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PLOS Pathogens, a leader in the pathogens research community, is committed to advancing Open Science practices that promote transparency, reproducibility, and trust in research. Open Science, which involves the unrestricted sharing of research components, has numerous benefits, including increased equity, access to research findings, and the ability to build on existing science. PLOS Pathogens has long advocated for Open Science and is already compliant with funder policies. The journal has also implemented experimental features, such as the Accessible Data icon, to encourage data sharing and engagement. The pathogens research community has demonstrated its commitment to cooperative Open Science through initiatives like community-curated virus databases and the sharing of research materials. However, there is still a need to address barriers, such as the cost of research, to achieve truly equitable Open Science. PLOS Pathogens remains dedicated to promoting open, high-quality, and peer-reviewed science in collaboration with the research community. [Extracted from the article]

Background Malaria remains a serious health problem because resistance develops to all currently used drugs when their parasite targets mutate. Novel antimalarial drug targets are urgently needed to reduce global [...]

It has been demonstrated that a methanol solution containing 2 x 10(super -3) M La(OTf)3, at (super s)(Sub s)PH values around neutrality can be used to promote the methanolysis of paraxon with a 10(super 9) -fold acceleration over the base reaction at the (super s)(Sub s)PH. The system seemed to provide the largest reported acceleration for many man-made catalyst capable of promoting the solvolysis of a phosphate triester.

Amines were reported to catalyze the epoxidation of alkenes using oxone (2KHSO5+KHSO4+K2SO4), and significant levels to asymmetric induction were observed. From screening a series of amines based on 2-substituted pyrrolidines, it has been found that more consistent and reproducible results are achieved with HCI salt of the amine compared to the amine itself.

A total synthesis of the laurencia metabolite (+)-obtusenyne has been completed. The key steps include a sharpless kinetic resolution and an asymmetric glycolate alkylation to establish the stereogenic centers adjacent to the either linkage and a ring-closing metathesis reaction to construct the nine-membered ether without the aid of a cyclic conformational constraint.

The catalysis of the reaction of carbon dioxide with epoxides using the (salen)Cr(super III)Cl complex as catalyst, where H2salen = N,N'-bis(3,5-di-tert-butysalicylidene)-1,2-cyclohexenediimine (1), to provide copolymer and cyclic carbonate has been investigated by in situ infrared spectroscopy.

The preparation of the first photochromic, organometallic derivative of the diarylethene class, the CpRu-complexed benzodimethyldihydropyrene 3, in which the organometallic is directly attached to the photochromic core, is described. The negative dark purple photochrome 3 readily bleaches to form the almost colorless cyclophanediene 3' on irradiation with visible light.

The cell-permeable dihydrofolate reductase inhibitor methotrexate was covalently linked to a ligand for the protein FKBP to create a bifunctional molecule called MTXSLF. The studies demonstrate a potentially general strategy for modulating the biological activity of synthetic molecules that depends on the ligand-binding properties of a nontarget protein.

I could read rapidly emerging (and often changing) COVID-19 literature, become versed in the science of transmission pathways, diverse outcomes of infection, and how to apply them to students safely returning to and resuming campus life. On-campus RT-PCR testing of symptomatic persons and screening of student athletes were in place by the semester's start. The departure of undergraduate students led to rapid decline in campus infection levels (but it should be noted that this also greatly reduced the number of persons on campus). [Extracted from the article]

Hundreds of mutations in a single gene result in rare diseases, but why mutations induce severe or attenuated states remains poorly understood. Defect in glycine decarboxylase (GLDC) causes Non-ketotic Hyperglycinemia (NKH), a neurological disease associated with elevation of plasma glycine. We unified a human multiparametric NKH mutation scale that separates severe from attenuated neurological disease with new in silico tools for murine and human genome level-analyses, gathered in vivo evidence from mice engineered with top-ranking attenuated and a highly pathogenic mutation, and integrated the data in a model of pre- and post-natal disease outcomes, relevant for over a hundred major and minor neurogenic mutations. Our findings suggest that highly severe neurogenic mutations predict fatal, prenatal disease that can be remedied by metabolic supplementation of dams, without amelioration of persistent plasma glycine. The work also provides a systems approach to identify functional consequences of mutations across hundreds of genetic diseases. Our studies provide a new framework for a large scale understanding of mutation functions and the prediction that severity of a neurogenic mutation is a direct measure of pre-natal disease in neurometabolic NKH mouse models. This framework can be extended to analyses of hundreds of monogenetic rare disorders where the underlying genes are known but understanding of the vast majority of mutations and why and how they cause disease, has yet to be realized. Author summary: Building models of human genetic disease, both computational and animal, is an essential part of understanding the disease, designing treatments, and testing therapies. Here, we have developed new in silico tools to build models for the rare neurological disorder non-ketotic hyperglycinemia (NKH), which is caused by mutations in glycine decarboxylase (GLDC), a protein that degrades glycine. We first applied a mutation scoring tool to GLDC in both the human and mouse genomes, and then used this data to develop a computational model for predicting which mutations would be well-modeled in mice, and how severe their disease would be. We then validated this computational model by genetically-engineering a mutation predicted to cause mild disease and another predicted to cause severe disease. Our predictions were correct and we used them to develop a model relevant for over a hundred major and minor neurogenic mutations that suggests that the more severe the mutation, the greater chance it will cause disease that starts before birth and is likely to be fatal unless rescued by modifying diet. This study also demonstrates the power of in silico analyses for guiding the development of genetic disease models and incorporating them into scalable models that can be applied to understand hundreds of mutations that cause disease. [ABSTRACT FROM AUTHOR]

Although current malaria therapies inhibit pathways encoded in the parasite's genome, we have looked for anti-malaria drugs that can target an erythrocyte component because development of drug resistance might be suppressed if the parasite cannot mutate the drug's target. In search for such erythrocyte targets, we noted that human erythrocytes express tyrosine kinases, whereas the Plasmodium falciparum genome encodes no obvious tyrosine kinases. We therefore screened a library of tyrosine kinase inhibitors from Eli Lilly and Co. in a search for inhibitors with possible antimalarial activity. We report that although most tyrosine kinase inhibitors exerted no effect on parasite survival, a subset of tyrosine kinase inhibitors displayed potent anti-malarial activity. Moreover, all inhibitors found to block tyrosine phosphorylation of band 3 specifically suppressed P. falciparum survival at the parasite egress stage of its intra-erythrocyte life cycle. Conversely, tyrosine kinase inhibitors that failed to block band 3 tyrosine phosphorylation but still terminated the parasitemia were observed to halt parasite proliferation at other stages of the parasite's life cycle. Taken together these results suggest that certain erythrocyte tyrosine kinases may be important to P. falciparum maturation and that inhibitors that block these kinases may contribute to novel therapies for P. falciparum malaria. [ABSTRACT FROM AUTHOR]

Von Hippel-Lindau disease (VHL) is an autosomal dominant rare disease that causes the formation of angiogenic tumors. When functional, pVHL acts as an E3 ubiquitin ligase that negatively regulates hypoxia inducible factor (HIF). Genetic mutations that perturb the structure of pVHL result in dysregulation of HIF, causing a wide array of tumor pathologies including retinal angioma, pheochromocytoma, central nervous system hemangioblastoma, and clear cell renal carcinoma. These VHL-related cancers occur throughout the lifetime of the patient, requiring frequent intervention procedures, such as surgery, to remove the tumors. Although VHL is classified as a rare disease (1 in 39,000 to 1 in 91,000 affected) there is a large heterogeneity in genetic mutations listed for observed pathologies. Understanding how these specific mutations correlate with the myriad of observed pathologies for VHL could provide clinicians insight into the potential severity and onset of disease. Using a select set of 285 ClinVar mutations in VHL, we developed a multiparametric scoring algorithm to evaluate the overall clinical severity of missense mutations in pVHL. The mutations were assessed according to eight weighted parameters as a comprehensive evaluation of protein misfolding and malfunction. Higher mutation scores were strongly associated with pathogenicity. Our approach establishes a novel in silico method by which VHL-specific mutations can be assessed for their severity and effect on the biophysical functions of the VHL protein. [ABSTRACT FROM AUTHOR]

Monogenetic diseases provide unique opportunity for studying complex, clinical states that underlie neurological severity. Loss of glycine decarboxylase (GLDC) can severely impact neurological development as seen in non-ketotic hyperglycinemia (NKH). NKH is a neuro-metabolic disorder lacking quantitative predictors of disease states. It is characterized by elevation of glycine, seizures and failure to thrive, but glycine reduction often fails to confer neurological benefit, suggesting need for alternate tools to distinguish severe from attenuated disease. A major challenge has been that there are 255 unique disease-causing missense mutations in GLDC, of which 206 remain entirely uncharacterized. Here we report a Multiparametric Mutation Score (MMS) developed by combining in silico predictions of stability, evolutionary conservation and protein interaction models and suitable to assess 251 of 255 mutations. In addition, we created a quantitative scale of clinical disease severity comprising of four major disease domains (seizure, cognitive failure, muscular and motor control and brain-malformation) to comprehensively score patient symptoms identified in 131 clinical reports published over the last 15 years. The resulting patient Clinical Outcomes Scores (COS) were used to optimize the MMS for biological and clinical relevance and yield a patient Weighted Multiparametric Mutation Score (WMMS) that separates severe from attenuated neurological disease (p = 1.2 e-5). Our study provides understanding for developing quantitative tools to predict clinical severity of neurological disease and a clinical scale that advances monitoring disease progression needed to evaluate new treatments for NKH. Author summary: Neurodegenerative disorders frequently have diverse, severe symptoms and health outcomes that can be difficult to predict. The rare disease non-ketotic hyperglycinemia (NKH) additionally has a wide range of disease-causing mutations in glycine decarboxylase (GLDC), a protein that breaks down glycine. But measuring glycine is not sufficient to foretell disease outcome. A method to predict whether a mutation will cause severe or more mild forms of NKH would be very helpful to both understanding the disease as well as developing treatments for it. We used computation-based approaches to develop a mutation score that comprehensively predicts how mutations decrease GLDC function. After training against clinical data, the score was able to predict whether a mutation will cause severe or attenuated disease. This study utilizes the power of computational and multidisciplinary analyses to advance understanding and treatment of genetically caused neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

This integration is part of a Wellcome Trust-funded PLOS open science initiative to explore how PLOS can improve data sharing and engagement with the data that have been shared [[6]]. It is clear that sharing data via a repository has tangible benefits for the community whether they are authors or readers and that I PLOS Pathogens i could, and should, do more to promote sharing of data in this way. [Extracted from the article]

Background: Shprintzen-Goldberg syndrome (SGS) is an extremely rare collagenopathy, most often caused by autosomaldominant mutations in the SKI proto-oncogene, which is a component of the transforming growth factor beta (TGF-b) signaling pathway. Approximately 50-60 cases of SGS have been recorded in the literature worldwide since its discovery in 1982. This collagen disorder affects bone and vascular development throughout the body, resulting in craniosynostosis, scoliosis, chest deformities, and aortic root dilation. Patients may have problems in the central nervous system, including Chiari 1 malformation, hydrocephalus, and dilation of the lateral ventricles. Unfortunately, the symptoms of SGS closely parallel those of related collagenopathies involving mutations in the TGF-b signaling pathway, which makes accurate diagnosis difficult without genetic testing, especially in cases with complex presentation. Case Report: In this report we present the unique and complex disease manifestations in a 9-year-old girl with SGS. The patient had severe cervical spinal instability that resolved after surgical occipital-C4 fusion with an autograft from the rib. Midface distraction surgery was used to treat the patient's craniosynostosis and related facial deformities. This surgery was complicated by loss of 750 mL of blood due to insufficient dura and prominent vasculature. Conclusions: Connective tissue symptoms associated with SGS can involve dural and vascular problems, as seen in this case report. Thus, the risk of extreme blood loss should be anticipated any time midface distraction surgery is performed on an SGS patient. Continued research is needed to define how this case relates to the SGS patient population. [ABSTRACT FROM AUTHOR]

spontaneously on the surface of single-crystal micro-spheres, in CO-saturated 0.1 M HCIO4 aqueous solutions have been examined, using potential step-SHG. Inspection of voltammetric curves obtained with massive Pt(111) crystals indicate that, in the region in which the forward transition occurs, the current increases, suggesting that the decrease in theta co is caused by electrooxidation, rather than simple desorption of CO.

The finding that the disastereoselectivity observed upon sequential transformation of an achiral substrate bearing two remote prochiral centers can sometimes be used to calculate catalyst enantioselectivy is discussed. It is shown that in some specialized cases, it is possible to evaluate the enantioselectivity of racemic catalysts without the need for resolution.

On the basis of the UV absorption spectra of the A,C alternating oligosilanes, the first cut experimental evidence has been obtained for the idea that the sigma-conjugation in polsilances does not effectively extend through a tetrasilane fragment with a small dihedral angle such as a cisoid turn.