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The gut microbiome may be related to the prevalence of overweight and obesity, but high interindividual variability of the human microbiome complicates our understanding. Obesity often occurs concomitantly with micronutrient deficiencies that impair energy metabolism. Microbiota composition is affected by diet. Host-microbiota interactions are bidirectional. We propose three pathways whereby these interactions may modulate the gut microbiome and obesity: (1) ingested compounds or derivatives affecting small intestinal transit, endogenous secretions, digestion, absorption, microbiome balance, and gut barrier function directly affect host metabolism; (2) substrate availability affecting colonic microbial composition and contact with the gut barrier; and (3) microbial end products affecting host metabolism. The quantity/concentration, duration, and/or frequency (circadian rhythm) of changes in these pathways can alter the gut microbiome, disrupt the gut barrier, alter host immunity, and increase the risk of and progression to overweight and obesity. Host-specific characteristics (e.g., genetic variations) may further affect individual sensitivity and/or resilience to diet- and microbiome-associated perturbations in the colonic environment. In this narrative review, the effects of selected interventions, including fecal microbiota transplantation, dietary calorie restriction, dietary fibers and prebiotics, probiotics and synbiotics, vitamins, minerals, and fatty acids, on the gut microbiome, body weight, and/or adiposity are summarized to help identify mechanisms of action and research opportunities.

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STUDY DESIGN: Cross-sectional cohort study. OBJECTIVES: To examine: (1) the self-reported frequency of specific prescription benzodiazepine use, (2) concurrent benzodiazepine and opioid use, and (3) sociodemographic, SCI, and opioid use factors associated with frequent benzodiazepine use. SETTING: Community. METHODS: Participants included 918 community dwelling adults with chronic ( > 1 year) traumatic SCI originally identified from a specialty hospital or a state-based surveillance system. Self-reported frequency of specific prescription benzodiazepines and opioids used, concurrent use, and factors associated with use were assessed. RESULTS: Twenty percent reported any benzodiazepine use in the past year and 13% reported at least weekly use. Concurrent daily or weekly use of benzodiazepines and opioids was reported by 6.5%, with those individuals taking an average of 1.1 (0.4) benzodiazepines and 1.4 (0.6) opioids. Compared to younger adults, those 50-65 years old had lower odds of at least weekly benzodiazepine use (OR = 0.50, 95% CI, 0.29-0.89, p-value = 0.02). Non-Hispanic Blacks reported lower use of benzodiazepines compared to non-Hispanic whites (OR = 0.32, 95% CI, 0.15-0.68, p-value = <0.01). Weekly opioid use was associated with higher odds of using benzodiazepines (OR = 3.10, 95%CI, 1.95-4.95, p-value = <0.01). CONCLUSIONS: Benzodiazepine use was commonly reported among those with SCI. Despite the potential risks, a high portion of those who reported benzodiazepine use also reported prescription opioid use. The findings highlight the need for monitoring of prescription medication use to avoid potentially risky concurrent use and adverse outcomes.

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Computational models that can predict growth and remodeling of the heart could have important clinical applications. However, the time it takes to calibrate and run current models while considering data uncertainty and variability makes them impractical for routine clinical use. This study aims to address this need by creating a computational framework to efficiently predict cardiac growth probability. We utilized a biophysics model to rapidly simulate cardiac growth following mitral valve regurgitation (MVR). Here we developed a two-tiered Bayesian History Matching approach augmented with Gaussian process emulators for efficient calibration of model parameters to align with growth outcomes within a 95% confidence interval. We first generated a synthetic data set to assess the accuracy of our framework, and the effect of changes in data uncertainty on growth predictions. We then calibrated our model to match baseline and chronic canine MVR data and used an independent data set to successfully validate the ability of our calibrated model to accurately predict cardiac growth probability. The combined biophysics and machine learning modeling framework we proposed in this study can be easily translated to predict patient-specific cardiac growth.

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AIM: To investigate the influence of diabetes mellitus (DM) in a murine model of peri-implantitis (PI). MATERIALS AND METHODS: Twenty-seven 4-week-old C57BL/6J male mice had their first and second maxillary left molars extracted. Eight weeks later, one machined implant was placed in each mouse. Four weeks after osseointegration, the mice were divided into three groups: (a) control (C), (b) PI and (c) DM + PI. DM was induced by streptozotocin (STZ) administration. After DM induction, PI was induced using ligatures for 2 weeks. The hemimaxillae were collected for micro-CT and histological analyses. The primary outcomes consisted of linear (mm) and volumetric (mm3) bone loss. Secondary outcomes were based on histological analysis and included inflammatory infiltrate, osteoclastic activity, matrix organization, composition and remodelling. Data are presented as means ± SEM. Statistical analyses were performed using one-way ANOVA, followed by Tukey's test. RESULTS: Gingival tissue oedema was detected in the PI and DM + PI groups. Micro-CT showed significantly increased linear and volumetric bone loss in the DM + PI group compared to the C and PI groups. H&E staining showed greater inflammatory response and bone resorption in the PI and DM + PI groups than in the C group. The DM + PI group had significantly higher osteoclast numbers than the C and PI groups. Picrosirius red stained less for types I and III collagen in the PI and DM + PI groups than in the C group. There was a significant increase in monocyte/macrophage (CD-11b) counts and matrix metalloproteinases (MMP-2 and MMP-8) marker levels and a significant decrease in the matrix metalloproteinases inhibition marker (TIMP-2) levels in the DM + PI group compared to the C and PI groups. CONCLUSIONS: DM exacerbates PI-induced soft-tissue inflammation, matrix degradation and bone loss.

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Immunotherapy has made significant strides in cancer treatment with strategies like checkpoint blockade antibodies and adoptive T cell transfer. Chimeric antigen receptor T cells (CAR-T) have emerged as a promising approach to combine these strategies and overcome their limitations. This review explores CAR-T cells as a living drug for cancer treatment. CAR-T cells are genetically engineered immune cells designed to target and eliminate tumor cells by recognizing specific antigens. The study involves a comprehensive literature review on CAR-T cell technology, covering structure optimization, generations, manufacturing processes, and gene therapy strategies. It examines CAR-T therapy in haematologic cancers and solid tumors, highlighting challenges and proposing a suicide gene-based mechanism to enhance safety. The results show significant advancements in CAR-T technology, particularly in structure optimization and generation. The manufacturing process has improved for broader clinical application. However, a series of inherent challenges and side effects still need to be addressed. In conclusion, CAR-T cells hold great promise for cancer treatment, but ongoing research is crucial to improve efficacy and safety for oncology patients. The proposed suicide gene-based mechanism offers a potential solution to mitigate side effects including cytokine release syndrome (the most common toxic side effect of CAR-T therapy) and the associated neurotoxicity.

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To improve the provision of psychotherapy, many countries have now established clinical practice guidelines for the treatment of specific disorders and mental health concerns. These guidelines have typically been based on evidence from meta-analyses of randomized clinical trials with minimal consideration of findings from qualitative research designs. This said, there has been growing interest in incorporating qualitative research in guideline development processes from both stakeholders and guideline development bodies. In this international collaboration, 19 qualitative psychotherapy researchers from 10 countries articulated the benefits of including qualitative findings within the guideline development process and generated recommendations for guideline developers. The underlying question of this report was "Why and how should qualitative research be used in efforts to develop guidance for psychotherapy practice?" The advantages of reviewing qualitative findings included the ability to identify treatment patterns at the level of in-session dynamics, cultural contexts, interpersonal relationships, and internal experiences, thereby creating guidance that is responsive to clients' needs in the moment-to-moment therapy process. Recommendations are offered at the systemic level (e.g., guideline formation processes, methods of education, research funding priorities). Also, methodological advice is offered for guideline developers when selecting to incorporate qualitative research in the implementation of an expanded guideline development process. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

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Chronic lymphocytic leukemia (CLL) is a malignancy of mature B cells, and it is the most frequent form of leukemia diagnosed in Western countries. It is characterized by the proliferation and accumulation of neoplastic B lymphocytes in the blood, lymph nodes, bone marrow and spleen. We report the synthesis and antiproliferative effects of a series of novel ethanoanthracene compounds in CLL cell lines. Structural modifications were achieved via the Diels-Alder reaction of 9-(2-nitrovinyl)anthracene and 3-(anthracen-9-yl)-1-arylprop-2-en-1-ones (anthracene chalcones) with dienophiles, including maleic anhydride and N-substituted maleimides, to afford a series of 9-(E)-(2-nitrovinyl)-9,10-dihydro-9,10-[3,4]epipyrroloanthracene-12,14-diones, 9-(E)-3-oxo-3-phenylprop-1-en-1-yl)-9,10-dihydro-9,10-[3,4]epipyrroloanthracene-12,14-diones and related compounds. Single-crystal X-ray analysis confirmed the structures of the novel ethanoanthracenes 23f, 23h, 24a, 24g, 25f and 27. The products were evaluated in HG-3 and PGA-1 CLL cell lines (representative of poor and good patient prognosis, respectively). The most potent compounds were identified as 20a, 20f, 23a and 25n with IC50 values in the ranges of 0.17-2.69 µM (HG-3) and 0.35-1.97 µM (PGA-1). The pro-apoptotic effects of the potent compounds 20a, 20f, 23a and 25n were demonstrated in CLL cell lines HG-3 (82-95%) and PGA-1 (87-97%) at 10 µM, with low toxicity (12-16%) observed in healthy-donor peripheral blood mononuclear cells (PBMCs) at concentrations representative of the compounds IC50 values for both the HG-3 and PGA-1 CLL cell lines. The antiproliferative effect of the selected compounds, 20a, 20f, 23a and 25n, was mediated through ROS flux with a marked increase in cell viability upon pretreatment with the antioxidant NAC. 25n also demonstrated sub-micromolar activity in the NCI 60 cancer cell line panel, with a mean GI50 value of 0.245 µM. This ethanoanthracene series of compounds offers potential for the further development of lead structures as novel chemotherapeutics to target CLL.

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BACKGROUND: Three-quarters of pregnancy-related deaths occur from 1 day to 1 year after birth, and medical complications frequently occur after birth. Postpartum health concerns are often urgent, requiring timely medical care, which may contribute to a reliance on acute care. One approach to improving postpartum health is to investigate birthing parents' accounts of acute care use in the months after birth, which is what we did in this study. METHODS: This mixed-methods study included questionnaire responses, semi-structured interviews, and chart review of 18 English-speaking individuals who used acute care in the 90 days after birth in the southeastern United States. Interviews were conducted remotely, recorded, and professionally transcribed. Qualitative data were inductively coded to iteratively develop categories and themes with respect to contributors and barriers to postpartum acute care use. RESULTS: Birthing parents engaged in complex decision-making processes to decide where and when to seek postpartum acute care in response to their urgent health concerns. Many described fear and uncertainty about their postpartum health. Most participants contacted a healthcare practitioner before using acute care, followed their guidance, and were treated or otherwise reassured at the acute care visit. DISCUSSION: These findings suggest multilevel opportunities for strengthening healthcare systems, including better-preparing individuals for the postpartum period and structuring care to accommodate birthing parents and include their support systems. The insights from this study can inform multilevel strategies for strengthening healthcare so that birthing parents are safe and well postpartum.

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Prenatal multivitamins, including folic acid, are commonly consumed in excess, whereas choline, an essential nutrient and an important source of labile methyl groups, is underconsumed. Here, we characterized profiles of one-carbon metabolism and related pathways and patterns of DNA methylation in offspring exposed to excess or imbalanced micronutrients prenatally. Pregnant Wistar rats were fed either recommended 1× vitamins (RV), high 10× vitamins (HV), high 10× folic acid with recommended choline (HFolRC), or high 10× folic acid with no choline (HFolNC). Offspring were weaned to a high-fat diet for 12 weeks. Circulating metabolites were analyzed with a focus on the hypothalamus, an area known to be under epigenetic regulation. HV, HFolRC, and HFolNC males had higher body weight (BW) and lower plasma choline and methionine consistent with lower hypothalamic S-adenosylmethionine (SAM):S-adenosylhomocysteine (SAH) and global DNA methylation compared with RV. HV and HFolNC females had higher BW and lower plasma 5-methyltetrahydrofolate and methionine consistent with lower hypothalamic global DNA methylation compared with RV. Plasma dimethylglycine (DMG) and methionine were higher as with hypothalamic SAM:SAH and global DNA methylation in HFolRC females without changes in BW compared with RV. Plasma trimethylamine and trimethylamine-N-oxide were higher in males but lower in females from HFolRC compared with RV. Network modeling revealed a link between the folate-dependent pathway and SAH, with most connections through DMG. Final BW was negatively correlated with choline, DMG, and global DNA methylation. In conclusion, prenatal intake of excess or imbalanced micronutrients induces distinct metabolic and epigenetic perturbations in offspring that reflect long-term nutritional programming of health.

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BACKGROUND: Veterans with substance use disorder (SUD) are at high risk for cognitive problems due to neurotoxic effects of chronic drug and alcohol use coupled in many cases with histories of traumatic brain injury (TBI). These problems may in turn result in proneness to SUD relapse and reduced adherence to medical self-care regimens and therefore reliance on health care systems. However, the direct relationship between cognitive function and utilization of Veterans Health Administration (VHA) SUD and other VHA health care services has not been evaluated. We sought initial evidence as to whether neurocognitive performance relates to repeated health care engagement in Veterans as indexed by estimated VHA care costs. METHODS: Neurocognitive performance in 76 Veterans being treated for SUD was assessed using CNS-Vital Signs, a commercial computerized cognitive testing battery, and related to histories of outpatient and inpatient/residential care costs as estimated by the VHA Health Economics Resource Center. RESULTS: After controlling for age, an aggregate metric of overall neurocognitive performance (Neurocognition Index) correlated negatively with total VHA health care costs, particularly with SUD-related outpatient care costs but also with non-mental health-related care costs. Barratt Impulsiveness Scale scores also correlated positively with total VHA care costs. CONCLUSIONS: In Veterans receiving SUD care, higher impulsivity and lower cognitive performance were associated with greater health care utilization within the VHA system. This suggests that veterans with SUD who show lower neurocognitive performance are at greater risk for continued health problems that require healthcare engagement. Cognitive rehabilitation programs developed for brain injury and other neurological conditions could be tried in Veterans with SUD to improve their health outcomes.

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BACKGROUND: There is limited understanding of the relationships between prescription opioid and benzodiazepine use and indices of health-related quality of life (HRQOL) among those with spinal cord injuries (SCI). OBJECTIVE: To identify the relationships between self-reported prescription opioid and benzodiazepine use and two indicators of HRQOL, number of days in poor physical health and poor mental health in the past 30 days among adults with SCI. METHODS: A cross-sectional cohort study of 918 adults with chronic (>1 year), traumatic SCI living in the Southeastern United States was conducted. Participants completed a self-report assessment (SRA). RESULTS: In the preliminary model, both opioid and benzodiazepine use were associated with a greater number of days in poor physical health and poor mental health in the past month. After controlling for health conditions (pain intensity, spasticity, anxiety and perceived sleep insufficiency), opioid use was associated with 2.04 (CI = 0.69; 3.39) additional poor physical health days in the past 30 days, and benzodiazepine use was associated with 2.18 (CI = 0.70; 3.64) additional days of poor mental health. Age was associated with greater number of poor physical health days and fewer poor mental health days. Lower income was associated with poor mental health days. Most of the health conditions were significantly related to the number of past month poor physical and mental health days. CONCLUSIONS: Opioid and benzodiazepine use are associated with poor physical and mental HRQOL, even after controlling for health conditions. Treatment strategies should consider potential unanticipated negative consequences of pharmacological interventions.

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Interactions between bacterial microbiota and epibenthic species of the dinoflagellate Prorocentrum may define the onset and persistence of benthic harmful algal blooms (bHABs). Chemical ecological interactions within the dinoflagellate phycosphere potentially involve a complex variety of organic molecules, metabolites, and toxins, including undefined bioactive compounds. In this study, the bacterial diversity and core members of the dinoflagellate-associated microbiota were defined from 11 strains of three epibenthic Prorocentrum species, representing three geographically disjunct locations within Mexican coastal waters. Microbiota profiles in stable monoclonal Prorocentrum cultures were obtained by sequencing amplicons of the V3-V4 region of the 16S rRNA gene. Thirteen classes of bacteria were identified among dinoflagellate clones, where Alphaproteobacteria, Gammaproteobacteria, and Bacteroidia were consistently dominant. The bacterial community structure exhibited significantly different grouping by the location of origin of dinoflagellate clones. No significant diversity difference was found among free-living or unattached bacteria in the dinoflagellate culture medium (M) compared with those in closer association with the dinoflagellate host cells (H). Twelve taxa were defined as core members of the bacterial assemblage, representing the genera Algiphilus, Cohaesibacter, Labrenzia, Mameliella, Marinobacter, Marivita, Massilia, Muricauda, Roseitalea, and an unclassified member of the Rhodobacteraceae. The core members are inferred to significantly contribute to primary and secondary metabolic functions, but no direct correlation with dinoflagellate toxigenicity was apparent. Overall the bacterial profile and implied gene functionality indicated a suite of positive interactions, suggesting either mutualism or commensalism with the dinoflagellate. The further characterization and interpretation of specific gene functions and interactions between bacteria and dinoflagellates, such as epibenthic members of genus Prorocentrum, are key to understanding their role in toxigenesis and bHAB development.

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INTRODUCTION: Traumatic brain injury (TBI) is among the most common conditions in the military. VA Caribbean Healthcare System (VACHS) patients with Traumatic Brain Injury (TBI) have a higher mortality rate than Veterans in other VA health care systems in the United States. The main goal of this study was to develop sociodemographic profiles and outline health characteristics of Hispanic patients with TBI treated at the VA Caribbean Healthcare System in a search for potential explanations to account for the higher mortality rate. This study advocates for equity in health services provided for minorities inside the militia. MATERIALS AND METHODS: Data collected from electronic medical records and VA databases were used to create sociodemographic and health characteristics profiles, in addition to survival models. The population of the study were post 911 Veteran soldiers who had been diagnosed with TBI. Adjusted models were created to provide hazard ratios (HR) for mortality risk. RESULTS: Out of the 16,549 files available from all 10 selected VA sites, 526 individuals were identified as treated at the VACHS. Of 526 subjects screened, 39 complied with the inclusion/exclusion criteria. Results include: 94.4% male, 48.7% between the ages of 21 and 41 years, 89.7% have depression, 66.7% have post-traumatic stress disorder (PTSD), 82.1% receive occupational therapy, 94.9% have severe headaches, 100% suffer from pain, 94.9% have memory problems, and 10.3% have had suicidal thoughts. Over 60% had a first-hand explosion experience, be it just the explosion or with another type of injury. Data showed that 33% of our patients had a Magnetic Resonance Imaging (MRI), 31% had a CT, 15.4% had a SPECT, and 2.6% had PET scan. Significant associations were found between MRIs and speech therapies, and MRIs and total comorbidities. The Cox proportional-hazards model for survival adjusted for age, gender, race/ethnicity, and comorbidities shows that VACHS Veterans diagnosed with a TBI had a higher mortality risk rate (HR 1.23 [95% CI 1.10, 1.37]) when compared to the other 9 health centers with the highest percentage of Hispanic Veterans. CONCLUSIONS: Since explosions were the most common mechanism of injury, further research is needed into the experiences of Veterans in connection with this specific variable. A high percentage of the patients suffered from depression and PTSD. Additionally, over half of the patients had an unmeasured TBI severity. The effects these aspects have on symptomatology and how they hinder the recovery process in Hispanic patients should be examined in further detail. It is also important to highlight that family and friends' support could be key for injury treatment. This study highlights the use of the 4 types of scans (MRI, CT, PET/CT, and SPECT/CT) as ideal diagnosis tools. The alarming number of patients with suicidal thoughts should be a focus in upcoming studies. Future studies should aim to determine whether increased death rates in TBI Veterans can be linked to other United States islander territories. Concepts, such as language barriers, equal resource allocation, and the experiences of Veterans with TBIs should be further explored in this Veteran population.

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INTRODUCTION: Medicaid coverage of doula services is increasing as a policy strategy to reduce maternal health inequities in the United States. However, early adopter states struggled to offer accessible, equitable Medicaid doula benefits when implementation began. California began covering doula services through its Medicaid program, Medi-Cal, in 2023. Managed care plans (MCPs) and risk-bearing organizations (RBOs) play an important role in ensuring pregnant and birthing people can access doula support through Medicaid benefits. MATERIALS AND METHODS: Between 2021 and 2022, we conducted 14 interviews with MCP and RBO staff (n = 20) representing a total of 14 MCPs and RBOs. Data were analyzed in two stages: 1) rapid assessment process and 2) using the Consolidated Framework for Implementation Research (CFIR) to identify specific facilitators and barriers to Medi-Cal doula benefit implementation. RESULTS: We identified 10 facilitators and 16 barriers across the five CFIR domains. Results indicate a general lack of familiarity with doula care and highlight the importance of relationship building with doulas and collaboration among plans. CONCLUSIONS: In California, these findings can help guide improvements to emerging implementation challenges and evaluation efforts. Our findings can also help other states in the planning and Medicaid doula benefit design process.

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OBJECTIVE: To identify the relations of 3 frequently used prescription opioids (hydrocodone, oxycodone, tramadol) with unintentional injuries, including fall-related and non-fall-related injuries among adults with chronic, traumatic spinal cord injury (SCI). DESIGN: Cross-sectional cohort study. SETTING: Community setting; Southeastern United States. PARTICIPANTS: Adult participants (N=918) with chronic traumatic SCI were identified from a specialty hospital and state population-based registry and completed a self-report assessment. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Self-reported fall-related and non-fall-related unintentional injuries serious enough to receive medical care in a clinic, emergency room, or hospital within the previous 12 months. RESULTS: Just over 20% of participants reported ≥1 unintentional injury in the past year, with an average of 2.16 among those with ≥1. Overall, 9.6% reported fall-related injuries. Only hydrocodone was associated with any past-year unintentional injuries. Hydrocodone taken occasionally (no more than monthly) or regularly (weekly or daily) was related to 2.63 (95% confidence interval [CI], 1.52-4.56) or 2.03 (95% CI, 1.15-3.60) greater odds of having ≥1 unintentional injury in the past year, respectively. Hydrocodone taken occasionally was also associated with past-year non-fall-related injuries (OR, 2.20; 95% CI, 1.12-4.31). Each of the 3 opioids was significantly related to fall-related injuries. Taking hydrocodone occasionally was associated with 2.39 greater odds of fall-related injuries, and regular use was associated with 2.31 greater odds. Regular use of oxycodone was associated with 2.44 odds of a fall-related injury (95% CI, 1.20-4.98), and regular use of tramadol was associated with 2.59 greater odds of fall-related injury (95% CI, 1.13-5.90). CONCLUSIONS: Injury prevention efforts must consider the potential effect of opioid use, particularly hydrocodone. For preventing fall-related injuries, each of the 3 opioids must be considered.

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AIMS: Despite clear guideline recommendations for initiating four drug classes in all patients with heart failure (HF) with reduced ejection fraction (HFrEF) and the availability of rapid titration schemes, information on real-world implementation lags behind. Closely following the 2021 ESC HF guidelines and 2023 focused update, the TITRATE-HF study started to prospectively investigate the use, sequencing, and titration of guideline-directed medical therapy (GDMT) in HF patients, including the identification of implementation barriers. METHODS AND RESULTS: TITRATE-HF is an ongoing long-term HF registry conducted in the Netherlands. Overall, 4288 patients from 48 hospitals were included. Among these patients, 1732 presented with de novo, 2240 with chronic, and 316 with worsening HF. The median age was 71 years (interquartile range [IQR] 63-78), 29% were female, and median ejection fraction was 35% (IQR 25-40). In total, 44% of chronic and worsening HFrEF patients were prescribed quadruple therapy. However, only 1% of HFrEF patients achieved target dose for all drug classes. In addition, quadruple therapy was more often prescribed to patients treated in a dedicated HF outpatient clinic as compared to a general cardiology outpatient clinic. In each GDMT drug class, 19% to 36% of non-use in HFrEF patients was related to side-effects, intolerances, or contraindications. In the de novo HF cohort, 49% of patients already used one or more GDMT drug classes for other indications than HF. CONCLUSION: This first analysis of the TITRATE-HF study reports relatively high use of GDMT in a contemporary HF cohort, while still showing room for improvement regarding quadruple therapy. Importantly, the use and dose of GDMT were suboptimal, with the reasons often remaining unclear. This underscores the urgency for further optimization of GDMT and implementation strategies within HF management.

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Food intake and energy balance are tightly regulated by a group of hypothalamic arcuate neurons expressing the proopiomelanocortin (POMC) gene. In mammals, arcuate-specific POMC expression is driven by two cis-acting transcriptional enhancers known as nPE1 and nPE2. Because mutant mice lacking these two enhancers still showed hypothalamic Pomc mRNA, we searched for additional elements contributing to arcuate Pomc expression. By combining molecular evolution with reporter gene expression in transgenic zebrafish and mice, here, we identified a mammalian arcuate-specific Pomc enhancer that we named nPE3, carrying several binding sites also present in nPE1 and nPE2 for transcription factors known to activate neuronal Pomc expression, such as ISL1, NKX2.1, and ERα. We found that nPE3 originated in the lineage leading to placental mammals and remained under purifying selection in all mammalian orders, although it was lost in Simiiformes (monkeys, apes, and humans) following a unique segmental deletion event. Interestingly, ablation of nPE3 from the mouse genome led to a drastic reduction (>70%) in hypothalamic Pomc mRNA during development and only moderate (<33%) in adult mice. Comparison between double (nPE1 and nPE2) and triple (nPE1, nPE2, and nPE3) enhancer mutants revealed the relative contribution of nPE3 to hypothalamic Pomc expression and its importance in the control of food intake and adiposity in male and female mice. Altogether, these results demonstrate that nPE3 integrates a tripartite cluster of partially redundant enhancers that originated upon a triple convergent evolutionary process in mammals and that is critical for hypothalamic Pomc expression and body weight homeostasis.

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The mechanism of loss of propylparaben potency from formulations when in contact with polyvinyl chloride has been determined. It is caused by the adsorption of propylparaben onto polyvinyl chloride surfaces. The adsorption kinetics is best described using a pseudo-second order model based on non-linear fit. The rate of adsorption increases with increasing bulk concentration of propylparaben. Adsorption equilibrium isotherm was fitted to three isotherm models: Langmuir, Freundlich, and Temkin, using non-linear fit. The Freundlich and Temkin models show the best fit, indicating a multi-layer adsorption. Using this case study, we present a methodology to provide mechanistic insights into the compatibility data between pharmaceutical ingredients and product contact materials when sorption is involved.

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