FLEXR GUI: a graphical user interface for multi-conformer modeling of proteins.

Proteins are well known 'shapeshifters' which change conformation to function. In crystallography, multiple conformational states are often present within the crystal and the resulting electron-density map. Yet, explicitly incorporating alternative states into models to disentangle multi-conformer ensembles is challenging. We previously reported the tool FLEXR, which, within a few minutes, automatically separates conformational signal from noise and builds the corresponding, often missing, structural features into a multi-conformer model. To make the method widely accessible for routine multi-conformer building as part of the computational toolkit for macromolecular crystallography, we present a graphical user interface (GUI) for FLEXR, designed as a plugin for Coot 1. The GUI implementation seamlessly connects FLEXR models with the existing suite of validation and modeling tools available in Coot. We envision that FLEXR will aid crystallographers by increasing access to a multi-conformer modeling method that will ultimately lead to a better representation of protein conformational heterogeneity in the Protein Data Bank. In turn, deeper insights into the protein conformational landscape may inform biology or provide new opportunities for ligand design. The code is open source and freely available on GitHub at https://github.com/TheFischerLab/FLEXR-GUI.

Impact of the operative technique on mid- and long-term results following paediatric heart transplantation.

AIMS: The aim of this study is to evaluate and compare the impact of the bicaval technique versus the biatrial technique (by Lower and Shumway) in paediatric heart transplant patients. Only a few studies investigate this matter regarding the long-term outcome after paediatric heart transplantation. We compared the two surgical methods regarding survival, the necessity of pacemaker implantation. METHODS AND RESULTS: All 134 patients (aged <18 years) - (group-1) biatrial (n = 84), versus (group-2) bicaval (n = 50), who underwent heart transplantation between October 1988 and December 2021, were analysed. Freedom from events were estimated using the Kaplan-Meier method. Potential differences were analysed using the log rank test and Cox proportional hazard models. Mean ± standard deviation: Bypass time (per minutes) was higher in the group 1 as compared with group 2 (P = 0.050). Survival was not significantly different (P = 0.604) in either groups. Eighteen patients required permanent pacemaker implantation in the group 1 and only one patient required it in the group 2 (P = 0.001). CONCLUSIONS: Paediatric heart transplantation using bicaval technique results similar long-term survival compared with the biatrial technique. The incidence of atrial rhythm disorders was significantly higher in the biatrial group, requiring a higher frequency of pacemaker implantation in this group. As a results, the bicaval technique has replaced the biatrial technique in our centre.

Utilizing EPR spectroscopy to investigate the liquid adsorption properties of bimetallic MIL-53(Al/Cr) MOF.

The flexibility of the MIL-53(M) metal-organic framework (MOF) has been elucidated through various characterization methodologies, particularly in gas and liquid adsorption processes. However, to the best of our knowledge, there has been no prior electron paramagnetic resonance (EPR) characterization of liquid-phase adsorption in the MOF MIL-53(M), which offers insights into local geometric changes at the oxygen octahedron containing the metal ions of the framework. In this study, we investigate, for the first time, the pore transformations within the MIL-53(Al0.99Cr0.01) framework during liquid-phase adsorption using EPR spectroscopy. Our investigation concentrates explicitly on the adsorption of pure solvents, including water, methanol, ethanol, isopropanol, pyridine, and mixed water/methanol phases. The EPR spectroscopy on the (Al0.99Cr0.01) MOF has allowed us to witness and comprehend the transitions between the narrow pore and large pore phases by examining changes in the zero-field splitting parameters of the S = 3/2 Cr(iii) species. Of all the solvents examined, a robust and distinct spectral feature observed during methanol adsorption unequivocally indicates the pore opening.

Selective CK1α degraders exert antiproliferative activity against a broad range of human cancer cell lines.

Molecular-glue degraders are small molecules that induce a specific interaction between an E3 ligase and a target protein, resulting in the target proteolysis. The discovery of molecular glue degraders currently relies mostly on screening approaches. Here, we describe screening of a library of cereblon (CRBN) ligands against a panel of patient-derived cancer cell lines, leading to the discovery of SJ7095, a potent degrader of CK1α, IKZF1 and IKZF3 proteins. Through a structure-informed exploration of structure activity relationship (SAR) around this small molecule we develop SJ3149, a selective and potent degrader of CK1α protein in vitro and in vivo. The structure of SJ3149 co-crystalized in complex with CK1α + CRBN + DDB1 provides a rationale for the improved degradation properties of this compound. In a panel of 115 cancer cell lines SJ3149 displays a broad antiproliferative activity profile, which shows statistically significant correlation with MDM2 inhibitor Nutlin-3a. These findings suggest potential utility of selective CK1α degraders for treatment of hematological cancers and solid tumors.

Clinical course and follow-up of pediatric patients with COVID-19 vaccine-associated myocarditis compared to non-vaccine-associated myocarditis within the prospective multicenter registry-"MYKKE".

BACKGROUND: Since the onset of widespread COVID-19 vaccination, increased incidence of COVID-19 vaccine-associated myocarditis (VA-myocarditis) has been noted, particularly in male adolescents. METHODS: Patients <18 years with suspected myocarditis following COVID-19 vaccination within 21 days were enrolled in the PedMYCVAC cohort, a substudy within the prospective multicenter registry for pediatric myocarditis "MYKKE." Clinical data at initial admission, 3- and 9-months follow-up were monitored and compared to pediatric patients with confirmed non-vaccine-associated myocarditis (NVA-myocarditis) adjusting for various baseline characteristics. RESULTS: From July 2021 to December 2022, 56 patients with VA-myocarditis across 15 centers were enrolled (median age 16.3 years, 91% male). Initially, 11 patients (20%) had mildly reduced left ventricular ejection fraction (LVEF; 45%-54%). No incidents of severe heart failure, transplantation or death were observed. Of 49 patients at 3-months follow-up (median (IQR) 94 (63-118) days), residual symptoms were registered in 14 patients (29%), most commonly atypical intermittent chest pain and fatigue. Diagnostic abnormalities remained in 23 patients (47%). Of 21 patients at 9-months follow-up (259 (218-319) days), all were free of symptoms and diagnostic abnormalities remained in 9 patients (43%). These residuals were mostly residual late gadolinium enhancement in magnetic resonance imaging. Patients with NVA-myocarditis (n=108) more often had symptoms of heart failure (P = .003), arrhythmias (P = .031), left ventricular dilatation (P = .045), lower LVEF (P < .001) and major cardiac adverse events (P = .102). CONCLUSIONS: Course of COVID-19 vaccine-associated myocarditis in pediatric patients seems to be mild and differs from non-vaccine-associated myocarditis. Due to a considerable number of residual symptoms and diagnostic abnormalities at follow-up, further studies are needed to define its long-term implications.

Routine follow-up transjugular liver biopsy in Fontan patients: technical considerations and safety of an initial case series and literature review.

Introduction: Patients with Fontan palliation are susceptible to congestive hepatopathy and Fontan-associated liver disease (FALD) because of hemodynamic changes. The staging of liver fibrosis involves various methods, including invasive biopsy. Transjugular liver biopsy (TJLB) offers a less invasive alternative, enhancing liver disease surveillance in routine cardiac catheterization. We detail the technical aspects, share initial outcomes, and discuss existing literature. Methods/results: During routine follow-up cardiac catheterization indicated by hemodynamic or clinical alterations, four patients aged between 16 and 26 years with univentricular Fontan circulation and three patients with biventricular circulation underwent TJLB during routine surveillance catheterization. The examinations were performed under conscious sedation and local anesthesia without general anesthesia. Jugular access was obtained at the site of liver localization, and a 5 F multipurpose catheter was inserted into the liver veins. After hand angiography to delineate the local hepatic venous anatomy, an exchange wire was used to place the bioptome, and three consecutive biopsies were performed. There were no complications, especially perforation or bleeding. The technical success rate was 100%, with all obtained samples appropriate for histopathological diagnostics. The total additional procedure time was less than 20 min. Conclusion: TJLB is an attractive alternative method for obtaining liver specimens in the scope of FALD care. We believe that it should be performed during routine hemodynamic evaluations in Fontan patients and can be performed safely with very low additional time expenditure. As the biopsy site is intravascular, the risk of external bleeding or hematoma is significantly reduced despite the high intrahepatic pressures and the usually impaired coagulation profile in these patients. Based on our initial experience and the lower complication rates compared with other techniques, TJLB should be considered a standard approach in these patients and used more often during the long-term follow-up of Fontan patients. It can be performed in the same setting whenever a hemodynamic assessment of patients with congenital heart defects is required.

[Chest pain and cardiovascular diseases in women : Diagnostics and treatment]. / Brustschmerz und kardiovaskuläre Erkrankungen bei Frauen : Diagnostik und Therapie.

Cardiovascular diseases (CVD) are the leading cause of global mortality not only in men but also in women. The incidence of CVD significantly increases in women, especially after the menopause. Sex and gender differences in the incidence, prevalence and mortality of CVD are due to hormonal, anatomical, and sociocultural differences. As part of the primary and secondary prevention of coronary heart disease (CHD), risk factors specific for women, such as autoimmune diseases and pregnancy-associated diseases (e.g., gestational diabetes and pre-eclampsia) should also be taken into account in addition to the classical cardiovascular risk factors. Furthermore, in women with angina pectoris it should be considered that women in particular frequently suffer from ischemia with nonobstructive coronary arteries (INOCA) that can be caused, for example, by coronary microvascular dysfunction (CMD) or coronary spasms. Based on this, the diagnostics should not be terminated in symptomatic women after coronary angiography with normal epicardial vessels. A targeted diagnostics for CMD and coronary spasms should be carried out at an early stage.

Activation of the integrated stress response rewires cardiac metabolism in Barth syndrome.

Barth Syndrome (BTHS) is an inherited cardiomyopathy caused by defects in the mitochondrial transacylase TAFAZZIN (Taz), required for the synthesis of the phospholipid cardiolipin. BTHS is characterized by heart failure, increased propensity for arrhythmias and a blunted inotropic reserve. Defects in Ca2+-induced Krebs cycle activation contribute to these functional defects, but despite oxidation of pyridine nucleotides, no oxidative stress developed in the heart. Here, we investigated how retrograde signaling pathways orchestrate metabolic rewiring to compensate for mitochondrial defects. In mice with an inducible knockdown (KD) of TAFAZZIN, and in induced pluripotent stem cell-derived cardiac myocytes, mitochondrial uptake and oxidation of fatty acids was strongly decreased, while glucose uptake was increased. Unbiased transcriptomic analyses revealed that the activation of the eIF2α/ATF4 axis of the integrated stress response upregulates one-carbon metabolism, which diverts glycolytic intermediates towards the biosynthesis of serine and fuels the biosynthesis of glutathione. In addition, strong upregulation of the glutamate/cystine antiporter xCT increases cardiac cystine import required for glutathione synthesis. Increased glutamate uptake facilitates anaplerotic replenishment of the Krebs cycle, sustaining energy production and antioxidative pathways. These data indicate that ATF4-driven rewiring of metabolism compensates for defects in mitochondrial uptake of fatty acids to sustain energy production and antioxidation.

Liver stiffness in Fontan patients: the effect of respiration and food intake.

Objectives: For several years, patients with single ventricle hearts have been palliated according to the Fontan principle. One well known long-term consequence in these patients is the Fontan-associated liver disease and fibrosis, which occurs due to the chronically increased Central Venous Pressure (CVP) after Fontan palliation. It carries an increased risk of liver cirrhosis and hepatocellular carcinoma over time. Liver elastography (LE) is a non-invasive, safe, and feasible ultrasound method to determine liver stiffness and the stage of liver fibrosis. Usually, this examination must be performed in a sober condition and strict inspiratory hold to optimize the results and may therefore be difficult to perform on children as a routine examination. However, the influence of food intake and respiration on these results in Fontan patients is unclear. To optimize the implementation for this examination especially in children, the effects of food intake and breathing maneuvers on liver stiffness in patients with Fontan circulation were investigated. Methods: For this prospective study, 25 Fontan patients (group 1) and 50 healthy volunteers (group 2) were examined. The two groups were additionally divided into two age categories (group 1a: 10-19 years; group 1b: 20-29 years; group 2a: 15-19 years; group 2b: 20-25 years). Liver stiffness was measured by liver elastography once before food intake (=T0, with 6 h of fasting). Subsequently the participants consumed a standardized chocolate drink (500 mL) with nutritional distribution corresponding to a standardized meal (600 kcal). Liver stiffness was then determined 15, 30, 45, 60, 90, 120, 150, and 180 min after ingestion. Each measurement of liver stiffness was performed during maximal inspiratory and expiratory holds. The study was reviewed and approved by the responsible ethics committee. Results: In group 2 there was a significant increase in liver stiffness after food intake at T15, T30, and T45 during inspiration measurements (T0 = 4.0 kPa vs. T15 = 4.9 kPa, difference = 22.5%; T0 = 4.0 kPa vs. T30 = 4.9 kPa difference = 22.5%; T0 = 4.0 kPa vs. T45 = 4.3 kPa difference = 7.5%), as well as during expiration at T15 and T30 (T0 = 4.5 kPa vs. T15 = 5.1 kPa, difference = 14.7%; T0 = 4.5 kPa vs. T30 = 4.9 kPa difference = 7.8%). Whereas in Fontan patients (group 1) liver stiffness did not differ significantly at any time between fasting (T0) and postprandial values. The respiratory maneuvers in the healthy subjects (group 2) differed significantly only before food intake (T0) (group 2: insp = 3.97 kPa vs. exp. = 4.48 kPa difference = 11.3%). In the Fontan group (group 1), there was no significant difference between the respiratory phases at any point. The different age categories showed no significant difference in liver stiffness. Conclusion: With these results we could demonstrate for the first time that in Fontan patients the time of food intake (i.e., fasting) has no clinical significance for the values obtained in liver elastography. We could also demonstrate that the breathing maneuvers during the examination had only minimal clinical impact on the results of liver elastography in patients with normal circulation and no effect in patients with Fontan-circulation. Consequently, liver elastography for Fontan patients is reliable independently of food intake and breathing maneuvers and can also be performed on younger patients, who are unable to follow breathing commands or longer fasting periods, without any impairment of the results. These results should encourage a routine use of LE in the follow-up of Fontan patients.

Vagal Asystoles in a Boy With Prader-Willi Syndrome.

Prader-Willi syndrome (PWS) is a genetic hormonal disorder of the hypothalamic-pituitary-axis resulting in mental retardation, muscle hypotonia, hypogonadism, and hyperphagia leading to significant obesity. Cardiovascular morbidity and mortality in adult patients with PWS is higher than in healthy controls and mainly secondary to massive obesity. In childhood, mortality may result from respiratory or gastrointestinal illnesses. We present a case of a 10-year-old boy with PWS who experienced recurrent and asymptomatic episodes of sinus pauses caused by the ingestion of large gulps of apple juice, which could be provoked and reproduced. The asystoles could not be provoked by any other vagal maneuvers and an initial diagnostic workup revealed no indication for structural heart disease. Because of the asymptomatic character of the asystoles, no treatment was initially provided. When he re-presented 3 months later after a clinically relevant syncope at school, pacemaker therapy was initiated, and he has demonstrated no subsequent sinus pauses or syncopes. Regarding the rising awareness of subtle cardiac alterations including autonomic dysfunction and electrocardiogram changes in young patients with PWS and especially the occurrence of unexplained sudden deaths in childhood that may be precipitated by arrhythmia, we suggest that the utility of periodic screening for arrhythmia risk should be evaluated in children with PWS.

A multilocus genetic risk score for obesity: Association with BMI and metabolic alterations in a cohort with severe obesity.

Genome wide association studies have identified numerous single nucleotide polymorphisms (SNPs) associated with obesity, yet effect sizes of individual SNPs are small. Therefore, the aim of our study was to investigate whether a genetic risk score (GRS) comprising risk alleles of SNPs identified in the GIANT consortium meta-analyses shows association with body mass index (BMI) and other BMI related metabolic alterations in a cohort with an extreme phenotype. Genotyping of 93 SNPs was performed in 314 obese individuals (mean BMI 40.5 ± 7.8 kg/m², aged 45 ± 12 years), participating in a standardized weight reduction program, and in 74 lean controls (mean BMI 24.6 ± 3.3 kg/m², aged 41.7 ± 13.4 years). Allele numbers of all 93 SNPs were added to a GRS. Anthropometric parameters, parameters of glucose/insulin and lipid metabolism were assessed standardized after a 12 hours fast. GRS was significantly different between controls and obese individuals (unweighted GRS: 86.6 vs 89.0, P = .002; weighted GRS: 84.9 vs 88.3, P = .005). Furthermore, linear regression analysis showed significant associations of GRS with BMI ( P < .0001), weight ( P = .0005), waist circumference ( P = .0039), fat mass ( P < .0001) and epicardial fat thickness ( P = .0032), yet with small effect sizes ( r ² < 0.06). In conclusion, in our study GRS could differentiate between extreme obese and lean individuals, and was associated with BMI and its related traits, yet with small effect sizes.

Comparison of the Prolonged- and Immediate-Release Tacrolimus Capsule Formulation: The Patient's View and Medication Satisfaction of Patients After Pediatric Heart Transplantation.

BACKGROUND: Medication adherence is essential for long-term success after pediatric organ transplantation. Causes of reduced adherence should be detected early to improve the consequent medication intake. We describe the influence of switching from tacrolimus twice daily (tacrolimus-BID) to tacrolimus once daily (tacrolimus-QD) on medication satisfaction and medication adherence in patients after pediatric heart transplantation. METHODS: A retrospective analysis was conducted regarding patient satisfaction and adherence to the immunosuppressant tacrolimus after pediatric heart transplantation, before and after conversion from tacrolimus-BID to tacrolimus-QD, using questionnaires. RESULTS: Thirty-eight patients were enrolled (tacrolimus-BID: n = 35, mean age 15.7 ± 5.2 years; tacrolimus-QD: n = 38, mean age 16.2 ± 5.6 years). The amount of unadministered medication in the last 3 months did not differ between the 2 pharmaceutical forms. However, 17% (n = 6) reported unstable tacrolimus trough levels when taking tacrolimus-BID, vs 8% (n = 3) under tacrolimus-QD (P = .453). However, there was no statistically significant difference in the stability of the last 6 trough levels of each patient (P = .074). A total of 57% (n = 20) of patients had subjective side effects before conversion, compared to only 29% (n = 11) after conversion (P = .013). Regarding the intensity of the side effects, 6 patients reported strong/very strong side effects when taking tacrolimus-BID vs 1 patient when taking tacrolimus-QD (P = .250). In addition, the overall satisfaction with the immunosuppressant was higher under tacrolimus-QD (92% vs 83%; P = .508). However, this improvement was statistically not significant and may not be clinically relevant. CONCLUSIONS: The amount of forgotten medication was not reduced after conversion from tacrolimus-BID to tacrolimus-QD. However, subjective side effects as well as patient satisfaction improved under tacrolimus-QD.

Case report: Central venous catheter thrombosis complicated by chronic thromboembolic disease/pulmonary hypertension in two children requiring parenteral nutrition.

Chronic thromboembolic pulmonary hypertension is a rare but life-threatening complication of long-term central venous catheters (CVC) in children. However, evidence in terms of potential treatment strategies and outcome data remains scarce. We describe two cases of CVC-related thrombosis (Hickman-catheter) complicated by recurrent pulmonary emboli. One patient experienced a complete thromboembolic obstruction of the right pulmonary artery with normal pulmonary pressures and the second patient suffered from a central thromboembolic obstruction of both pulmonary arteries associated with severe pulmonary hypertension. Both patients successfully underwent surgical thromboendarterectomy with deep hypothermic circulatory arrest.

The orally bioavailable GSPT1/2 degrader SJ6986 exhibits in vivo efficacy in acute lymphoblastic leukemia.

Advancing cure rates for high-risk acute lymphoblastic leukemia (ALL) has been limited by the lack of agents that effectively kill leukemic cells, sparing normal hematopoietic tissue. Molecular glues direct the ubiquitin ligase cellular machinery to target neosubstrates for protein degradation. We developed a novel cereblon modulator, SJ6986, that exhibits potent and selective degradation of GSPT1 and GSPT2 and cytotoxic activity against childhood cancer cell lines. Here, we report in vitro and in vivo testing of the activity of this agent in a panel of ALL cell lines and xenografts. SJ6986 exhibited similar cytotoxicity to the previously described GSPT1 degrader CC-90009 in a panel of leukemia cell lines in vitro, resulting in apoptosis and perturbation of cell cycle progression. SJ6986 was more effective than CC-90009 in suppressing leukemic cell growth in vivo, partly attributable to favorable pharmacokinetic properties, and did not significantly impair differentiation of human CD34+ cells ex vivo. Genome-wide CRISPR/Cas9 screening of ALL cell lines treated with SJ6986 confirmed that components of the CRL4CRBN complex, associated adaptors, regulators, and effectors were integral in mediating the action of SJ6986. SJ6986 is a potent, selective, orally bioavailable GSPT1/2 degrader that shows broad antileukemic activity and has potential for clinical development.

FLEXR: automated multi-conformer model building using electron-density map sampling.

Protein conformational dynamics that may inform biology often lie dormant in high-resolution electron-density maps. While an estimated ∼18% of side chains in high-resolution models contain alternative conformations, these are underrepresented in current PDB models due to difficulties in manually detecting, building and inspecting alternative conformers. To overcome this challenge, we developed an automated multi-conformer modeling program, FLEXR. Using Ringer-based electron-density sampling, FLEXR builds explicit multi-conformer models for refinement. Thereby, it bridges the gap of detecting hidden alternate states in electron-density maps and including them in structural models for refinement, inspection and deposition. Using a series of high-quality crystal structures (0.8-1.85 Šresolution), we show that the multi-conformer models produced by FLEXR uncover new insights that are missing in models built either manually or using current tools. Specifically, FLEXR models revealed hidden side chains and backbone conformations in ligand-binding sites that may redefine protein-ligand binding mechanisms. Ultimately, the tool facilitates crystallographers with opportunities to include explicit multi-conformer states in their high-resolution crystallographic models. One key advantage is that such models may better reflect interesting higher energy features in electron-density maps that are rarely consulted by the community at large, which can then be productively used for ligand discovery downstream. FLEXR is open source and publicly available on GitHub at https://github.com/TheFischerLab/FLEXR.

Immobilization of Aspergillus sp. laccase on hierarchical silica MFI zeolite with embedded macropores.

Laccase from Aspergillus sp. (LC) was immobilized on functionalized silica hierarchical (microporous-macroporous) MFI zeolite (ZMFI). The obtained immobilized biocatalyst (LC#ZMFI) was characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (ATR-FTIR), N2 adsorption/desorption isotherms, solid-state NMR spectroscopy and thermogravimetric analysis (TGA) confirming the chemical anchoring of the enzyme to the zeolitic support. The optimal pH, kinetic parameters (KM and Vmax), specific activity, as well as both storage and operational stability of LC#ZMFI were determined. The LC#ZMFI KM and Vmax values amount to 10.3 µM and 0.74 µmol·mg-1 min-1, respectively. The dependence of specific activity on the pH for free and immobilized LC was investigated in the pH range of 2-7, The highest specific activity was obtained at pH = 3 for both free LC and LC#ZMFI. LC#ZMFI retained up to 50 % and 30 % of its original activity after storage of 21 and 30 days, respectively. Immobilization of laccase on hierarchical silica MFI zeolite allows to carry out the reaction under acidic pH values without affecting the support structure.

Pan-HSP90 ligand binding reveals isoform-specific differences in plasticity and water networks.

Isoforms of heat shock protein 90 (HSP90) fold oncoproteins that facilitate all 10 hallmarks of cancer. However, its promise as a therapeutic target remains unfulfilled as there is still no FDA-approved drug targeting HSP90 in disease. Among the reasons hindering progress are side effects caused by pan-HSP90 inhibition. Selective targeting of the four isoforms is challenging due to high sequence and structural similarity. Surprisingly, while decades of drug discovery efforts have produced almost 400 human HSP90 structures, no single ligand has been structurally characterized across all four human isoforms to date, which could reveal structural differences to achieve selectivity. To better understand the HSP90 landscape relevant for ligand binding and design we take a three-pronged approach. First, we solved the first complete set of structures of a single ligand bound to all four human isoforms. This enabled a systematic comparison of how side-chains and water networks respond to ligand binding across isoforms. Second, we expanded our analysis to publicly available, incomplete isoform-ligand series with distinct ligand chemistry. This highlighted general trends of protein and water mobility that differ among isoforms and impact ligand binding. Third, we further probed the Hsp90α conformational landscape for accommodating a congeneric series containing the purine scaffold common to HSP90 inhibitors. This revealed how minor ligand modifications flip ligand poses and perturb water and protein conformations. Taken together, this work illustrates how a systematic approach can shed new light on an "old" target and reveal hidden isoform-specific accommodations of congeneric ligands that may be exploited in ligand discovery and design.

Improvement of obstructive sleep apnea does not rescue left atrial enlargement in obese participants of a multimodal weight reduction program.

The aim of our study was to investigate the effect of obstructive sleep apnea (OSA) and its weight loss related improvement on left atrial (LA) area in individuals with severe obesity participating in a multimodal weight reduction (WR) program. Participants with obesity (body mass index, BMI, 40.2 ± 7.3 kg/m2) underwent a 1-year WR program. Phenotyping was performed at baseline and after 12 months. Individuals were categorized according to their baseline apnea-hypopnea-index (AHI) into "no OSA" (AHI < 5) and "OSA" (AHI ≥ 5). From a total of 84 study participants, 69 completed the program. Average WR was 19.0 ± 15.7 kg after 12 months. Participants with obesity and OSA had a larger LA area at baseline as compared to participants with obesity but without OSA (22.4 ± 5.6 vs 18.8 ± 3.8 cm2; P = .008). Linear regression showed significant associations of AHI and BMI with LA area. In contrast, despite a significant decrease of AHI in participants with OSA as compared to those without OSA at 1 year follow up (ΔAHI was -12 ± 14) ΔLA area did not significantly differ between groups. Multivariable linear regression showed no significant association of ΔAHI or ΔBMI with ΔLA. In conclusion, the presence of obstructive sleep apnea contributes to LA enlargement on top of obesity in our study cohort. Yet, successful WR with subsequently improved OSA was not associated with an improvement of LA area.

From PROTAC to inhibitor: Structure-guided discovery of potent and orally bioavailable BET inhibitors.

An X-ray structure of a CLICK chemistry-based BET PROTAC bound to BRD2(BD2) inspired synthesis of JQ1 derived heterocyclic amides. This effort led to the discovery of potent BET inhibitors displaying overall improved profiles when compared to JQ1 and birabresib. A thiadiazole derived 1q (SJ1461) displayed excellent BRD4 and BRD2 affinity and high potency in the panel of acute leukaemia and medulloblastoma cell lines. A structure of 1q co-crystalised with BRD4-BD1 revealed polar interactions with the AZ/BC loops, in particular with Asn140 and Tyr139, rationalising the observed affinity improvements. In addition, exploration of pharmacokinetic properties of this class of compounds suggest that the heterocyclic amide moiety improves drug-like features. Our study led to the discovery of potent and orally bioavailable BET inhibitor 1q (SJ1461) as a promising candidate for further development.