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Brown adipose tissue (BAT) regulates metabolic physiology. However, nearly all mechanistic studies of BAT protein function occur in a single inbred mouse strain, which has limited the understanding of generalizable mechanisms of BAT regulation over physiology. Here, we perform deep quantitative proteomics of BAT across a cohort of 163 genetically defined diversity outbred mice, a model that parallels the genetic and phenotypic variation found in humans. We leverage this diversity to define the functional architecture of the outbred BAT proteome, comprising 10,479 proteins. We assign co-operative functions to 2,578 proteins, enabling systematic discovery of regulators of BAT. We also identify 638 proteins that correlate with protection from, or sensitivity to, at least one parameter of metabolic disease. We use these findings to uncover SFXN5, LETMD1, and ATP1A2 as modulators of BAT thermogenesis or adiposity, and provide OPABAT as a resource for understanding the conserved mechanisms of BAT regulation over metabolic physiology.

Introduction Alopecia areata (AA) is a disease that manifests as patchy hair loss on the scalp and other parts of the body; severe disease may result in disfigurement, functional impairment, and significant psychological distress. This condition is understood to be caused by autoimmunity to the hair follicle and subsequent arrest of hair growth. New medications, baricitinib and ritlecitinib, belong to the Janus kinase (JAK) inhibitor family and are among the first FDA-approved treatments for severe AA. In this manuscript, we aim to answer the question: What treatment options exist for AA in the military health care system (MHS)? In doing so, we review the pathogenesis, physical and psychosocial impact of AA, conventional treatment of AA, and the efficacy and safety of baricitinib and ritlecitinib. Methods A literature search was performed using PubMed, Embase, and Ovid for the history and pathogenesis of AA, psychosocial impact of disease, functional impairments, and current treatments. Keywords "alopecia areata," "current therapy for alopecia areata," "pathogenesis alopecia areata," "baricitinib," "ritlecitinib," "JAK inhibitor alopecia," "JAK inhibitor safety," "baricitinib efficacy," "alopecia eyelash," "alopecia nails," and "psychosocial impact of alopecia" were used for the search. The TRICARE manual was searched for guidelines applicable to the treatment of AA, DoD Instruction 6130.03 Volume 2 for medical standards for military service, and the U.S. Central Command Modification 15 for fitness of deployment to Central Command area of operations. Results Traditional treatments such as intralesional steroids may be effective for some patients, but difficulty lies in controlling extensive or refractory disease. Janus kinase inhibitors, baricitinib and ritlecitinib, are found effective at improving severe refractory disease; baricitinib induced hair regrowth in 32.6% more patients than placebo, and ritlecitinib was found to be superior to placebo by at least 24%. Currently, there is no coverage for therapeutic treatment of hair growth in the MHS. Additionally, military members are disqualified for continued service if they require immunomodulator medications such as baricitinib and ritlecitinib. Those on immunomodulators are unable to deploy worldwide. Conclusions Baricitinib and ritlecitinib are effective treatments for widespread, progressive, and refractory AA. Although JAK inhibitors demonstrate improved effectiveness compared to non-immunomodulator treatments, their use in the MHS for this purpose is limited. [ABSTRACT FROM AUTHOR]

Simple Summary: The appropriate use of antibiotics among companion animal (CA) practitioners has recently been a subject of interest. Surveys can assist in understanding the role of CA veterinarians in antimicrobial use. This study aimed to survey the antimicrobial prescribing practices of Sri Lankan veterinarians associated with common dog and cat bacterial infections of the skin, ear, and urinary tract, and to identify factors associated with bacterial culture and antimicrobial susceptibility testing (AST) to aid in the selection of the most appropriate antibiotic treatment. A survey was distributed among Sri Lankan veterinarians. Most veterinarians were from CA-only practices (63%); the remainder worked in government, mixed, or other practices. Based on the World Health Organization's criteria, 2% (13/783) of cases were treated with drugs authorized for human use only; 24% (187/783) were treated with highest-priority critically important antimicrobials; 5% (37/783) were treated with critically important antimicrobials, and 67% (523/783) were treated with highly important antimicrobials. The antimicrobial treatment of abscesses, skin, and urinary and ear infections was based on AST for only 12% (72/579) of animals. When used, AST was significantly associated with the prescribing of tetracyclines, ear or urinary tract infections, the practice type, and continuing professional development. Education is recognized as a pathway toward improved veterinary antimicrobial stewardship and part of One Health programs. Veterinarians are essential in antimicrobial stewardship. Companion animal (CA) practitioners have recently received more attention. There are few relevant studies on CA antimicrobial prescribing practices in South Asia. A cross-sectional survey on the antimicrobial prescribing practices of Sri Lankan veterinarians associated with six common CA infections and factors associated with bacterial culture and antimicrobial susceptibility testing (AST) was conducted. A survey of antimicrobial prescribing practices was distributed via email or professional events among veterinarians treating CAs. There were 127 respondents. Most were from CA-only practices (63%); the remainder worked in government, mixed, or other practices. Based on the World Health Organization's criteria, 1.7% (13/783) of cases were treated with drugs authorized for human use only; 23.9% (187/783) were treated with highest-priority critically important antimicrobials; 4.7% (37/783) were treated with critically important antimicrobials, and 66.8% (523/783) were treated with highly important antimicrobials. The antimicrobial treatment of abscesses, skin, urinary, and ear infections was usually empirical, with only 12.4% (72/579) of cases utilizing AST to guide diagnosis and treatment. The use of AST was significantly associated with the type of antibiotic prescribed, the medical condition, the practice type, and continuing professional development, with the latter recognized as a pathway toward improved veterinary antimicrobial stewardship and the implementation of a One Health approach. [ABSTRACT FROM AUTHOR]

We discuss a woman with a history of non-melanoma skin cancer who presented with a new erythematous macule on her right temple. On examination with Wood lamp the well-demarcated macule fluoresced pink making neoplasm unlikely. Further history and physical examination suggested an inadvertent ink stain and the patient was spared a biopsy highlighting the importance of eliciting a good history and performing a detailed physical examination with additional tools such as a Wood lamp when necessary.

The efficacy of β-lactam antibiotics is threatened by the emergence and global spread of metallo-β-lactamase (MBL) mediated resistance, specifically New Delhi metallo-β-lactamase-1 (NDM-1). By utilization of fragment-based drug discovery (FBDD), a new class of inhibitors for NDM-1 and two related β-lactamases, IMP-1 and VIM-2, was identified. On the basis of 2,6-dipicolinic acid (DPA), several libraries were synthesized for structure-activity relationship (SAR) analysis. Inhibitor 36 (IC50 = 80 nM) was identified to be highly selective for MBLs when compared to other Zn(II) metalloenzymes. While DPA displayed a propensity to chelate metal ions from NDM-1, 36 formed a stable NDM-1:Zn(II):inhibitor ternary complex, as demonstrated by 1H NMR, electron paramagnetic resonance (EPR) spectroscopy, equilibrium dialysis, intrinsic tryptophan fluorescence emission, and UV-vis spectroscopy. When coadministered with 36 (at concentrations nontoxic to mammalian cells), the minimum inhibitory concentrations (MICs) of imipenem against clinical isolates of Eschericia coli and Klebsiella pneumoniae harboring NDM-1 were reduced to susceptible levels.

Understanding causes of insect population declines is essential for the development of successful conservation plans, but data limitations restrict assessment across spatial and temporal scales. Museum records represent a source of historical data that can be leveraged to investigate temporal trends in insect communities. Native lady beetle decline has been attributed to competition with established alien species and landscape change, but the relative importance of these drivers is difficult to measure with short‐term field‐based studies. We assessed distribution patterns for native lady beetles over 12 decades using museum records, and evaluated the relative importance of alien species and landscape change as factors contributing to changes in communities. We compiled occurrence records for 28 lady beetle species collected in Ohio, USA, from 1900 to 2018. Taxonomic beta‐diversity was used to evaluate changes in lady beetle community composition over time. To evaluate the relative influence of temporal, spatial, landscape, and community factors on the captures of native species, we constructed negative binomial generalized additive models. We report evidence of declines in captures for several native species. Importantly, the timing, severity, and drivers of these documented declines were species‐specific. Land cover change was associated with declines in captures, particularly for Coccinella novemnotata which declined prior to the arrival of alien species. Following the establishment and spread of alien lady beetles, processes of species loss/gain and turnover shifted communities toward the dominance of a few alien species beginning in the 1980s. Because factors associated with declines in captures were highly species‐specific, this emphasizes that mechanisms driving population losses cannot be generalized even among closely related native species. These findings also indicate the importance of museum holdings and the analysis of species‐level data when studying temporal trends in insect populations. [ABSTRACT FROM AUTHOR]

Simple Summary: Factors affecting dog owners' compliance with veterinary medication recommendations were examined, and barriers and aids to administering medications were identified. Findings revealed that older dogs had more compliant owners, and clients who used no aids for medication were more likely to be compliant. Almost half of owners reported not being shown how to administer the medication, and one-third faced challenges, mainly due to resistant pets. Nearly half of the surveyed clients were noncompliant, which is higher than previously reported in other studies. Our study highlights the necessity of enhancing client compliance with veterinary medication instructions for dogs. It emphasizes the importance of providing standardized instructions and guidance, including demonstrating how to administer medications. Ensuring that prescribed oral medications are palatable and easy to administer before patient discharge may contribute to improved patient outcomes. Client compliance with prescribed medication instructions to treat their pets is a concern. This study describes factors associated with the noncompliance of dog owners with veterinary recommendations for medication, as well as client-reported barriers and aids to administering medications. A cross-sectional survey of dog owners' compliance with veterinary medication recommendations was performed from 9 January 2019 to 18 July 2020. A convenience sample of owners who prescribed medication for their dogs during or following elective veterinary examination was surveyed regarding medication administration experience and compliance. Owners were followed up to determine if the course of medication had been completed. Compliance data were analyzed descriptively. Logistic regression was performed with compliance as the outcome. Medication noncompliance was recorded for 47% (71/151) of owners. Increasing dog age was associated with better owner compliance (p < 0.05). Pet owners who used "nothing" as an aid to medicating were less likely to be noncompliant (p < 0.05). Forty-seven percent (71/151) of owners reported that "nobody" showed them how to administer the medication. One-third of dog owners (47/151) reported challenges in medicating their pets. The most common reason cited by clients reporting challenges was a resistant pet. Demonstration of medication administration techniques and discussion about available aids to medicating a pet may improve client compliance. [ABSTRACT FROM AUTHOR]

Author(s): Yizhi Sun [sup.1] [sup.2] , Janane F. Rahbani [sup.3] [sup.4] , Mark P. Jedrychowski [sup.1] [sup.2] , Christopher L. Riley [sup.1] [sup.2] , Sara Vidoni [sup.1] [sup.2] , Dina [...], Adaptive thermogenesis has attracted much attention because of its ability to increase systemic energy expenditure and to counter obesity and diabetes.sup.1-3. Recent data have indicated that thermogenic fat cells use creatine to stimulate futile substrate cycling, dissipating chemical energy as heat.sup.4,5. This model was based on the super-stoichiometric relationship between the amount of creatine added to mitochondria and the quantity of oxygen consumed. Here we provide direct evidence for the molecular basis of this futile creatine cycling activity in mice. Thermogenic fat cells have robust phosphocreatine phosphatase activity, which is attributed to tissue-nonspecific alkaline phosphatase (TNAP). TNAP hydrolyses phosphocreatine to initiate a futile cycle of creatine dephosphorylation and phosphorylation. Unlike in other cells, TNAP in thermogenic fat cells is localized to the mitochondria, where futile creatine cycling occurs. TNAP expression is powerfully induced when mice are exposed to cold conditions, and its inhibition in isolated mitochondria leads to a loss of futile creatine cycling. In addition, genetic ablation of TNAP in adipocytes reduces whole-body energy expenditure and leads to rapid-onset obesity in mice, with no change in movement or feeding behaviour. These data illustrate the critical role of TNAP as a phosphocreatine phosphatase in the futile creatine cycle. Tissue nonspecific alkaline phosphatase (TNAP) within mitochondria hydrolyses phosphocreatine to initiate a futile cycle of creatine dephosphorylation and phosphorylation in thermogenic fat cells.

The inhibitory-kappaB kinases (IKKs) IKKα and IKKβ play central roles in regulating the non-canonical and canonical NF-κB signalling pathways. Whilst the proteins that transduce the signals of each pathway have been extensively characterised, the clear dissection of the functional roles of IKKα-mediated non-canonical NF-κB signalling versus IKKβ-driven canonical signalling remains to be fully elucidated. Progress has relied upon complementary molecular and pharmacological tools; however, the lack of highly potent and selective IKKα inhibitors has limited advances. Herein, we report the development of an aminoindazole-pyrrolo[2,3-b]pyridine scaffold into a novel series of IKKα inhibitors. We demonstrate high potency and selectivity against IKKα over IKKβ in vitro and explain the structure–activity relationships using structure-based molecular modelling. We show selective target engagement with IKKα in the non-canonical NF-κB pathway for both U2OS osteosarcoma and PC-3M prostate cancer cells by employing isoform-related pharmacodynamic markers from both pathways. Two compounds (SU1261 [IKKα Ki = 10 nM; IKKβ Ki = 680 nM] and SU1349 [IKKα Ki = 16 nM; IKKβ Ki = 3352 nM]) represent the first selective and potent pharmacological tools that can be used to interrogate the different signalling functions of IKKα and IKKβ in cells. Our understanding of the regulatory role of IKKα in various inflammatory-based conditions will be advanced using these pharmacological agents. [ABSTRACT FROM AUTHOR]