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Despite intense interest in expanding chemical space, libraries containing hundreds-of-millions to billions of diverse molecules have remained inaccessible. Here we investigate structure-based docking of 170 million make-on-demand compounds from 130 well-characterized reactions. The resulting library is diverse, representing over 10.7 million scaffolds that are otherwise unavailable. For each compound in the library, docking against AmpC β-lactamase (AmpC) and the D 4 dopamine receptor were simulated. From the top-ranking molecules, 44 and 549 compounds were synthesized and tested for interactions with AmpC and the D 4 dopamine receptor, respectively. We found a phenolate inhibitor of AmpC, which revealed a group of inhibitors without known precedent. This molecule was optimized to 77 nM, which places it among the most potent non-covalent AmpC inhibitors known. Crystal structures of this and other AmpC inhibitors confirmed the docking predictions. Against the D 4 dopamine receptor, hit rates fell almost monotonically with docking score, and a hit-rate versus score curve predicted that the library contained 453,000 ligands for the D 4 dopamine receptor. Of 81 new chemotypes discovered, 30 showed submicromolar activity, including a 180-pM subtype-selective agonist of the D 4 dopamine receptor. Using a make-on-demand library that contains hundreds-of-millions of molecules, structure-based docking was used to identify compounds that, after synthesis and testing, are shown to interact with AmpC β-lactamase and the D 4 dopamine receptor with high affinity.

The MRGPRX family of receptors (MRGPRX1–4) is a family of mas-related G-protein-coupled receptors that have evolved relatively recently 1 . Of these, MRGPRX2 and MRGPRX4 are key physiological and pathological mediators of itch and related mast cell-mediated hypersensitivity reactions 2 – 5 . MRGPRX2 couples to both G i and G q in mast cells 6 . Here we describe agonist-stabilized structures of MRGPRX2 coupled to G i1 and G q in ternary complexes with the endogenous peptide cortistatin-14 and with a synthetic agonist probe, respectively, and the development of potent antagonist probes for MRGPRX2. We also describe a specific MRGPRX4 agonist and the structure of this agonist in a complex with MRGPRX4 and G q . Together, these findings should accelerate the structure-guided discovery of therapeutic agents for pain, itch and mast cell-mediated hypersensitivity. Structural studies of the itch receptors MRGPRX2 and MRGPRX4 in complex with endogenous and synthetic ligands provide a basis for the development of therapeutic compounds for pain, itch and mast cell-mediated hypersensitivity.

Onion (Allium cepa L.) is an important vegetable crop widely grown for diverse culinary and nutraceutical properties. Being a shallow-rooted plant, it is prone to drought. In the present study, transcriptome sequencing of drought-tolerant (1656) and drought-sensitive (1627) onion genotypes was performed to elucidate the molecular basis of differential response to drought stress. A total of 123206 and 139252 transcripts (average transcript length: 690 bases) were generated after assembly for 1656 and 1627, respectively. Differential gene expression analyses revealed upregulation and downregulation of 1189 and 1180 genes, respectively, in 1656, whereas in 1627, upregulation and downregulation of 872 and 1292 genes, respectively, was observed. Genes encoding transcription factors, cytochrome P450, membrane transporters, and flavonoids, and those related to carbohydrate metabolism were found to exhibit a differential expression behavior in the tolerant and susceptible genotypes. The information generated can facilitate a better understanding of molecular mechanisms underlying drought response in onion.

Thyroid hormones are vital in metabolism, growth and development 1 . Thyroid hormone synthesis is controlled by thyrotropin (TSH), which acts at the thyrotropin receptor (TSHR) 2 . In patients with Graves’ disease, autoantibodies that activate the TSHR pathologically increase thyroid hormone activity 3 . How autoantibodies mimic thyrotropin function remains unclear. Here we determined cryo-electron microscopy structures of active and inactive TSHR. In inactive TSHR, the extracellular domain lies close to the membrane bilayer. Thyrotropin selects an upright orientation of the extracellular domain owing to steric clashes between a conserved hormone glycan and the membrane bilayer. An activating autoantibody from a patient with Graves’ disease selects a similar upright orientation of the extracellular domain. Reorientation of the extracellular domain transduces a conformational change in the seven-transmembrane-segment domain via a conserved hinge domain, a tethered peptide agonist and a phospholipid that binds within the seven-transmembrane-segment domain. Rotation of the TSHR extracellular domain relative to the membrane bilayer is sufficient for receptor activation, revealing a shared mechanism for other glycoprotein hormone receptors that may also extend to other G-protein-coupled receptors with large extracellular domains. Cryo-electron microscopy structures of the thyrotropin receptor reveal the basis for the activation of the receptor by autoantibodies in patients with Graves’ disease.

Paralogs often exhibit functional redundancy, allowing them to effectively compensate for each other’s loss. However, this buffering mechanism is frequently disrupted in cancer, exposing unique paralog-specific vulnerabilities. Here, we identify a selective dependency on the splicing factor TRA2A . We find that TRA2A and its paralog TRA2B are synthetic lethal partners that function as widespread and largely redundant activators of both alternative and constitutive splicing. While loss of TRA2A alone is typically neutral due to compensation by TRA2B , we discover that a subset of cancer cell lines are highly TRA2A -dependent. Upon TRA2A depletion, these cell lines exhibit a lack of paralog buffering specifically on shared splicing targets, leading to defects in mitosis and cell death. Notably, TRA2B overexpression rescues both the aberrant splicing and lethality associated with TRA2A loss, indicating that paralog compensation is dosage-sensitive. Together, these findings reveal a complex dosage-dependent relationship between paralogous splicing factors, and highlight how dysfunctional paralog buffering can create a selective dependency in cancer.

Pulmory rehabilitation (PR) is being used in the routine magement of patients of obstructive sleep apnea (OSA) at some centers. However, the studies documenting benefits of PR in OSA lack standardization in terms of outcome measures. A study was hence planned to determine the efficacy of PR on exercise capacity, health related quality of life (HRQOL), day time sleepiness and sleep-quality of life (QOL) in patients of OSA. As a part of comprehensive therapy, patients diagnosed with OSA are maged with continuous positive airway pressure (CPAP), 8 weeks thrice weekly outpatient hospital-based PR and medical treatment at the Pulmory Medicine Department, Government Medical College and Hospital, Chandigarh. However, some patients refuse for PR because of time constraints and travel issues. Patients with newly diagnosed OSA without co-existing respiratory disease, who agreed for the CPAP, PR and medical magement were enrolled in group A. The patients who refused for PR but were ready for CPAP and medical magement were enrolled in Group B; 30 patients were taken in each group. Exercise capacity, HRQOL, day time sleepiness and sleep-QOL were determined at baseline and at 8-weeks follow-up by 6-minute walk distance (6MWD), St. George's Respiratory Questionire (SGRQ), Epworth Sleepiness Scale (ESS) and Functiol Outcomes of Sleep Questionire (FOSQ) and compared amongst the two groups. Four patients from group A were excluded as they did not complete PR; 26 patients from group A and 30 patients from group B were filly alyzed. At baseline, both groups were matched with respect to age, gender, apnea-hypopnea index (AHI), body mass index (BMI), FEV1%predicted, 6MWD, SGRQ, ESS and FOSQ. At follow up at 8 weeks, BMI, 6MWD, SGRQ, ESS and FOSQ improved significantly from baseline in group A (p<0.001). FEV1%predicted also improved but non significantly. In group B, FEV1%predicted, BMI, 6MWD, SGRQ, ESS and FOSQ score did not improve significantly from baseline. Mean improvement from baseline in BMI, 6MWD, SGRQ, ESS and FOSQ was significantly more in group A than group B (p<0.001, p<0.001, p=0.041, p<0.001 and p<0.001, respectively). PR, being beneficial, should be incorporated in standard magement of OSA.

ABSTRACT Aim: The purpose of this study was to assess the short-term perioral soft tissue variations of the lips before and after treatment cases in 15 patients with bi-maxillary protrusion using treated lateral cephalograms who had already achieved active growth. Methodology: Fifteen pre-treatment and post-treatment lateral cephalometric radiographs of 18-25-year-old individuals with bimaxillary protrusion treated with all four 1st premolar extractions were accessed from the records. From the reference planes and landmarks, 13 horizontal, 10 vertical, and 2 angular measurements were noted. Statistical comparisons between pre-treatment and post-treatment measurements were measured by a paired t-test to assess the importance of the mean variations at the predetermined significance level. Pearson's correlation coefficient (R) was utilized to assess the strength and significance of the linear relationship between the mean differences for paired (dependent and independent) variables. Results: Pearson's correlation exhibited a noteworthy positive association between the horizontal changes in upper lip position and the horizontal changes of the upper incisor tip point (H-tU1) (R = 0.748), the upper incisor cervical point (H-cU1) (R = 0.707), the lower incisor tip point (H-tL1) (R = 0.839), and the lower incisor cervical point (H-cL1) (R = 0.767). This indicated that upper lip changes are the aftermath of the retraction of the upper and lower incisors in class I bi-maxillary protrusion malocclusion. Conclusion: Thick upper lips showed more retraction of the upper lip in correlation with retraction of the incisors as compared with thin lips. The lower incisor cervical point displayed the strongest association with lower lip retraction.

Testis-specific histone variants are crucial to promote open chromatin structure to enable nucleosome disassembly in the final stages of spermiogenesis. However, even after histone replacement, mature sperm retain a proportion of these variants, the function of which is unknown. The present study aimed to understand the functional relevance of the retained H2B and H2A variants, TH2B and TH2A. While no literature is available on the phenotype of TH2A knockouts, TH2B/TH2A double knockout male mice are reported to be infertile. In this study, ChIP-seq analysis was done for TH2B and TH2A to understand the epigenomics of the retained TH2B and TH2A, using murine caudal sperm. Distribution across genomic partitions revealed ∼35% of the TH2B peaks within ±5 kb of TSS whereas TH2A peaks distribution was sparse at TSS. Gene Ontology revealed embryo development as the most significant term associated with TH2B. Also, based on genomic regions, TH2B was observed to be associated with spindle assembly and various meiosis-specific genes, which is an important finding as TH2A/TH2B DKO mice have been reported to have defective cohesin release. A comparison of mouse and human TH2B-linked chromatin revealed 26% overlap between murine and human TH2B-associated genes. This overlap included genes crucial for embryogenesis. Most importantly, heterogeneity in the epigenetic landscape of TH2A and TH2B was seen, which is intriguing as TH2B and TH2A are well reported to be present in the same nucleosomes to promote open chromatin. Additionally, unlike TH2B, TH2A was enriched on the mitochondrial chromosome. TH2A was found to be associated with Nuclear insertion of Mitochondrial DNA sequences (NUMTs) in sperm. A comprehensive analysis of these observations indicates novel functions for the sperm-retained TH2B and TH2A.

Background/Objectives: This study aimed to evaluate the effect of a mouth rinse, MucoPEG™, containing a polyethylene glycol derivative, on oral dryness, compared to Biotène® Dry Mouth Gentle Oral Rinse (Biotène®). Methods: Forty-two subjects with mild oral dryness with a Challacombe scale score of 1 or more were enrolled in the study across two sites using an open-label randomized crossover design. Subjects used either Biotène® or MucoPEG™ twice daily for two weeks (Period 1) with a one-week washout period and then crossed over to the other product for two weeks (Period 2). The subjects provided a rating on a Visual Analogue Scale (VAS) for tongue and oral dryness and completed the Dry Mouth Relief Questionnaire (DMRQ), Dry Mouth Product Performance and Attributes Questionnaire (PPAQ), and Dry Mouth Inventory (DMI). Results: Both MucoPEG™ and Biotène® demonstrated overall improvements in oral dryness symptoms with no statistically significant difference observed between products when both periods were combined. However, a statistically significant difference favoring MucoPEG™ was observed during Period 2. No significant sequence or period effects were detected. DMRQ and DMI responses were generally comparable between products. However, MucoPEG™ was associated with higher patient-reported ratings for sustained moisturizing and lubricating effects at 240 min post-application on the PPAQ only. No adverse events were reported. Conclusions: In this study MucoPEG™ demonstrated clinical performance comparable to that of Biotène® in improving symptoms of oral dryness and was well tolerated. Although outcomes showed no significant differences between the two products, a subset of patient-reported outcomes suggests a potential advantage of MucoPEG™ in sustained symptom relief, consistent with its PEG-derivative formulation mechanism. However, these observations require validation. Further studies using parallel-group designs may help to clarify potential differences in long-term and sustained efficacy, thereby supporting the potential value of MucoPEG™ as an alternative therapeutic option for the management of xerostomia.

Kalmegh (Andrographis paniculata (Burm. F.) Nees) is one of the most important medicinal plants and has been widely explored as traditional medicine. To exploit its natural genetic diversity and initiations of molecular breeding to develop novel cultivars or varieties, developments of genomic resources are essential. Four microsatellite-enriched genomic libraries—(CT)14, (GT)12, (AG)15 and (AAC)8—were constructed using the genomic DNA of A. paniculata. Initially, 183 recombinant colonies were screened for the presence of CT, GT, AG, and AAC microsatellite repeats, out of which 47 clones found positive for the desired simple sequence repeats (SSRs). It was found that few colonies had more than one desirable SSR. Thus, a sum of 67 SSRs were designed and synthesized for their validation among 42 A. paniculata accessions. Out of the 67 SSRs used for genotyping, only 41 were found to be polymorphic. The developed set of g-SSR markers showed substantial genetic variability among the selected A. paniculata accessions, with an average polymorphic information content (PIC) value of 0.32. Neighbor-joining tree analysis, population structure analysis, analysis of molecular variance (AMOVA), and principal coordinate analysis (PCoA) illustrated the considerable genetic diversity among them. The novel g-SSR markers developed in the present study could be important genomic resources for future applications in A. paniculata.