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Abstract Predicting olfactory perceptions from odorant molecules is challenging due to the complex and potentially discontinuous nature of the perceptual space for smells. In this study, we introduce a deep learning model, Mol-PECO (Molecular Representation by Positional Encoding of C oulomb Matrix), designed to predict olfactory perceptions based on molecular structures and electrostatics. Mol-PECO learns the efficient embedding of molecules by utilizing the Coulomb matrix, which encodes atomic coordinates and charges, as an alternative of the adjacency matrix and its Laplacian eigenfunctions as positional encoding of atoms. With a comprehensive dataset of odor molecules and descriptors, Mol-PECO outperforms traditional machine learning methods using molecular fingerprints and graph neural networks based on adjacency matrices. The learned embeddings by Mol-PECO effectively capture the odor space, enabling global clustering of descriptors and local retrieval of similar odorants. This work contributes to a deeper understanding of the olfactory sense and its mechanisms.

IntroductionThe COVID-19 Disease Map project is a large-scale community effort uniting 277 scientists from 130 Institutions around the globe. We use high-quality, mechanistic content describing SARS-CoV-2-host interactions and develop interoperable bioinformatic pipelines for novel target identification and drug repurposing. MethodsExtensive community work allowed an impressive step forward in building interfaces between Systems Biology tools and platforms. Our framework can link biomolecules from omics data analysis and computational modelling to dysregulated pathways in a cell-, tissue- or patient-specific manner. Drug repurposing using text mining and AI-assisted analysis identified potential drugs, chemicals and microRNAs that could target the identified key factors.ResultsResults revealed drugs already tested for anti-COVID-19 efficacy, providing a mechanistic context for their mode of action, and drugs already in clinical trials for treating other diseases, never tested against COVID-19. DiscussionThe key advance is that the proposed framework is versatile and expandable, offering a significant upgrade in the arsenal for virus-host interactions and other complex pathologies.

Abstract Pv11 is an insect cell line established from the midge Polypedilum vanderplanki, whose larval form exhibits an extreme desiccation tolerance known as anhydrobiosis. Pv11 itself is also capable of anhydrobiosis, which is induced by trehalose treatment. Here we report the successful construction of a genome editing system for Pv11 cells and its application to the identification of signaling pathways involved in anhydrobiosis. Using the Cas9-mediated gene knock-in system, we established Pv11 cells that stably expressed GCaMP3 to monitor intracellular Ca2+ mobilization. Intriguingly, trehalose treatment evoked a transient increase in cytosolic Ca2+ concentration, and further experiments revealed that the calmodulin–calcineurin–NFAT pathway contributes to tolerance of trehalose treatment as well as desiccation tolerance, while the calmodulin–calmodulin kinase–CREB pathway conferred only desiccation tolerance on Pv11 cells. Thus, our results show a critical contribution of the trehalose-induced Ca2+ surge to anhydrobiosis and demonstrate temporally different roles for each signaling pathway.

Abstract We need to effectively combine the knowledge from surging literature with complex datasets to propose mechanistic models of SARS‐CoV‐2 infection, improving data interpretation and predicting key targets of intervention. Here, we describe a large‐scale community effort to build an open access, interoperable and computable repository of COVID‐19 molecular mechanisms. The COVID‐19 Disease Map (C19DMap) is a graphical, interactive representation of disease‐relevant molecular mechanisms linking many knowledge sources. Notably, it is a computational resource for graph‐based analyses and disease modelling. To this end, we established a framework of tools, platforms and guidelines necessary for a multifaceted community of biocurators, domain experts, bioinformaticians and computational biologists. The diagrams of the C19DMap, curated from the literature, are integrated with relevant interaction and text mining databases. We demonstrate the application of network analysis and modelling approaches by concrete examples to highlight new testable hypotheses. This framework helps to find signatures of SARS‐CoV‐2 predisposition, treatment response or prioritisation of drug candidates. Such an approach may help deal with new waves of COVID‐19 or similar pandemics in the long‐term perspective.

Abstract Angkor Wat temple, mainly composed of sandstone blocks, displays a type of religious architecture that signifies the worldviews of the Khmer and Hindu religions. The temple is a part of a UNESCO World Heritage site. However, there are numerous occurrences of hollows, i.e., depression-like notches, that have developed at the base of its sandstone pillars due to wet–dry and salt weathering. These pillars are variably weathered due to differences in the directions of the pillar surfaces and galleries in the temple. In this study, we analyze the differences in the hollow depths based on the sandstone hardness and water content, as well as a 5-year record of the temperature and humidity in the galleries. The results show that the hollow depths are profound in the outsides of the inner pillars and shallow on the northern side of the first gallery. The hollow depth increases with increasing values obtained by multiplying water content and moisture fluctuations, resulting from direct insolation together with rainfall.

Water is essential for living organisms. Terrestrial organisms are incessantly exposed to the stress of losing water, desiccation stress. Avoiding the mortality caused by desiccation stress, many organisms acquired molecular mechanisms to tolerate desiccation. Larvae of the African midge, Polypedilum vanderplanki, and its embryonic cell line Pv11 tolerate desiccation stress by entering an ametabolic state, anhydrobiosis, and return to active life after rehydration. The genes related to desiccation tolerance have been comprehensively analyzed, but transcriptional regulatory mechanisms to induce these genes after desiccation or rehydration remain unclear. Here, we comprehensively analyzed the gene regulatory network in Pv11 cells and compared it with that of Drosophila melanogaster, a desiccation sensitive species. We demonstrated that nuclear transcription factor Y subunit gamma-like, which is important for drought stress tolerance in plants, and its transcriptional regulation of downstream positive feedback loops have a pivotal role in regulating various anhydrobiosis-related genes. This study provides an initial insight into the systemic mechanism of desiccation tolerance.

The Pv11, an insect cell line established from the midge Polypedilum vanderplanki, is capable of extreme hypometabolic desiccation tolerance, so-called anhydrobiosis. We previously discovered that heat shock factor 1 (HSF1) contributes to the acquisition of desiccation tolerance by Pv11 cells, but the mechanistic details have yet to be elucidated. Here, by analyzing the gene expression profiles of newly established HSF1-knockout and -rescue cell lines, we show that HSF1 has a genome-wide effect on gene regulation in Pv11. The HSF1-knockout cells exhibit a reduced desiccation survival rate, but this is completely restored in HSF1-rescue cells. By comparing mRNA profiles of the two cell lines, we reveal that HSF1 induces anhydrobiosis-related genes, especially genes encoding late embryogenesis abundant proteins and thioredoxins, but represses a group of genes involved in basal cellular processes, thus promoting an extreme hypometabolism state in the cell. In addition, HSF1 binding motifs are enriched in the promoters of anhydrobiosis-related genes and we demonstrate binding of HSF1 to these promoters by ChIP-qPCR. Thus, HSF1 directly regulates the transcription of anhydrobiosis-related genes and consequently plays a pivotal role in the induction of anhydrobiotic ability in Pv11 cells.

Introduction: The COVID-19 Disease Map project is a large-scale community effort uniting 277 scientists from 130 Institutions around the globe. We use high-quality, mechanistic content describing SARS-CoV-2-host interactions and develop interoperable bioinformatic pipelines for novel target identification and drug repurposing. Methods: Extensive community work allowed an impressive step forward in building interfaces between Systems Biology tools and platforms. Our framework can link biomolecules from omics data analysis and computational modelling to dysregulated pathways in a cell-, tissue- or patient-specific manner. Drug repurposing using text mining and AI-assisted analysis identified potential drugs, chemicals and microRNAs that could target the identified key factors. Results: Results revealed drugs already tested for anti-COVID-19 efficacy, providing a mechanistic context for their mode of action, and drugs already in clinical trials for treating other diseases, never tested against COVID-19. Discussion: The key advance is that the proposed framework is versatile and expandable, offering a significant upgrade in the arsenal for virus-host interactions and other complex pathologies. [ABSTRACT FROM AUTHOR]

Central hypothyroidism and dyslipidemia are well-known adverse events (AEs) of bexarotene therapy. Although hypothyroidism is known to cause dyslipidemia, no study has examined the association between hypothyroidism and dyslipidemia in patients undergoing bexarotene therapy. The aim of this study is to examine this association. A retrospective observational study was performed among 294 patients who initiated bexarotene therapy in Japan (nation-wide postmarketing complete surveillance). Jonckheere-Terpstra (one sided) test was performed to evaluate the effect of the bexarotene dose on lipid metabolisms, and regression analyses were performed to evaluate associations of bexarotene dose, free thyroxine (FT4), body mass index (BMI), and lipid metabolisms. Most patients developed hypothyroidism. Two-third of patients showed FT4 values below the lower limit at 1 week. Triglycerides (TG) increased in a bexarotene dose–dependent manner, and grade ≥3 AEs on hypertriglyceridemia was observed in 39% of the patients. Additionally, one-third of grade ≥3 AEs on hypertriglyceridemia occurred within 1 week. The delta_FT4 (difference in FT4 from baseline) negatively correlated with TG increase at 1 week (p = 0.012) but not with low density lipoprotein cholesterol (LDL-C) increase at any week. Bexarotene-induced hypothyroidism is almost inevitable and occurred quickly. Bexarotene-induced hypertriglyceridemia showed positive bexarotene dose dependency and negative delta_FT4 dependency. Prophylactic and appropriate thyroid hormone compensation therapy and starting bexarotene at low doses with subsequent titration while managing dyslipidemia may have a beneficial effect for the successful continuation of bexarotene therapy without severe endocrine and metabolic AEs.

In this study, we propose a fabrication method to obtain composites of poly(vinyl alcohol) (PVA)/ionic cellulose nanofibers, in which a fiber structure is manipulated through a reconstruction of 2,2,6,6-tetramethyl-piperidinyl-1-oxyl radical (TEMPO)-oxidized cellulose nanofiber (TCNF) or the carboxymethyl cellulose nanofiber (CMCNF) heterogeneous microfibril gels using electrospinning method. The key concept is to assemble nanofibers from thin few-nanometer-scale width cellulose nanofibers (microfibrils) to thicker several-hundred-nanometer-scale width cellulose nanofibers by electrospinning insoluble microfibril-gel-dispersion in PVA solution. In the case of CMCNF, nanofibers with less-fused structures were successfully reconstructed via electrospinning. Energy-dispersive X-ray spectroscopy revealed that sodium ions exist in the fibers, where they function as counter ions of carboxylate groups of polyelectrolyte moiety of CMCNF. Thus, the obtained composites do contain both ionic cellulose nanofibers and PVA. The proposed fabrication route can be used to fabricate composites as nonwoven fabrics of polyelectrolyte nanofibers. These natural polymer based ionic fabrics will be widely useful to propose low-environmental-impact polymer actuators and active sensing elements involving the ion transport phenomena.

Biased agonism is a frontier field in GPCR research. Acquired hypocalciuric hypercalcemia (AHH) is a rare disease caused by calcium-sensing receptor (CaSR) autoantibodies, to date, showing either simple blocking or biased properties (i.e., stimulatory or blocking effects on different downstream signaling pathways). This emphasizes the importance of the Gi/o (pertussis toxin–sensitive G proteins, whose βγ subunits activate multiple signals, including ERK1/2) in regulating parathyroid hormone secretion. We here describe 3 patients with symptomatic AHH who shared characteristics with the 2 cases we previously reported as follows: (a) elderly (74–87 years at diagnosis), (b) male, (c) unexpectedly showed no other autoimmune diseases, (d) showed spontaneously fluctuating Ca levels from approximately normal to near fatally high ranges, (e) acute exacerbations could be successfully treated with prednisolone and/or calcimimetics, (f) the presence of CaSR autoantibodies that operated as biased allosteric modulators of CaSR, and (g) were likely to be conformational (i.e., recognizing and, thereby, stabilizing a unique active conformation of CaSR that activates Gq/11, activating phosphatidylinositol turnover, but not Gi/o). Our observations with these prominent commonalities may provide new insights into the phenotype and characteristics of AHH and the mechanisms by which the biased agonism of GPCRs operate.

Abstract Background Primary aldosteronism (PA) plus subclinical Cushing’s syndrome (SCS), PASCS, has occasionally been reported. We aimed to clinically characterize patients with PASCS who are poorly profiled. Methods A population-based, retrospective, single-center, observational study was conducted in 71 patients (age, 58.2 ± 11.2 years; 24 males and 47 females) who developed PA (n = 45), SCS (n = 12), or PASCS (n = 14). The main outcome measures were the proportion of patients with diabetes mellitus (DM), serum potassium concentration, and maximum tumor diameter (MTD) on the computed tomography (CT) scans. Results The proportion of DM patients was significantly greater in the PASCS group than in the PA group (50.0% vs. 13.9%, p

Aims/Introduction. To investigate whether the occurrence of early worsening of diabetic retinopathy in patients with type 2 diabetes diagnosed with simple or preproliferative diabetic retinopathy at their first visit differed according to HbA1c reduction and/or treatment intensification. Materials and Methods. Our study design was a retrospective observational study. Subjects with type 2 diabetes diagnosed with either simple or preproliferative diabetic retinopathy by ophthalmologists at their first visit and followed up for 6–18 months thereafter were included and divided into worsening and nonworsening groups. Thereafter, baseline characteristics and changes in HbA1c and therapy over a year were investigated. Results. Among the 88 subjects with simple diabetic retinopathy, 16% improved to no retinopathy, 65% retained their simple diabetic retinopathy, 18% worsened to preproliferative diabetic retinopathy, and 1% worsened to proliferative diabetic retinopathy. Among the 47 subjects with preproliferative diabetic retinopathy, 9% improved to simple diabetic retinopathy, 72% retained their preproliferative diabetic retinopathy, and 19% worsened to proliferative diabetic retinopathy. Patients with simple diabetic retinopathy had an odds ratio of 1.44 for worsening retinopathy with a 1% increase in baseline HbA1c. Meanwhile, the odds ratios for worsening retinopathy with a 1% decrease in HbA1c from baseline at 3, 6, and 12 months were 1.34, 1.31, and 1.38, respectively. Among patients with simple diabetic retinopathy, significantly more new interventions were introduced in the worsening group than in the nonworsening group. Conclusions. Increased baseline HbA1c, a substantial decrease in HbA1c, and intensified therapy were identified as risk factors for early worsening of diabetic retinopathy in patients with simple diabetic retinopathy at the first visit. Patients should therefore be intimately followed for retinopathy after their first visit.

To describe the burden associated with different anti-vascular endothelial growth factor (VEGF) treatment strategies for wet age-related macular degeneration (wAMD) in a real-word setting in Japan.Single-center, cross-sectional survey of caregivers of patients with wAMD performed in a hospital in Mito-City, a rural area in Japan. Caregiver burden was evaluated using the Burden Index of Caregivers (BIC-11), and depressive symptoms were assessed by the Center for Epidemiologic Studies Depression scale. Retrospective medical chart review was conducted to monitor resource use and visual acuity outcomes in patients. The productivity loss of caregivers accompanying patients on hospital visits was estimated using the human capital method.Seventy-one patient-caregiver pairs were included. Most caregivers were female (74.6%), spouse/partner (54.9%), employed (46.5%), and the primary caregiver (85.9%). Patients received anti-VEGF treatment as follows: treat-and-extend (T&E; n = 42), switch (from as-needed [PRN] to T&E; n = 18), PRN (n = 10), and other (n = 1). Caregiver-related burden (total BIC-11 scores) were 4.29 (T&E) 4.60 (PRN), and 5.33 (switch) (p = NS). The mean number of hospital visits was lower with T&E than PRN (7.88 vs. 14.0 [p = 0.00674] in year 1 and 5.68 vs. 9.0 in year 2). For patients who switched from PRN to T&E, the mean number of hospital visits decreased from 13.21 to 7.43 (p