction methods were evaluated to minimize matrix effects and maximize analyte recoveries. The method was accurate in the range of 81.1% - 117%; repeatability was estimated in the range of 1.5% - 13.6% across multiple concentrations. The linear regression correlation coefficient (R 2 ) was greater than 0.9959 for all analytes, and the limit of detection (LOD) was determined for nicotine, NNK, and NNN at 1 ng/mL 0.005 ng/mL, and 0.006 ng/ mL, respectively. Our method was found to be appropriate for the analysis of nicotine, NNN, and NNK in the porcine buccal epithelium and PBS extracts of smokeless tobacco products., (© 2022. The Author(s).)

Biomass conversion to fuels and chemicals is crucial to decarbonization, but choosing an advantageous upgrading pathway out of many options is challenging. Rigorously evaluating all candidate pathways (process simulation, product property testing) requires a prohibitive amount of research effort; even simple upgrading schemes have hundreds of possible permutations. We present a method enabling high-throughput screening by approximating upgrading unit operations and drop-in compatibility of products ( e.g. , fuel properties) and apply it to volatile fatty acid (VFA) conversion to liquid transportation fuels via a MATLAB script, VFA Upgrading to Liquid Transportation fUels Refinery Estimation (VULTURE). VULTURE selects upgrading configurations that maximize fuel blend bio-derived content. We validate VULTURE's approximations through surrogate fuel property testing and process simulation. Techno-economic and life cycle analyses suggest that VFA upgrading processes down-selected by VULTURE are profitable and have low carbon intensities, demonstrating the potential for the strategy to accelerate process development timelines at decreased costs., Competing Interests: DRV is Chief Technology Officer and EDC is an employee of Alder Fuels, LLC., (© 2022.)

Competitive fitness assays in liquid culture have been a mainstay for characterizing experimental evolution of microbial populations. Growth of microbial strains has also been extensively characterized by colony size and could serve as a useful alternative if translated to per generation measurements of relative fitness. To examine fitness based on colony size, we established a relationship between cell number and colony size for strains of Saccharomyces cerevisiae robotically pinned onto solid agar plates in a high-density format. This was used to measure growth rates and estimate relative fitness differences between evolved strains and their ancestors. After controlling for edge effects through both normalization and agar-trimming, we found that colony size is a sensitive measure of fitness, capable of detecting 1% differences. While fitnesses determined from liquid and solid mediums were not equivalent, our results demonstrate that colony size provides a sensitive means of measuring fitness that is particularly well suited to measurements across many environments., Competing Interests: The authors have declared that no competing interests exist.

We looked at the mutational fingerprints of three antiretroviral (anti-HIV) agents, azidothymidine (AZT), stavudine (STAV), and didanosine (DIDA) in the rpoB system of Escherichia coli and compared them with each other and with the fingerprints of trimethoprim and of spontaneous mutations in a wild-type and a mutT background. All three agents gave virtually identical fingerprints in the wild-type background, causing only A:T→C:G changes at 3 of the 12 A:T→C:G possible sites among the total of 92 possible base substitution mutations, even though AZT and STAV are thymidine analogs but DIDA is an adenosine analog. As all three agents are reverse transcriptase inhibitors, and act as chain blockers, the common fingerprint may be a property of chain blocking agents., (© 2022 Environmental Mutagen Society.)

Biotic homogenization-increasing similarity of species composition among ecological communities-has been linked to anthropogenic processes operating over the last century. Fossil evidence, however, suggests that humans have had impacts on ecosystems for millennia. We quantify biotic homogenization of North American mammalian assemblages during the late Pleistocene through Holocene (~30,000 ybp to recent), a timespan encompassing increased evidence of humans on the landscape (~20,000-14,000 ybp). From ~10,000 ybp to recent, assemblages became significantly more homogenous (>100% increase in Jaccard similarity), a pattern that cannot be explained by changes in fossil record sampling. Homogenization was most pronounced among mammals larger than 1 kg and occurred in two phases. The first followed the megafaunal extinction at ~10,000 ybp. The second, more rapid phase began during human population growth and early agricultural intensification (~2,000-1,000 ybp). We show that North American ecosystems were homogenizing for millennia, extending human impacts back ~10,000 years., (© 2022. The Author(s).)

Decomposition of polymers by heterogeneous catalysts presents a promising approach for reuse of waste plastics. We demonstrated non-hydrogenative decomposition of model polyolefins over proton-form and metal (Cu, Ni) ion-exchanged beta (BEA) zeolites at moderate temperatures (around 300 °C). Near complete polyolefin decomposition was observed in batch reactions monitored by thermogravimetric analysis, while decomposition at partial conversion was studied in flow reactions. Ni-exchanged zeolites produced H 2 at substantially higher rates (>10x) than other catalysts while also uniquely resisting deactivation over time. Application of the delplot formalism offered insights into the reaction network for polyolefin decomposition over Ni/BEA most notably that H 2 is solely a primary product. We deduce that H 2 production is catalyzed by activation of C-H bonds at ionic Ni sites, and H 2 prevents buildup of polyaromatic coke species in Ni-exchanged zeolites that deactivate Cu-exchanged and protonic zeolites., (© 2022 Wiley-VCH GmbH.)

Under harsh Pleistocene climates, migration and other forms of seasonally patterned landscape use were likely critical for reproductive success of mastodons ( Mammut americanum ) and other megafauna. However, little is known about how their geographic ranges and mobility fluctuated seasonally or changed with sexual maturity. We used a spatially explicit movement model that coupled strontium and oxygen isotopes from two serially sampled intervals (5+ adolescent years and 3+ adult years) in a male mastodon tusk to test for changes in landscape use associated with maturation and reproductive phenology. The mastodon's early adolescent home range was geographically restricted, with no evidence of seasonal preferences. Following inferred separation from the matriarchal herd (starting age 12 y), the adolescent male's mobility increased as landscape use expanded away from his natal home range (likely central Indiana). As an adult, the mastodon's monthly movements increased further. Landscape use also became seasonally structured, with some areas, including northeast Indiana, used only during the inferred mastodon mating season (spring/summer). The mastodon died in this area (>150 km from his core, nonsummer range) after sustaining a craniofacial injury consistent with a fatal blow from a competing male's tusk during a battle over access to mates. Northeast Indiana was likely a preferred mating area for this individual and may have been regionally significant for late Pleistocene mastodons. Similarities between mammutids and elephantids in herd structure, tusk dimorphism, tusk function, and the geographic component of male maturation indicate that these traits were likely inherited from a common ancestor.

Heparan sulfate (HS) is a highly sulfated natural carbohydrate that plays crucial roles in cancer, inflammation, and angiogenesis. Heparanase (HPSE) is the sole HS degrading endoglycosidase that cleaves HS at structure-dependent sites along the polysaccharide chain. Overexpression of HPSE by cancer cells correlates with increased tumor size and enhanced metastasis. Previously we have shown that a tetramer HS mimetic is a potent HPSE inhibitor displaying remarkable anticancer activity in vivo. Building on that work, we report the synthesis and testing of a novel library of single entity trimer glycolipid mimetics that effectively inhibit HPSE at low nanomolar concentrations. A lipophilic arm was introduced to assess whether an improvement of pharmacokinetics and plasma residence time would offset the reduction in charge and multivalency. Preclinical tests in a mouse syngeneic model showed effective tumor growth inhibition by the tetramer but not the trimer glycomimetic., (© 2022 The Authors. Chemistry - An Asian Journal published by Wiley-VCH GmbH.)

Axial gradient echo T2*-weighed MRI of the spine is a valuable diagnostic tool with several advantages over axial T2-weighted TSE MRI, but it suffers from a low signal-to-noise ratio (SNR) and inconsistent image quality. This work investigates the potential of spiral MRI to reduce artifacts and produce improved SNR and image quality in axial T2*-weighted gradient echo MRI of the spine of pediatric patients. For the purposes of image quality evaluation, 15 pediatric patients were recruited among those scheduled for a routine spine or brain exam at 1.5 T. Pediatric spine images were rated by three pediatric neuroradiologists on a subjective scale of 1-5 using four image quality criteria. Image quality scores were evaluated using non-parametric Wilcoxon signed-rank testing and a mixed effects logistic regression model. Significant differences were found in the image quality scores in favor of spiral MRI. The odds of spiral images receiving an overall image quality score higher than 3 was 16.3 times greater than the odds of Cartesian images receiving a score higher than 3 (p < 0.001, 95% CI of 4.6 to 86) as calculated using a mixed effects logistic regression model. A quantitative comparison was also performed on a single volunteer to illustrate the SNR benefit of spiral MRI. In conclusion, spiral MRI was found to provide equal or better image quality than Cartesian MRI in axial T2*-weighted gradient echo MRI in the spine of a small cohort of pediatric patients at 1.5 T., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The three-dimensional (3D) propagation effects of horizontal refraction and diffraction were measured on a tetrahedral hydrophone array deployed near the coast of Block Island, RI. Linear frequency modulated chirp signals, centered at 1 kHz with a 400 Hz bandwidth, were transmitted from a ship moving out of the acoustic shadow zone blocked by the island from the perspective of the hydrophone array. The observed shadow zone boundary was consistent with the prediction made by a 3D sound propagation model incorporating high-resolution bathymetry and realistic sound speed obtained from a data-assimilated regional ocean model. The 3D modal ray calculation provided additional insight into the frequency dependence of the signal spreading. This analysis found that the modes at higher frequencies can propagate closer to the coast of the island with shallower modal cutoff depths, where the sound energy penetrates the sloping seafloor at supercritical incidence. The evidence of horizontal caustics of the sound was shown in the parabolic equation and modal ray models by comparing to the arrival pattern observed in the data. The arrival angle measurements on the tetrahedral array show the complex propagation patterns, including the diffracted energy in the island shadow and acoustic energy refracted away from the island.

Theories of early cooperation in human society often draw from a small sample of ethnographic studies of surviving populations of hunter-gatherers, most of which are now sedentary. Borneo hunter-gatherers (Punan, Penan) have seldom figured in comparative research because of a decades-old controversy about whether they are the descendants of farmers who adopted a hunting and gathering way of life. In 2018 we began an ethnographic study of a group of still-nomadic hunter-gatherers who call themselves Punan Batu (Cave Punan). Our genetic analysis clearly indicates that they are very unlikely to be the descendants of neighbouring agriculturalists. They also preserve a song language that is unrelated to other languages of Borneo. Dispersed travelling groups of Punan Batu with fluid membership use message sticks to stay in contact, co-operate and share resources as they journey between rock shelters and forest camps. Message sticks were once widespread among nomadic Punan in Borneo, but have largely disappeared in sedentary Punan villages. Thus the small community of Punan Batu offers a rare glimpse of a hunting and gathering way of life that was once widespread in the forests of Borneo, where prosocial behaviour extended beyond the face-to-face community, facilitating successful collective adaptation to the diverse resources of Borneo's forests., (© The Author(s) 2022.)

Class III β-tubulin (βIII-tubulin) is frequently overexpressed in human tumors and is associated with resistance to microtubule-targeting agents, tumor aggressiveness, and poor patient outcome. Understanding the mechanisms regulating βIII-tubulin expression and the varied functions βIII-tubulin may have in different cancers is vital to assess the prognostic value of this protein and to develop strategies to enhance therapeutic benefits in βIII-tubulin overexpressing tumors. Here we gather all the available evidence regarding the clinical implications of βIII-tubulin overexpression in cancer, describe factors that regulate βIII-tubulin expression, and discuss current understanding of the mechanisms underlying βIII-tubulin-mediated resistance to microtubule-targeting agents and tumor aggressiveness. Finally, we provide an overview of emerging therapeutic strategies to target tumors that overexpress βIII-tubulin., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The present research investigates how psychological mechanisms and social network structures generate patterns of cultural change and diversity. The two psychological mechanisms studied here are cultural drift and indirect minority influence; the former is parameterized by an error rate ε) and the latter by a leniency threshold (λ). The patterns of cultural change are examined in terms of magnitude (small vs. large), speed (gradual vs. rapid), and frequency (frequent vs. rare). Diversity and polarization in a society are examined in terms of global cultural variation (inverse Simpson index) and local neighborhood difference (Hamming distance). Key findings are that in networks with high connectivity or local community structures (complete, scale-free, random, and modular networks) cultural drift can produce a rapid, large, and rare pattern of cultural change (punctuated equilibrium), whereas in lattice or small world networks, it produces a more gradual change pattern. Indirect minority influence robustly produces a gradual, small, and frequent pattern of cultural change (gradualism) across various network structures. When cultural change occurs in social networks that have a modular community structure, indirect minority influence generates a regime of cultural diversity whereas cultural drift generates a polarized regime. Finally, cultural drift and indirect minority influence generate distinct tipping points for social change in different network structures, but prediction of whether and when cultural change emerges is difficult at tipping points in both cases. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

The statistical analysis of historic pressure and temperature profiles from radiosonde launches for use in the fitting of molecular oxygen line shapes is presented. As the O 2 mixing ratio is nearly constant throughout the lower atmosphere, only variations in pressure and temperature profiles will affect the fit of observed O 2 features in Laser Heterodyne Radiometry (LHR) spectra. Radiosonde temperature and pressure data are extracted from the Integrated Global Radiosonde Archive (IGRA) for a given station, date, and launch time. Data may be extracted for a single launch, for the same date over several years, and/or within a window centered on a target date. The temperature and pressure profiles are further characterized by the statistical variation in coefficients of polynomial fits in altitude. The properties of the probability distributions for each coefficient are used to constrain fits of O 2 line shapes through Nelder-Mead optimization. The refined temperature and pressure profiles are then used in the retrieval of vertically resolved mixing ratios for greenhouse gases (GHGs) measured in the same instrument. In continuous collections, each vertical profile determination may be treated as a Bayesian prior to inform subsequent measurements and provide an estimate of uncertainties.

We have extensively characterized base substitution mutations in the 795 base pair (bp) long E. coli thyA gene to define as many of the base substitution mutational sites that inactivate the gene as possible. The resulting catalog of mutational sites constitutes a system with up to 5 times as many sites for monitoring each of the six base substitution mutations as the widely used rpoB/Rif r system. We have defined 75 sites for the G:C -> A:T transition, 68 sites for the G:C -> T:A transversion, 53 sites for the G:C -> C:G transversion, 49 sites for the A:T -> G:C transition, 39 sites for the A:T -> T:A transversion, and 59 sites for the A:T -> C:G transversion. The system is thus comprised of 343 base substitution mutations at 232 different base pairs, all of which can be sequenced with a single primer pair. This allows for the examination of mutational spectra using a more detailed probe of known mutations, while still allowing one to compare the number of repeated occurrences at specific sites. We have examined several mutagens and mutators with this system, and show its utility by looking at the spectrum of cisplatin, that has a single hotspot, underscoring the value of having as large an array of sites as possible at which one can monitor repeat occurrences. To test for regions of the gene that might be hotspots for a number of mutagens, or "hot" (mutaphilic) regions, we have looked at the ratio of mutations per set of an equal number of mutational sites throughout the gene. The resulting graphs suggest that there are "hot" regions at intervals, and this may reflect aspects of secondary structures, of the higher order structure of the chromosome, or perhaps the nucleoid structure of the chromosome plus histone-like protein complexes., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Cigarette smoking is the major cause of chronic obstructive pulmonary disease. Considerable attention has been paid to the reduced harm potential of nicotine-containing inhalable products such as electronic cigarettes (e-cigarettes). We investigated the effects of mainstream cigarette smoke (CS) and e-vapor aerosols (containing nicotine and flavor) generated by a capillary aerosol generator on emphysematous changes, lung function, and molecular alterations in the respiratory system of female Apoe -/- mice. Mice were exposed daily (3 h/day, 5 days/week) for 6 months to aerosols from three different e-vapor formulations-(1) carrier (propylene glycol and vegetable glycerol), (2) base (carrier and nicotine), or (3) test (base and flavor)-or to CS from 3R4F reference cigarettes. The CS and base/test aerosol concentrations were matched at 35 µg nicotine/L. CS exposure, but not e-vapor exposure, led to impairment of lung function (pressure-volume loop area, A and K parameters, quasi-static elastance and compliance) and caused marked lung inflammation and emphysematous changes, which were confirmed histopathologically and morphometrically. CS exposure caused lung transcriptome (activation of oxidative stress and inflammatory responses), lipidome, and proteome dysregulation and changes in DNA methylation; in contrast, these effects were substantially reduced in response to the e-vapor aerosol exposure. Compared with sham, aerosol exposure (carrier, base, and test) caused a slight impact on lung inflammation and epithelia irritation. Our results demonstrated that, in comparison with CS, e-vapor aerosols induced substantially lower biological and pathological changes in the respiratory tract associated with chronic inflammation and emphysema.

Effective treatments for chronic pain without abuse liability are urgently needed. One in 5 adults suffer chronic pain and half of these patients report inefficient treatment. Mu opioid receptor agonists (MOP), including oxycodone, tramadol and morphine, are often prescribed to treat chronic pain, however, use of drugs targeting MOP can lead to drug dependency, tolerance and overdose deaths. Kappa opioid receptor (KOP) agonists have antinociceptive effects without abuse potential; however, they have not been utilised clinically due to dysphoria and sedation. We hypothesise that mixed opioid receptor agonists targeting the KOP and delta opioid receptor (DOP) would have a wider therapeutic index, with the rewarding effects of DOP negating the negative effects of KOP. MP1104, an analogue of 3-Iodobenzoyl naltrexamine, is a novel mixed opioid receptor agonist with potent antinociceptive effects mediated via KOP and DOP in mice without rewarding or aversive effects. In this study, we show MP1104 has potent, long-acting antinociceptive effects in the warm-water tail-withdrawal assay in male and female mice and rats; and is longer acting than morphine. In the paclitaxel-induced neuropathic pain model in mice, MP1104 reduced both mechanical and cold allodynia and unlike morphine, did not produce tolerance when administered daily for 23 days. Moreover, MP1104 did not induce sedative effects in the open-field locomotor activity test, respiratory depression in mice using whole-body plethysmography, or have cross-tolerance with morphine. This data supports the therapeutic development of mixed opioid receptor agonists, particularly mixed KOP/DOP agonists, as non-addictive pain medications with reduced tolerance., (Copyright © 2020. Published by Elsevier Ltd.)