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Abstract Allosteric modulation of muscarinic acetylcholine receptors (mAChR) has been identified as a potential strategy for regulating cholinergic signaling in the treatment of various neurological disorders. Most positive allosteric modulators (PAMs) of mAChR enhance agonist affinity and potency, while very few PAMs (e.g., amiodarone) selectively enhance G protein coupling efficacy. The key structural features of amiodarone responsible for enhancement of mAChR efficacy were examined in CHO cells expressing M1 receptors. Subsequent incorporation of these structural features into previously identified allosteric modulators of potency (i.e., n-benzyl isatins) generated ligands that demonstrated similar or better enhancement of mAChR efficacy, lower in vivo toxicity, and higher allosteric binding affinity relative to amiodarone. Notable ligands include 8a, c which respectively demonstrated the strongest binding affinity and the most robust enhancement of mAChR efficacy as calculated from an allosteric operational model. Amiodarone derivatives and hybrid ligands were additionally screened in wildtype zebrafish (Danio rerio) to provide preliminary in vivo toxicity data as well as to observe effects on locomotor and turning behaviors relative to other mAChR PAMs. Several compounds, including 8a, c, reduced locomotor activity and increased measures of turning behaviors in zebrafish, suggesting that allosteric modulation of muscarinic receptor efficacy might be useful in the treatment of repetitive behaviors associated with autism spectrum disorder (ASD) and other neuropsychiatric disorders.

Abstract Cauldrons, vessels that are simultaneously common and enigmatic, offer insights into past cultural and social traditions. While assumed to possess a special function, what these cauldrons contained is still largely mysterious. These vessels, such as those made from bronze or copper alloys, function as reservoirs for ancient organics through the antibacterial qualities provided by the metal surfaces. Here we show, through protein analysis, that cauldrons from the Final Bronze Age (ca. 2700 BP) were primarily used to collect blood from ruminants, primarily caprines, likely for the production of sausages in a manner similar to contemporary practices in Mongolia’s rural countryside. Our findings present a different function from the recent findings of cooked meat in copper-alloy vessels from the northern Caucasus 2000 years earlier, exposing the diversity in food preparation techniques. Our secondary findings of bovine milk within the cauldron, including peptides specific to Bos mutus, pushes back their regional domestication into the Bronze Age.

Abstract Background Protecting public health from infectious diseases often relies on the cooperation of citizens, especially when self-care interventions are the only viable tools for disease mitigation. Accordingly, social aspects related to public opinion have been studied in the context of the recent COVID-19 pandemic. However, a comprehensive understanding of the effects of opinion-related factors on disease spread still requires further exploration. Methods We propose an agent-based simulation framework incorporating opinion dynamics within an epidemic model based on the assumption that mass media channels play a leading role in opinion dynamics. The model simulates how opinions about preventive interventions change over time and how these changes affect the cumulative number of cases. We calibrated our simulation model using YouGov survey data and WHO COVID-19 new cases data from 15 different countries. Based on the calibrated models, we examine how different opinion-related factors change the consequences of the epidemic. We track the number of total new infections for analysis. Results Our results reveal that the initial level of public opinion on preventive interventions has the greatest impact on the cumulative number of cases. Its normalized permutation importance varies between 69.67% and 96.65% in 15 models. The patterns shown in the partial dependence plots indicate that other factors, such as the usage of the pro-intervention channel and the response time of media channels, can also bring about substantial changes in disease dynamics, but only within specific ranges of the dominant factor. Conclusions Our results reveal the importance of public opinion on intervention during the early stage of the pandemic in protecting public health. The findings suggest that persuading the public to take actions they may be hesitant about in the early stages of epidemics is very costly because taking early action is critical for mitigating infectious diseases. Other opinion-related factors can also lead to significant changes in epidemics, depending on the average level of public opinion in the initial stage. These findings underscore the importance of media channels and authorities in delivering accurate information and persuading community members to cooperate with public health policies.

The North Central Asia Isotopic Database (NCAID) is an open-access dataset of stable isotope measurements from archaeological remains, spanning from the Early Neolithic until present-day in North Central Asia. With 3,143 individual entries corresponding to data accumulated over more than 20 years of research, this comprehensive dataset encompasses measurements of stable carbon and nitrogen isotopes in organic fractions from archaeological humans, animals, and plants. NCAID incorporates diverse supporting information, providing geographical information, archaeological context descriptions, and chronology. This resource facilitates research into past human lifeways, paleo-environments/climates, and animal management practices throughout North Central Asia and will be continually updated as more novel data is released.

Abstract Mood disorders, including depression and anxiety, affect almost one-fifth of the world’s adult population and are becoming increasingly prevalent. Mutations in circadian clock genes have previously been associated with mood disorders both directly and indirectly through alterations in circadian phase, suggesting that the circadian clock influences multiple molecular pathways involved in mood. By targeting previously identified single nucleotide polymorphisms (SNPs) that have been implicated in anxiety and depressive disorders, we use a combination of statistical and machine learning techniques to investigate associations with the generalized anxiety disorder assessment (GAD-7) scores in a UK Biobank sample of 90,882 individuals. As in previous studies, we observed that females exhibited higher GAD-7 scores than males regardless of genotype. Interestingly, we found no significant effects on anxiety from individual circadian gene variants; only circadian genotypes with multiple SNP variants showed significant associations with anxiety. For both sexes, severe anxiety is associated with a 120-fold increase in odds for individuals with CRY2_AG(rs1083852)/ZBTB20_TT(rs1394593) genotypes and is associated with a near 40-fold reduction in odds for individuals with PER3-A_CG(rs228697)/ZBTB20_TT(rs1394593) genotypes. We also report several sex-specific associations with anxiety. In females, the CRY2/ZBTB20 genotype combination showed a > 200-fold increase in odds of anxiety and PER3/ZBTB20 and CRY1 /PER3-A genotype combinations also appeared as female risk factors. In males, CRY1/PER3-A and PER3-B/ZBTB20 genotype combinations were associated with anxiety risk. Mediation analysis revealed direct associations of CRY2/ZBTB20 variant genotypes with moderate anxiety in females and CRY1/PER3-A variant genotypes with severe anxiety in males. The association of CRY1/PER3-A variant genotypes with severe anxiety in females was partially mediated by extreme evening chronotype. Our results reinforce existing findings that females exhibit stronger anxiety outcomes than males, and provide evidence for circadian gene associations with anxiety, particularly in females. Our analyses only identified significant associations using two-gene combinations, underscoring the importance of combined gene effects on anxiety risk. We describe novel, robust associations between gene combinations involving the ZBTB20 SNP (rs1394593) and risk of anxiety symptoms in a large population sample. Our findings also support previous findings that the ZBTB20 SNP is an important factor in mood disorders, including seasonal affective disorder. Our results suggest that reduced expression of this gene significantly modulates the risk of anxiety symptoms through direct influences on mood-related pathways. Together, these observations provide novel links between the circadian clockwork and anxiety symptoms and identify potential molecular pathways through which clock genes may influence anxiety risk.

The waterways adjacent to Washington DC, USA have a history of contamination from heavy metals, nutrients, pesticides, and industrial chemicals. Among the chemicals of concern are PAHs, which are a historical contaminant but also have modern pyrogenic and petrogenic sources in the area’s waterways. Another group of contaminants that are of emerging interest are siloxanes (silicones), which are widely used as lubricants, sealants, and cosmetics. Some lower-molecular-weight siloxanes are regulated by the EU in recognition of harm to aquatic life, but there are no restrictions in the United States. In fact, studies examining water pollutants do not typically test for siloxanes. Here, we present the concentrations of specific PAHs and siloxanes from surface sediments in the Potomac and Anacostia Rivers (including the Anacostia’s tributaries) collected between 2018 and 2023. Both D5 (decamethylcyclopentasiloxane) and D6 (dodecamethylcyclohexasiloxane) were found in most locations, with concentrations averaging 0.13 and 0.006 mg/g (dry mass), respectively. Pyrene, fluoranthene, bibenzyl, and phenanthrene were also found in the Anacostia and some of its tributaries, with concentrations increasing downstream. In the Potomac, concentrations were generally lower than those observed in the Anacostia. Based on ratios of pyrene to fluoranthene + pyrene, the likely source of PAHs was petrogenic.

Silver-Russell syndrome (SRS, OMIM, 180860) is a rare genetic disorder with a wide spectrum of symptoms. The most common features are intrauterine growth retardation (IUGR), poor postnatal development, macrocephaly, triangular face, prominent forehead, body asymmetry, and feeding problems. The diagnosis of SRS is based on a combination of clinical features. Up to 60% of SRS patients have chromosome 7 or 11 abnormalities, and G] (NM_000612) in a child with severe IUGR and clinical features of SRS and confirm the utility of targeted exome sequencing in patients with negative results to common genetic analyses. In addition, we report that long-term growth hormone treatment improves height SDS in this patient.

Proteomic evidence from permafrost human dental calculus indicates consumption of yak milk in Mongolia as early as 1270 CE.

Background:: There is an urgent need to develop a cytomegalovirus (CMV) vaccine as it remains the leading cause of birth defects in the United States. While several CMV vaccine candidates are currently in late-stage clinical trials, the most effective vaccination program remains an open research question. Methods:: To take into account the critical uncertainties when evaluating the vaccine impact on both vertical (congenital) and horizontal CMV transmissions, we developed a CMV agent-based model representative of the US population and contact network structures. Results:: We evaluated 648 vaccination scenarios under various assumptions of vaccination age, vaccine efficacy, protection duration, and vaccination coverage. The optimal age of vaccination under all scenarios is shown to be during early childhood. However, a relatively modest benefit was also seen with vaccination of females of reproduction age (around age of 25) assuming near universal coverage and long vaccine-mediated protection. Conclusions:: This study highlights the important need for a pediatric vaccination program in mitigating CMV in the United States. Our model is poised to investigate further location-based vaccine effectiveness questions in future planning of both clinical trials as well as eventual program implementation.

Abstract Background Up to 50% of cases of Shiga-toxin-producing Escherichia coli hemolytic uremic syndrome occur in adults, and the clinical presentation is variable. Microbiological analyses must be performed in all patients with thrombotic microangiopathy to identify Shiga-toxin-producing Escherichia coli, even in the absence of diarrhea. Case presentation A 79-year-old Caucasian woman was admitted to hospital because of severe proctitis. In the following days, the patient’s level of consciousness declined, and she developed acute kidney injury, thrombocytopenia, and hemolytic anemia. Shiga-toxin-producing Escherichia coli was found in fecal cultures, suggesting the diagnosis of hemolytic uremic syndrome. In the following days, her clinical conditions improved, but thrombocytopenia worsened, and the patient developed posterior tibial vein thrombosis. The discordant evolution of thrombocytopenia compared with other clinical and laboratory parameters prompted a new evaluation of its causes. Diagnosis of heparin-induced thrombocytopenia was confirmed by heparin-induced platelet aggregation assay and positive antibodies to platelet factor 4. Conclusions A discordant evolution of platelet count in patients with thrombotic microangiopathy requires a systematic reevaluation of the thrombocytopenia.

Millet is a highly adaptable plant whose cultivation dramatically altered ancient economies in northern Asia. The adoption of millet is associated with increased subsistence reliability in semi-arid settings and perceived as a cultigen compatible with pastoralism. Here, we examine the pace of millet’s transmission and locales of adoption by compiling stable carbon isotope data from humans and fauna, then comparing them to environmental variables. The Bayesian modelling of isotope data allows for the assessment of changes in dietary intake over time and space. Our results suggest variability in the pace of adoption and intensification of millet production across northern Asia.

Organizational crises have often stimulated scholarly theorizing that has been productive for our field. Rarely, however, are there opportunities to theorize regarding crises that happen in our own professional associations. A crisis experienced by Professor Anita McGahan when she was the President of the Academy of Management, described in an accompanying article, has presented such an opportunity. In this set of nine brief reflections, several scholars have considered how McGahan’s actions with regard to that crisis can be understood conceptually and how they may stimulate development of previously established conceptual perspectives. These reflections make evident that McGahan’s actions cannot be appreciated without recognition of the complex dilemmas to which she was responding. These dilemmas include issues of trustworthy leadership, gendered power, leader voice, sensemaking and learning, organizational identities, psychological contracts, institutional leadership, and “good bureaucracy”.

Background: In this case study, multiple participants in a large urban school district used the Whole School, Whole Community, Whole Child (WSCC) model to guide development of a district wellness policy. The model's health education component is highlighted, focusing on concerns for special needs students and ones speaking English as a New Language (ENL). Methods: Organizational structure was developed around the WSCC model and district wellness policy implementation through coordination, collaboration, and communication (3Cs) of programs, policies, and processes/practices (3Ps). Results: The WSCC approach guided the creation of a district wellness policy that influenced programming for students with special needs and required Youth Risk Behavior Survey (YRBS) data collection. Using YRBS and School Health Index (SHI) data in planning sexual health education illustrated improvements over time. Formation of the "School Health and Wellness Collaborative" under WSCC improved family engagement in sexual health education programs and practices. Relationships were established with community partners to impact student's sexual risk behaviors. Finally, the district co-created and implemented an evidenced-based sexual health curriculum, modifying it for special education and ENL students. Conclusions: The WSCC approach is system changing. It takes time to develop the relationships vital to improve the 3Cs and 3Ps. Success is enhanced with a district wellness coordinator, the right people at the table, valid health data, and administrative and board support.