Radical surgical resection with molecular margins is associated with improved survival in IDH wildtype GBM.

BACKGROUND: Survival is variable in patients with glioblastoma IDH wild-type (GBM), even after comparable surgical resection of radiographically-detectable disease, highlighting the limitations of radiographic assessment of infiltrative tumor anatomy. The majority of post-surgical progressive events are failures within 2cm of the resection margin, motivating supramaximal resection strategies to improve local control. However, which patients benefit from such radical resections remains unknown. METHODS: We developed a predictive model to identify which IDH wild-type GBM are amenable to radiographic gross total resection (GTR). We then investigated whether GBM survival heterogeneity following GTR is correlated with microscopic tumor burden a by analyzing tumor cell content at the surgical margin with a rapid qPCR-based method for detection of TERT promoter mutation. RESULTS: Our predictive model for achievable GTR, developed on retrospective radiographic and molecular data of GBM patients undergoing resection, had an AUC of 0.83, sensitivity of 62%, and specificity of 90%. Prospective analysis of this model in 44 patients found 89% of patients were correctly predicted to achieve a RV<4.9cc. Of the 44 prospective patients undergoing rapid qPCR TERT promoter mutation analysis at the surgical margin, 7 had undetectable TERT mutation, of which 5 also had a gross total resection (RV<1cc). In these 5 patients at 30 months follow up, 75% showed no progression, compared to 0% in the group with TERT mutations detected at the surgical margin (p=0.02). CONCLUSIONS: These findings identify a subset of patients with GBM that may derive local control benefit from radical resection to undetectable molecular margins.

SARS-CoV-2 Spike protein triggers gut impairment since mucosal barrier to innermost layers: From basic science to clinical relevance.

Studies have reported the occurrence of gastrointestinal (GI) symptoms, primarily diarrhea, in COVID-19. However, the pathobiology regarding COVID-19 in the GI tract remains limited. This work aimed to evaluate SARS-CoV-2 Spike protein interaction with gut lumen in different experimental approaches. Here, we present a novel experimental model with the inoculation of viral protein in the murine jejunal lumen, in vitro approach with human enterocytes, and molecular docking analysis. Spike protein led to increased intestinal fluid accompanied by Cl- secretion, followed by intestinal edema, leukocyte infiltration, reduced glutathione levels, and increased cytokine levels [interleukin (IL)-6, tumor necrosis factor-α, IL-1ß, IL-10], indicating inflammation. Additionally, the viral epitope caused disruption in the mucosal histoarchitecture with impairment in Paneth and goblet cells, including decreased lysozyme and mucin, respectively. Upregulation of toll-like receptor 2 and toll-like receptor 4 gene expression suggested potential activation of local innate immunity. Moreover, this experimental model exhibited reduced contractile responses in jejunal smooth muscle. In barrier function, there was a decrease in transepithelial electrical resistance and alterations in the expression of tight junction proteins in the murine jejunal epithelium. Additionally, paracellular intestinal permeability increased in human enterocytes. Finally, in silico data revealed that the Spike protein interacts with cystic fibrosis transmembrane conductance regulator (CFTR) and calcium-activated chloride conductance (CaCC), inferring its role in the secretory effect. Taken together, all the events observed point to gut impairment, affecting the mucosal barrier to the innermost layers, establishing a successful experimental model for studying COVID-19 in the GI context.

A New Murine Undernutrition Model Based on Complementary Feeding of Undernourished Children Causes Damage to the Morphofunctional Intestinal Epithelium Barrier.

BACKGROUND: Complementary feeding is critical in establishing undernutrition. However, experimental undernourished diets do not represent the amount of nutrients in the complementary diets of undernourished children. OBJECTIVES: To develop, validate, and evaluate the impact of a new murine model of undernutrition on the intestinal epithelium, based on the complementary diet of undernourished children from 7 countries with low-socioeconomic power belonging to the Malnutrition-Enteric Diseases (MAL-ED) cohort study. METHODS: We used the difference in the percentage of energy, macronutrients, fiber and zinc in the complementary diet of children without undernutrition compared with stunting (height-for-age Z-score < -2) for the MAL-ED diet formulation. Subsequently, C57BL/6 mice were fed a control diet (AIN-93M diet) or MAL-ED diet for 28 d. Weight was measured daily; body composition was measured every 7 d; lactulose:mannitol ratio (LM) and morphometry were evaluated on days 7 and 28; the cotransport test and analysis of intestinal transporters and tight junctions were performed on day 7. RESULTS: The MAL-ED diet presented -8.03% energy, -37.46% protein, -24.20% lipid, -10.83% zinc, +5.93% carbohydrate, and +45.17% fiber compared with the control diet. This diet rapidly reduced weight gain and compromised body growth and energy reserves during the chronic period (P < 0.05). In the intestinal epithelial barrier, this diet caused an increase in the LM (P < 0.001) and reduced (P < 0.001) the villous area associated with an increase in FAT/CD36 in the acute period and increased (P < 0.001) mannitol excretion in the chronic period. CONCLUSIONS: The MAL-ED diet induced undernutrition in mice, resulting in acute damage to the integrity of the intestinal epithelial barrier and a subsequent increase in the intestinal area during the chronic period. This study introduces the first murine model of undernutrition for the complementary feeding phase, based on data from undernourished children in 7 different countries.

Medical Management to Treat Chronic Non-healing Ulcers: A Case Series.

INTRODUCTION: Chronic non-healing leg ulcers are skin defects below the knee that resist healing for more than six weeks. They cause physical, emotional, and economic burdens to patients and society. OBJECTIVES: To introduce an innovative medical strategy that targets the chronic inflammation component in non-healing ulcers (NHUs) with rheumatic features and to evaluate its potential effectiveness in achieving complete healing. METHODS: We employed an empirical medical therapy regimen, which combined medications like deflazacort, colchicine, dapsone, hydroxychloroquine, and azathioprine. We retrospectively selected 25 patients with chronic pedal ulcers who underwent our therapy. RESULTS: The mean duration of ulcers was 7.84 years, and the time to heal was 5.97 months. Among 25 patients, 19 had atypical ulcers, four had venous ulcers, and two had diabetic neuropathy ulcers. Four patients with venous ulcers additionally underwent endovenous laser ablation. CONCLUSION: Our medical strategy showed promising results in healing chronic NHUs with rheumatic features without significant steroid-induced adverse effects.

Deep generative models of LDLR protein structure to predict variant pathogenicity.

The complex structure and function of low density lipoprotein receptor (LDLR) makes classification of protein-coding missense variants challenging. Deep generative models, including Evolutionary model of Variant Effect (EVE), Evolutionary Scale Modeling (ESM), and AlphaFold 2 (AF2), have enabled significant progress in the prediction of protein structure and function. ESM and EVE directly estimate the likelihood of a variant sequence but are purely data-driven and challenging to interpret. AF2 predicts LDLR structures, but variant effects are explicitly modeled by estimating changes in stability. We tested the effectiveness of these models for predicting variant pathogenicity compared to established methods. AF2 produced two distinct conformations based on a novel hinge mechanism. Within ESM's hidden space, benign and pathogenic variants had different distributions. In EVE, these distributions were similar. EVE and ESM were comparable to Polyphen-2, SIFT, REVEL, and Primate AI for predicting binary classifications in ClinVar. However, they were more strongly correlated with experimental measures of LDL uptake. AF2 poorly performed in these tasks. Using the UK Biobank to compare association with clinical phenotypes, ESM and EVE were more strongly associated with serum LDL-C than Polyphen-2. ESM was able to identify variants with more extreme LDL-C levels than EVE and had a significantly stronger association with atherosclerotic cardiovascular disease. In conclusion, AF2 predicted LDLR structures do not accurately model variant pathogenicity. ESM and EVE are competitive with prior scoring methods for prediction based on binary classifications in ClinVar but are superior based on correlations with experimental assays and clinical phenotypes.

A study of subcutaneous emphysema, factors contributing to its development, resolution and management with different modalities.

Subcutaneous emphysema is defined as an escape of air in subcutaneous tissue. It is one of the most common complications after inter-costal chest tube drainage. Subcutaneous emphysema is usually benign requiring no specific treatment, but extensive subcutaneous emphysema can be uncomfortable and alarming for the patient. It can rarely lead to airway compromise, respiratory failure and death. Factors leading to its development, following chest tube insertion and methods of management, have not been extensively studied and published. This was an analytical study done over a period of two years, on indoor patients who developed subcutaneous emphysema. These cases were managed using four different modalities and were analyzed for various factors contributing to the development, severity, and resolution of subcutaneous emphysema. Results of this study highlight that the cases of hydropneumothorax and secondary pneumothorax were significantly more predisposed to the development of severe subcutaneous emphysema (following intercostal chest tube insertion) and large air leak as compared to others. Larger air leak develops higher grades of subcutaneous emphysema. The average time for resolution of subcutaneous emphysema was similar among the different modalities of management compared in the study.

Cascading Effect of Large Molecular Motion in Crystals: A Topotactic Polymorphic Transition Paves the Way to Topochemical Polymerization.

A topochemical polymerization governed by a topotactic polymorphic transition is reported. A monomer functionalized with azide and an internal alkyne crystallized as an unreactive polymorph with two molecules in the asymmetric unit. The molecules are aligned in a head-to-head fashion, thereby avoiding the azide-alkyne proximity for the topochemical azide-alkyne cycloaddition (TAAC) reaction. However, upon heating, one of the two conformers underwent a drastic 180° rotation, leading to a single-crystal-to-single-crystal (SCSC) polymorphic transition to a reactive form, wherein the molecules are head-to-tail arranged, ensuring azide-alkyne proximity. The new polymorph underwent TAAC reaction to form a trisubstituted 1,2,3-triazole-linked polymer. These results, showing unexpected topochemical reactivity of a crystal due to the intermediacy of an SCSC polymorphic transition from an unreactive form to a reactive form, highlight that predicting topochemical reactivity by relying on the static crystal structure can be misleading.

Dimension Engineering of Stimuli-Responsive 1D Molecular Crystals into Unusual 2D and 3D Zigzag Waveguides.

We demonstrate an innovative technique to achieve organic 2D and 3D waveguides with peculiar shapes from an acicular, stimuli-responsive molecular crystal, (2Z,2'Z)-3,3'-(anthracene-9,10-diyl)bis(2-(3,5-bis(trifluoromethyl)phenylacrylonitrile), Ant-CF3 . The greenish-yellow fluorescent (FL) Ant-CF3 molecular crystals exhibit laser power-dependent permanent mechanical bending in 2D and 3D. Investigation of a single-crystal using spatially-resolved Raman/FL/electron microscopy, and theoretical calculations revealed photothermal (Z,E)/(E,E) isomerization-assisted transition from crystalline to amorphous phase at the laser-exposed regions. This phenomenon facilitates the dimension engineering of a 1D crystal waveguide into 2D waveguide on a substrate or a 3D waveguide in free space. The bends can be used as interconnection points to couple different optical elements. The presented technique has broader implications in organic photonics and other crystal-related photonic technologies.

Age adjusted Charlson comorbidity index (a-CCI) AS a tool to predict 30-day post-operative outcome in general surgery patients.

INTRODUCTION: Age adjusted Charlson comorbidity index (a-CCI) is an established scoring system to predict long-term mortality. However, its role in predicting 30-day post-operative outcome in general surgery patients is not well elucidated. METHODS: This was a prospective observational study. Consecutive patients operated under general anaesthesia between January 2019 and December 2020 were enrolled. Their a-CCI was calculated and stratified as Grade 0 comorbidities (a-CCI score = 0), Grade A comorbidities (a-CCI score = 1 and 2) and Grade B comorbidities (a-CCI score ≥ 3). Post-operative complications were graded according to Clavien Dindo (CD) grading system and classified as minor complications (CD Grades I and II), major complications (CD Grades III-IV) and mortality (CD Grade V). Binary logistic regression and multi-nominal logistic regression analysis were done and relative risk ratios were calculated. RESULT: A total of 925 patients were enrolled. The mean age was 42.75 (14-85 ± 10) years. 31% of our patients had complications within 30 days of surgery which included mortality in 2.7%. Compared with patients with Grade 0 comorbidities, the odds of getting complications is 1.2 times more in patients with Grade A comorbidities and 1.84 times more in patients with Grade B comorbidities (P = 0.205, 0.001 respectively). In comparison to patients with Grade 0 co-morbidities, risk of mortality is 3 and 17.86 times more in patients with Grade A and Grade B comorbidities (P = 0.121 and < 0.001 respectively). CONCLUSION: a-CCI has clinical relevance in general surgical patients and can predict early post-operative outcome. It should be a part of our armamentarium for pre-operative assessment of surgical patients.

Feasibility of 'parkrun' for people with knee osteoarthritis: A mixed methods pilot study.

Objective: To investigate the feasibility of 'parkrun' for people with knee osteoarthritis (OA) and examine its potential to improve symptoms and increase physical activity. Design: This uncontrolled mixed methods pilot study enrolled people with knee OA not meeting physical activity guidelines. Participants were asked to walk in four consecutive parkrun events supervised by an exercise physiologist/physiotherapist. Feasibility was assessed by recruitment data (numbers screened and time to enrol 15 participants), adherence to the protocol, acceptability (measured by confidence, enjoyment, difficulty ratings and qualitative interviews), and safety (adverse events). Secondary measures were changes in knee pain, function, stiffness, and physical activity levels. Results: Participants (n â€‹= â€‹17) were enrolled over 11 months and recruitment was slower than anticipated. Fourteen participants attended all four parkruns and three of these participants shortened the 5 â€‹km course to ∼3 â€‹km. Across all four parkruns, 75% of participants reported high confidence that they could complete the upcoming parkrun and the majority (87%) enjoyed participating. Most participants rated parkrun either "slightly difficult" (38.5%) or "moderately difficult" (35%) and two mild adverse events were reported. Participants showed improvements in knee pain, function, stiffness, and physical activity levels. Conclusions: This pilot study demonstrates parkrun's feasibility, acceptability, safety and, its potential to improve knee OA symptoms and physical activity levels. Participating in parkrun was acceptable and enjoyable for some, but not all participants. The scalability, accessibility and wide appeal of parkrun supports the development of larger programs of research to evaluate the use of parkrun for people with knee OA.

Incentivising public transport use for physical activity gain: process evaluation of the COVID-19 disrupted trips4health randomised controlled trial.

BACKGROUND: Partnering with a public transport (PT) provider, state government, and local government, the single-blinded randomised controlled trial, trips4health, investigated the impact of PT use incentives on transport-related physical activity (PA) in Tasmania, Australia. The intervention involved 16-weeks of incentives (bus trip credits) for achieving weekly PT use targets, supported by weekly text messages. This study objective was to conduct a process evaluation of the COVID-19 disrupted trips4health study. METHODS: The Medical Research Council UK's framework for complex public health interventions guided the process evaluation. Participant reach, acceptability, fidelity and feasibility were evaluated. Administrative and post-intervention survey data were analysed descriptively. Semi-structured interviews with intervention participants (n = 7) and PT provider staff (n = 4) were analysed thematically. RESULTS: Due to COVID-19, trips4health was placed on hold (March 2020) then stopped (May 2020) as social restrictions impacted PT use. At study cessation, 116 participants (approximately one third of target sample) had completed baseline measures, 110 were randomised, and 64 (n = 29 in the intervention group; n = 35 in the control group) completed post-intervention measures. Participants were 18 - 80 years (average 44.5 years) with females (69%) and those with tertiary education (55%) over-represented. The intervention was delivered with high fidelity with 96% of bus trip credits and 99% of behavioural text messages sent as intended. Interviewed PT staff said implementation was highly feasible. Intervention participant acceptability was high with 90% reporting bus trip incentives were helpful and 59% reporting the incentives motivated them to use PT more. From a total of 666 possible bus trip targets, 56% were met with 38% of intervention participants agreeing and 41% disagreeing that 'Meeting the bus trip targets was easy'. Interviews and open-ended survey responses from intervention participants revealed incentives motivated bus use but social (e.g., household member commitments) and systemic (e.g., bus availability) factors made meeting bus trip targets challenging. CONCLUSIONS: trips4health demonstrated good acceptability and strong fidelity and feasibility. Future intervention studies incentivising PT use will need to ensure a broader demographic is reached and include more supports to meet PT targets. TRIAL REGISTRATION: ACTRN12619001136190 .

Demographic Trends in Emergency Department Visits for Psychiatric Concerns During the COVID-19 Pandemic.

Objective: To describe changes in emergency department (ED) psychiatric visits during the pandemic in both rural and nonrural regions in the United States. Methods: This cohort study was performed across 22 EDs in the Midwest and Southern United States from January 1, 2019 to April 22, 2021. Prevalence of psychiatric visits before and after the COVID-19 pandemic, defined as starting on March 1, 2020, were compared. Psychiatric and nonpsychiatric visits were defined on the basis of primary clinician-assigned diagnosis. The primary end point was average daily visits normalized to the average daily visit count before the pandemic, labeled as relative mean daily visits (RMDVs). Results: Psychiatric visits decreased by 9% [RMDVs, 0.91; 95% confidence interval (CI), 0.89-0.93] during the pandemic period, whereas nonpsychiatric visits decreased by 17% (RMDVs, 0.83; 95% CI, 0.81-0.84). Black patients were the only demographic group with a significant increase in psychiatric visits during the pandemic (RMDVs, 1.12; 95% CI, 1.04-1.19). Periods of outbreaks of psychiatric emergencies were identified in most demographic groups, including among male and pediatric patients. However, the outbreaks detected among Black patients sustained the longest at 6 months. Unlike older adults who experienced outbreaks in the spring and fall of 2020, outbreaks among pediatric patients were detected later in 2021. Conclusion: In this multisite study, total ED visits declined during the pandemic; however, psychiatric visits declined less than nonpsychiatric visits. Black patients experienced a greater increase in psychiatric emergencies than other demographic groups. There is also a concern for increasing outbreaks of pediatric psychiatric visits as the pandemic progresses.

Sucralose hydrogels: Peering into the reactivity of sucralose versus sucrose under lipase catalyzed trans-esterification.

Sucralose differs from sucrose only by virtue of having three Cl groups instead of OH groups. Its intriguing features include being noncaloric, noncariogenic, ∼600 times sweeter than sucrose, stable at high temperatures/acidic pH's, and void of disagreeable aftertastes. These properties are attractive as food additive, one of which is as hydrogel obtainable via the technique of molecular gelation using a sucralose-derived low-molecular weight gelator (LMWG). Such hydrogels are highly responsive to external stimuli like temperature, because the LMWGs self-assemble via non-covalent interactions and could thus be utilized in applications like control-release. We found that sucralose to be unreactive under lipase biocatalysis, unlike sucrose. Hence, the aim of this work was (i) to use computational simulations to further understand sucralose's lack of enzymatic reactivity and (ii) to synthesize the sucralose-based amphiphiles using conventional chemical synthesis and systematically study their tendency towards hydrogelation. Sucrose and sucralose were docked with a high-resolution atomic structure of lipase B from Candida antarctica, modeling the esterification transition state with an active site serine. In extended molecular dynamics simulations, sucrose remained in the active site due to multiple sugar-protein hydrogen bonds. The oxygen-to-chlorine substitutions in sucralose disrupted this hydrogen bonding network. Consistent with observed lack of enzymatic conversion, in multiple simulations, sucralose would rapidly dissociate from the active site. The sucralose-based LMWGs were subsequently synthesized using base-catalyzed conventional chemical synthesis. Three of the sucralose-based amphiphiles (SL-5, SL-6 and SL-7) proved to be successful hydrogelators. The gelators also showed the ability to gel selected beverages. The LMWGs gelled quantities of water and beverage up to 71 and 55 times their weight, respectively, and remain thermally stable up to 144 °C.

Biomarkers in the Prediction of Hemorrhagic Transformation in Acute Stroke: A Systematic Review and Meta-Analysis.

BACKGROUND: Hemorrhagic transformation (HT) is a complication that occurs spontaneously or after thrombolysis in acute ischemic stroke (AIS) and can increase morbidity and mortality. The association of biomarkers with the risk of HT has been variably reported. We conducted a systematic review of the literature and meta-analysis and sought to compare blood biomarkers associated with HT and its subtypes by evaluating its predictability and correlation with outcome in AIS. METHODS: The study protocol was registered in the PROSPERO database (CRD42020201334) and adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Among 2,230 articles identified from Cochrane Library, PubMed, and Web of Science databases, 30 quality-appraised articles were found eligible. Meta-analysis was conducted for matrix metalloproteinase-9 (MMP-9), cellular fibronectin (c-Fn), ferritin, S100 calcium-binding protein B (S100B), and neutrophil-lymphocyte ratio (NLR). We also reviewed biomarkers for correlation with the functional outcome at 90 days from stroke onset (poor outcome modified Rankin scale >2). RESULTS: The pooled diagnostic odds ratio (DORpooled) was the highest for baseline c-Fn levels (299.253 [95% CI, 20.508-4,366.709]), followed by MMP-9 (DORpooled, 29.571 [95% CI 17.750-49.267]) and ferritin (DORpooled, 24.032 [95% CI 2.557-225.871]). However, wide confidence intervals for ferritin and c-Fn suggested lesser reliability of the markers. Patients with MMP-9 levels ≥140 ng/mL were 29.5 times at higher risk of developing symptomatic HT after AIS (area under the curve = 0.881). S100B (DORpooled, 6.286 [95% CI, 1.861-21.230]) and NLR (DORpooled, 5.036 [95% CI, 2.898-8.749]) had lower diagnostic accuracies. Among the markers not included for meta-analysis, caveolin-1, thrombin-activated fibrinolysis inhibitor, plasminogen activator inhibitor-1, and soluble ST2 were highly sensitive. Elevated levels of MMP-9, ferritin, and NLR were found to be associated with poor functional outcomes and mortality. CONCLUSION: Of the 5 biomarkers, there was enough evidence that MMP-9 has higher diagnostic accuracy for predicting the risk of HT before thrombolysis. MMP-9, ferritin, and NLR also predicted poor short-term outcomes.

A Folding Insulator Defines Cryptic Domains in Tropomyosin.

Multidomain proteins are the product of evolutionary selection for diversity of function through concatenation and repurposing of existing modular units of structures. In structures of proteins with multiple domains, components are often globular units stitched together with flexible linkers. Multidomain proteins often fold as multiple distinct order-disorder transitions. However, the relationship between structure and folding is not always straightforward. Tropomyosin binds to actin in muscle and cytoskeletal filaments. The structure is that of a continuous ɑ-helix lacking domain boundaries, but unfolding shows distinct transitions suggesting at least three possible domains do exist. To explore how domains might occur in a continuous structure, we used Lifson-Roig helix-coil models with sequence domains of varying helical nucleation propensities. Of these models, ones with a central folding insulator, separating folding of N- and C-terminal domains, are most consistent with experimental folding studies. The positions of domain boundaries are identified by hydrogen-deuterium exchange mass spectrometry. The presence of structurally cryptic folding domains in tropomyosin could relate to its evolution and explain the uneven distribution of deleterious mutations that lead to various cardiomyopathies.

A2B- and A3-Type Boron(III)Subchlorins Derived from meso-Diethoxycarbonyltripyrrane: Synthesis and Photophysical Exploration.

The first direct fabrication of A2B- and A3-type B(III)subchlorins from meso-ethoxycarbonyl-substituted tripyrrane has been realized by condensation with appropriate acid chlorides (benzoyl chloride, butyryl chloride, and ethyl chlorooxoacetate). The aliphatic acid chloride-based annulation reaction is new to subporphyrinoid chemistry. The phenyl (6a)- or n-propyl (6b)-substituted derivatives could be oxidized to the corresponding B(III)subporphyrins upon refluxing with DDQ, whereas the triethoxycarbonyl moiety (6c) was found to be resistant to oxidation and exhibits the most red-shifted absorption (587 nm) and emission (604 nm). The study indicates that absorption and emission behaviors of the B(III)subchlorin can be tuned by the introduction of electron-rich or electron-deficient substituents at the meso-position. B(III)subchlorins 6a and 6c generate singlet oxygen efficiently (44 and 40%, respectively) and, thus, may find application as potential photosensitizers in photodynamic therapy (PDT).

1,2-Phenylene-Incorporated Smallest Expanded Calix[4]pyrrole via One-Step Synthesis of Tetrapyrrane: A Fluorescent Host for Fluoride Ion.

Synthesis of tetrapyrrane 8 from acetone and pyrrole via one-step condensation was achieved for the first time along with a much-improved yield of the tripyrrane 9. Diborylation of the tetrapyrrane and subsequent "1 + 1" cyclocoupling with 1,2-diiodobenzene following the Suzuki protocol generated novel o-phenylene incorporated macrocycle belonging to the smallest meso-expanded calix[4]pyrrole family. The latter macrocycle displays exclusive turn-on fluorescence sensing of fluoride ion upon complexation via a unique partial cone conformation supported by DFT analysis in acetonitrile solvent.

A physiological glucocorticoid rhythm is an important regulator of brown adipose tissue function.

OBJECTIVE: Brown adipose tissue (BAT) displays a strong circadian rhythm in metabolic activity, but it is unclear how this rhythm is regulated. As circulating levels of corticosterone coincide with the rhythm of triglyceride-derived fatty acid (FA) uptake by BAT, we investigated whether corticosterone regulates BAT circadian rhythm. METHODS: Corticosterone levels were flattened by implanting mice with subcutaneous corticosterone-releasing pellets, resulting in constant circulating corticosterone levels. RESULTS: Flattened corticosterone rhythm caused a complete loss of circadian rhythm in triglyceride-derived fatty acid uptake by BAT. This effect was independent of glucocorticoid receptor expression in (brown) adipocytes and was not caused by deregulation of clock gene expression or overexposure to glucocorticoids, but rather seemed mediated by reduced sympathetic innervation of BAT. In a mouse model of hyperlipidemia and metabolic syndrome, long-term experimental flattening of corticosterone - and thus rhythm in BAT function - resulted in adiposity. CONCLUSIONS: This study highlights that a physiological rhythm in glucocorticoids is an important regulator of BAT function and essential for the maintenance of metabolic health.

Meso-Free Boron(III)subchlorin and Its µ-Oxo Dimer with Interacting Chromophores.

Meso-free B(III)subchlorin 1 has been realized exclusively for the first time from meso-ethoxycarbonyl-substituted tripyrrane along with the first subchlorin dimer 2 as its µ-oxo analogue via a facile one-pot approach. The subchlorin is highly stable toward oxidation; hence, it was not contaminated with the corresponding subporphyrin analogue 3. The subchlorin (56%) and its dimer (30%) exhibit singlet oxygen generation ability for the first time. The B-O-B dimer displays strong exciton coupling between the two macrocycles.