Genome-wide CRISPR screens identify novel regulators of wild-type and mutant p53 stability.

Tumor suppressor p53 (TP53) is frequently mutated in cancer, often resulting not only in loss of its tumor-suppressive function but also acquisition of dominant-negative and even oncogenic gain-of-function traits. While wild-type p53 levels are tightly regulated, mutants are typically stabilized in tumors, which is crucial for their oncogenic properties. Here, we systematically profiled the factors that regulate protein stability of wild-type and mutant p53 using marker-based genome-wide CRISPR screens. Most regulators of wild-type p53 also regulate p53 mutants, except for p53 R337H regulators, which are largely private to this mutant. Mechanistically, FBXO42 emerged as a positive regulator for a subset of p53 mutants, working with CCDC6 to control USP28-mediated mutant p53 stabilization. Additionally, C16orf72/HAPSTR1 negatively regulates both wild-type p53 and all tested mutants. C16orf72/HAPSTR1 is commonly amplified in breast cancer, and its overexpression reduces p53 levels in mouse mammary epithelium leading to accelerated breast cancer. This study offers a network perspective on p53 stability regulation, potentially guiding strategies to reinforce wild-type p53 or target mutant p53 in cancer.

National guidelines for the diagnosis and treatment of hilar cholangiocarcinoma.

A consensus meeting of national experts from all major national hepatobiliary centres in the country was held on May 26, 2023, at the Pakistan Kidney and Liver Institute & Research Centre (PKLI & RC) after initial consultations with the experts. The Pakistan Society for the Study of Liver Diseases (PSSLD) and PKLI & RC jointly organised this meeting. This effort was based on a comprehensive literature review to establish national practice guidelines for hilar cholangiocarcinoma (hCCA). The consensus was that hCCA is a complex disease and requires a multidisciplinary team approach to best manage these patients. This coordinated effort can minimise delays and give patients a chance for curative treatment and effective palliation. The diagnostic and staging workup includes high-quality computed tomography, magnetic resonance imaging, and magnetic resonance cholangiopancreatography. Brush cytology or biopsy utilizing endoscopic retrograde cholangiopancreatography is a mainstay for diagnosis. However, histopathologic confirmation is not always required before resection. Endoscopic ultrasound with fine needle aspiration of regional lymph nodes and positron emission tomography scan are valuable adjuncts for staging. The only curative treatment is the surgical resection of the biliary tree based on the Bismuth-Corlette classification. Selected patients with unresectable hCCA can be considered for liver transplantation. Adjuvant chemotherapy should be offered to patients with a high risk of recurrence. The use of preoperative biliary drainage and the need for portal vein embolisation should be based on local multidisciplinary discussions. Patients with acute cholangitis can be drained with endoscopic or percutaneous biliary drainage. Palliative chemotherapy with cisplatin and gemcitabine has shown improved survival in patients with irresectable and recurrent hCCA.

Neurosurgery and social media: A bibliometric analysis of scientific production from 2004-2023.

BACKGROUND: Neurosurgery is a rapidly advancing surgical specialty. Social media has significantly impacted the landscape of advancements in the field of neurosurgery. Research on the subject of neurosurgery and social media plays a vital role in combating disability and mortality due to neurological diseases, especially in trauma-affected individuals by increasing cooperation and sharing of clinical experiences between neurosurgeons via social media. This study aimed to evaluate the global neurosurgery and social media research performance from 2004-2023. MATERIALS AND METHODS: All the data for neurosurgery and social media-related research publications from 2004 to 2023 were extracted from the Web of Science database and a comprehensive analysis was performed on the R-bibliometrix package. RESULTS: An increasing number of publications with an annual growth rate of 22.04% was observed, with >91% of total articles published in the last decade. The United States of America (USA), the United Kingdom (UK), Italy, France, Canada and India made up of more than 67% of the global contribution. Out of 1449 authors, Chaurasia B was the most productive with 14 publications and the most globally cited document was JEAN WC, 2020 with 117 citations. The University of Cambridge was the leading institutional affiliation. World Neurosurgery was the most productive with >60 articles. CONCLUSIONS: Exploring neurosurgery on social media enhances global collaboration, utilizing dynamic platforms for real-time knowledge exchange and holds immense potential for the field's global advancement.

Percutaneous Transhepatic Sphincterotome-Guided Management of Post-Living Donor Liver Transplant Biliary Anastomotic Stricture: An Innovative Approach.

Post-liver transplantation biliary complications remain a serious concern and are associated with reduced patient and graft survival. Among various biliary complications, anastomotic stricture (AS) is the most frequent and challenging one. The frequency of AS after living donor liver transplantation (LDLT) is higher as compared to deceased donor liver transplantation. The management involves endoscopic retrograde cholangiopancreatography and/or percutaneous transhepatic biliary drainage, but refractory cases necessitate surgical revision. We present a case of complex biliary AS in a 63-year-old man after LDLT. The conventional approaches including endoscopic retrograde cholangiopancreatography, percutaneous transhepatic cholangiography, and cholangioscope-guided interventions remained unsuccessful. An innovative approach using a wire-guided sphincterotome through percutaneous transhepatic route successfully managed the complex post-LDLT AS. This is perhaps the first reported case of novel utilization of sphincterotome through transhepatic route for the management of AS in LDLT, averting major surgical interventions with related morbidity and mortality.

A Cotton Rope in the Colon: A Rare Cause of Chronic Abdominal Pain.

Retained surgical sponge is a relatively rare medical condition with potential serious medicolegal implications. The term "gossypiboma" is frequently used to describe this condition. We present a case of a 40-cm-long retained surgical sponge in a 43-year-old woman who presented with unexplained chronic abdominal pain for several years. She had a history of open cholecystectomy, hepaticojejunostomy, and enteroenterostomy. Computed tomography scan revealed a large cotton sponge anchored within the large bowel. Surgical exploration is usually required for the retrieval of gossypiboma. However, it was successfully removed endoscopically using a diathermic needle knife with no immediate complications. The patient was discharged after 48 hours with marked improvement in her abdominal pain. This case emphasizes the emerging role of novel endoscopic interventions, resulting in excellent clinical outcomes, avoiding major surgical interventions, and providing cost-effective benefits.

Efficient Thorax Disease Classification and Localization Using DCNN and Chest X-ray Images.

Thorax disease is a life-threatening disease caused by bacterial infections that occur in the lungs. It could be deadly if not treated at the right time, so early diagnosis of thoracic diseases is vital. The suggested study can assist radiologists in more swiftly diagnosing thorax disorders and in the rapid airport screening of patients with a thorax disease, such as pneumonia. This paper focuses on automatically detecting and localizing thorax disease using chest X-ray images. It provides accurate detection and localization using DenseNet-121 which is foundation of our proposed framework, called Z-Net. The proposed framework utilizes the weighted cross-entropy loss function (W-CEL) that manages class imbalance issue in the ChestX-ray14 dataset, which helped in achieving the highest performance as compared to the previous models. The 112,120 images contained in the ChestX-ray14 dataset (60,412 images are normal, and the rest contain thorax diseases) were preprocessed and then trained for classification and localization. This work uses computer-aided diagnosis (CAD) system that supports development of highly accurate and precise computer-aided systems. We aim to develop a CAD system using a deep learning approach. Our quantitative results show high AUC scores in comparison with the latest research works. The proposed approach achieved the highest mean AUC score of 85.8%. This is the highest accuracy documented in the literature for any related model.

Evaluating patient safety research performance in Arab world countries: Changing trends and reflections.

Background and Objective: Patient safety is a major concern in health care. Research is an important tool to minimize preventable errors. Research performance and trends evaluation need to be identified for future guidance. Our objective was to evaluate the research performance in Arab World countries related to patient safety so that real picture is available to all stake holders for future application. Methods: This was a descriptive exploratory study carried at King Abdulaziz University Jeddah, using Bibliometric analyses on Web of Science extracted data, exploring the research publications related to Patient Safety from the Arab World in last two decades (2001-2020). Digital resources were used. Data collected was further explored to see the trends. Results: Only 2% of total worldwide publications on Patient Safety were from Arab World. A positive trend, however, has emerged since 2015. Out of 5940 documents identified, only 383 had single authorship. Egypt and Saudi Arab were the major contributors. Other countries had less or even zero publications. Researchers are coordinating with others in Western countries to enhance the research productivity. Cairo University with 734 publications had most affiliations. Publications on safety culture and medication safety were frequent. Hospital Acquired Infections and error reporting had limited research. Conclusion: Researches on patient safety in the Arab World are not sufficient. Countries other than Egypt and Saudi Arabia also need to contribute more frequently. Critical problems, like Hospital Acquired Infections, should have regular research from all countries to assist those treating patients and those making health related policies.

Clinical Characteristics of Hospitalized Patients With COVID-19: A Retrospective Cohort Study in Pakistan.

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a global pandemic of severe upper respiratory tract infections known as COVID-19. This single-center study aimed to investigate the demographics, comorbidities, symptoms, and disease severity of COVID-19 patients in Pakistan. METHODS: A retrospective descriptive study was conducted at the Pakistan Kidney and Liver Institute and Research Center from April 2020 to August 2020. A total of 430 PCR-positive COVID-19 patients were categorized into symptomatic and asymptomatic groups. The symptomatic group was further classified into severe and non-severe subgroups. Patients' demographics, comorbid conditions, presenting symptoms, laboratory parameters, and clinical outcomes were assessed in these two subgroups. Statistical tests were applied to determine significant differences. RESULTS: A total of 430 patients with COVID-19 presented in our center, of whom 334 (78%) were symptomatic and included in the study. Severe disease was observed in 83 (24.8%) symptomatic patients, with a male predominance (75.9%) and higher mean age (61.7 ± 13.2). Travel to high-risk destinations (p < 0.002) and close contact with COVID-19 patients (p < 0.001) were significant risk factors. Major comorbid conditions included diabetes mellitus (30.5%) and hypertension (39.8%). Frequent symptoms included fever (71.8%), cough (68.8%), dyspnea (53.8%), and myalgias (35.9%). Higher C-reactive protein (median = 12.76 vs. 1.45, p = 0.001), ferritin (median = 996.70 vs. 628, p = 0.004), and D-dimers (median = 1121 vs. 439.50, p = 0.009) were noted in severe vs non-severe disease. Lymphopenia was more prevalent in severe vs. non-severe disease (83.1% vs. 14.3% p-value = 0.033). More deaths (28.9%) and ICU admissions (53%) with a prolonged hospital stay (median = 25 days, IQR = 16.0-31.0) were noted in the severe group. CONCLUSION: This retrospective study provides insights into the clinical characteristics and outcomes of COVID-19 patients. Age, male gender, comorbidities, and specific symptoms were associated with disease severity. Inflammatory markers, including D-dimers, ferritin, and CRP, were elevated in severe cases. These findings contribute to a better understanding of COVID-19 and may aid in clinical management and decision-making for patients affected by the disease.

Analyzing COVID-19 Vaccination Side Effects Among the Adult Population in Jeddah, Saudi Arabia.

The COVID-19 pandemic has brought vaccination to the forefront of global attention. The Pfizer-BioNTech vaccine, an mRNA vaccine that encodes the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) glycoprotein spike, has emerged as a significant player in global vaccination efforts. It is generated from lipid nanoparticles and has been subject to various regulatory approvals and authorizations. The United Kingdom became the first country to approve the Pfizer vaccine on December 2, 2020. The World Health Organization (WHO) authorized the emergency use of the Pfizer vaccine on December 31, 2020, facilitating its production and distribution worldwide. In Saudi Arabia, as well as globally, concerns about the safety and effectiveness of vaccines have been raised. Several studies have reported side effects of the Pfizer vaccine, including rare conditions such as myocarditis. In our study, we aimed to systematically investigate the symptoms experienced after vaccination, considering the administration of three doses. We also explored the duration of these symptoms and whether they necessitated hospital visits, primary healthcare interventions, or resolved on their own. Our study employed an online cross-sectional design conducted in Jeddah, Saudi Arabia, utilizing an online self-reported survey. A total of 332 participants who met the predefined criteria were recruited for the study. The rate of COVID-19 infection after 1st and 2nd doses of Pfizer and AstraZeneca vaccines was significantly lower in middle-age subgroups (31-45 years), in comparison to young (18-30 years) and upper middle-age subgroups (46-60 years). For the AstraZeneca vaccine, the infection rate in the middle-aged group was higher after 2nd dose as compared to its 1st dose. Overall, greater infection rates were observed in upper-middle-aged subgroups with all doses of Pfizer and AstraZeneca vaccines. Fatigue and fever were the most common generalized side effects while redness/swelling/pain at the injection site, muscle pain, and joint pain were the most important local side-effects. Fatigue, fever, muscle pain, and joint pain were significantly common after 1st dose of Pfizer and fever was a significant side effect after 2nd dose of Pfizer in comparison to AstraZeneca doses. Understanding the spectrum of side effects associated with the vaccine is crucial for healthcare professionals and individuals receiving the vaccine, as it enables informed decision-making and appropriate management of potential adverse reactions.

Insights into the Value of Lyso-Gb1 as a Predictive Biomarker in Treatment-Naïve Patients with Gaucher Disease Type 1 in the LYSO-PROOF Study.

Gaucher disease (GD) is a rare autosomal recessive disorder arising from bi-allelic variants in the GBA1 gene, encoding glucocerebrosidase. Deficiency of this enzyme leads to progressive accumulation of the sphingolipid glucosylsphingosine (lyso-Gb1). The international, multicenter, observational "Lyso-Gb1 as a Long-term Prognostic Biomarker in Gaucher Disease"-LYSO-PROOF study succeeded in enrolling a cohort of 160 treatment-naïve GD patients from diverse geographic regions and evaluated the potential of lyso-Gb1 as a specific biomarker for GD. Using genotypes based on established classifications for clinical presentation, patients were stratified into type 1 GD (n = 114) and further subdivided into mild (n = 66) and severe type 1 GD (n = 48). Due to having previously unreported genotypes, 46 patients could not be classified. Though lyso-Gb1 values at enrollment were widely distributed, they displayed a moderate and statistically highly significant correlation with disease severity measured by the GD-DS3 scoring system in all GD patients (r = 0.602, p < 0.0001). These findings support the utility of lyso-Gb1 as a sensitive biomarker for GD and indicate that it could help to predict the clinical course of patients with undescribed genotypes to improve personalized care in the future.

Osteoprotegerin genetic polymorphisms and their influence on therapeutic response to ibandronate in postmenopausal osteoporotic females.

OBJECTIVES: The present study investigated osteoprotegerin (OPG) genetic polymorphisms and their influence on the therapeutic response to ibandronate in postmenopausal osteoporotic females. METHODS: This case-control study included 135 postmenopausal females (89 osteoporotic females and 46 non-osteoporotic females). Each osteoporotic patient received a monthly 150 mg ibandronate tablet for six months, and blood samples were taken before and after treatment. Bone mineral density (BMD) was measured using DEXA Scan. Three SNPs (A163G, T245G, and G1181C) of the OPG gene were selected for analysis. RESULTS: Serum OPG levels were significantly lower in osteoporotic subjects than in the control group. The percentage changes in OPG levels in the osteoporotic group before and after treatment with ibandronate were significant (p < .001). After six months of therapy with ibandronate, the percentage changes in OPG levels with AA, TT, TC, GC, and GG genotypes were significant. Following six months of ibandronate treatment, the AA genotype of rs3134069, TT, TC genotypes of rs3102735, GG, and GC genotypes of rs2073618 SNP showed a significant increase in OPG levels. Age, BMI, and GC polymorphism (rs2073618 (G/C) G1181C) were inversely associated with low BMD. Adjusted odds ratios (OR) showed that BMI, GC, GG polymorphism (rs2073618 (G/C) G1181C) and TC polymorphism (rs3102735 (T/C) A163G) were inversely associated with low BMD. CONCLUSION: The inverse association of rs2073618 and rs3102735 with low BMD indicates the protective role of these SNPs in our population. More research is needed to replicate these results in another cohort and to determine the molecular processes by which such SNPs may influence BMD.

A Survey on COVID-19 Data Analysis Using AI, IoT, and Social Media.

Coronaviruses are a well-established and deadly group of viruses that cause illness in both humans and animals. The novel type of this virus group, named COVID-19, was firstly reported in December 2019, and, with the passage of time, coronavirus has spread to almost all parts of the world. Coronavirus has been the cause of millions of deaths around the world. Furthermore, many countries are struggling with COVID-19 and have experimented with various kinds of vaccines to eliminate the deadly virus and its variants. This survey deals with COVID-19 data analysis and its impact on human social life. Data analysis and information related to coronavirus can greatly help scientists and governments in controlling the spread and symptoms of the deadly coronavirus. In this survey, we cover many areas of discussion related to COVID-19 data analysis, such as how artificial intelligence, along with machine learning, deep learning, and IoT, have worked together to fight against COVID-19. We also discuss artificial intelligence and IoT techniques used to forecast, detect, and diagnose patients of the novel coronavirus. Moreover, this survey also describes how fake news, doctored results, and conspiracy theories were spread over social media sites, such as Twitter, by applying various social network analysis and sentimental analysis techniques. A comprehensive comparative analysis of existing techniques has also been conducted. In the end, the Discussion section presents different data analysis techniques, provides future directions for research, and suggests general guidelines for handling coronavirus, as well as changing work and life conditions.

The Fatty Liver, Cirrhosis, and Liver Cancer Study (TENDENCY): Protocol for a Multicenter Case-Control Study.

BACKGROUND: Hepatocellular cancer (HCC) is associated with high mortality, and early diagnosis leads to better survival. Patients with cirrhosis, especially due to nonalcoholic fatty liver disease and viral hepatitis, are at higher risk of developing HCC and form the main screening group. The current screening methods for HCC (6-monthly screening with serum alpha fetoprotein and ultrasound liver) have low sensitivity; hence, there is a need for better screening markers for HCC. OBJECTIVE: Our study, TENDENCY, aims to validate the novel screening markers (methylated septin 9, urinary volatile organic compounds, and urinary peptides) for HCC diagnosis and study these noninvasive biomarkers in liver disease. METHODS: This is a multicenter, nested case-control study, which involves comparing the plasma levels of methylated septin 9 between confirmed HCC cases and patients with cirrhosis (control group). It also includes the comparison of urine samples for the detection of HCC-specific volatile organic compounds and peptides. Based on the findings of a pilot study carried out at University Hospital Coventry & Warwickshire, we estimated our sample size to be 308 (n=88, 29% patients with HCC; n=220, 71% patients with cirrhosis). Urine and plasma samples will be collected from all participants and will be frozen at -80 °C until the end of recruitment. Gas chromatography-mass spectrometry will be used for urinary volatile organic compounds detection, and capillary electrophoresis-mass spectrometry will be used for urinary peptide identification. Real-time polymerase chain reaction will be used for the qualitative detection of plasma methylated septin 9. The study will be monitored by the Research and Development department at University Hospital Coventry & Warwickshire. RESULTS: The recruitment stage was completed in March 2023. The TENDENCY study is currently in the analysis stage, which is expected to finish by November 2023. CONCLUSIONS: There is lack of effective screening tests for hepatocellular cancer despite higher mortality rates. The application of more sensitive plasma and urinary biomarkers for hepatocellular cancer screening in clinical practice will allow us to detect the disease at earlier stages and hence, overall, improve HCC outcomes. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/44264.

In vivo CRISPR screens reveal Serpinb9 and Adam2 as regulators of immune therapy response in lung cancer.

How the genetic landscape governs a tumor's response to immunotherapy remains poorly understood. To assess the immune-modulatory capabilities of 573 genes associated with altered cytotoxicity in human cancers, here we perform CRISPR/Cas9 screens directly in mouse lung cancer models. We recover the known immune evasion factors Stat1 and Serpinb9 and identify the cancer testis antigen Adam2 as an immune modulator, whose expression is induced by KrasG12D and further elevated by immunotherapy. Using loss- and gain-of-function experiments, we show that ADAM2 functions as an oncogene by restraining interferon and TNF cytokine signaling causing reduced presentation of tumor-associated antigens. ADAM2 also restricts expression of the immune checkpoint inhibitors PDL1, LAG3, TIGIT and TIM3 in the tumor microenvironment, which might explain why ex vivo expanded and adoptively transferred cytotoxic T-cells show enhanced cytotoxic efficacy in ADAM2 overexpressing tumors. Together, direct in vivo CRISPR/Cas9 screens can uncover genetic alterations that control responses to immunotherapies.

Cholangioscope-Guided Electrohydraulic Lithotripsy as a Rescue Technique for an Impacted Dormia Basket With Large Common Bile Duct Stone.

Impaction of Dormia basket while extracting common bile duct (CBD) stones during endoscopic retrograde cholangiopancreatography is a well-known but relatively rare complication. Its management could be very challenging and may require percutaneous, endoscopic, or major surgical intervention. In this study, we present a case of a 65-year-old man with a history of obstructive jaundice secondary to a large CBD stone. For stone extraction, mechanical lithotripsy with a Dormia basket was attempted resulting in its entrapment within CBD. Subsequently, the entrapped basket and large stone were retrieved using a novel technique of cholangioscope-guided electrohydraulic lithotripsy with excellent clinical outcomes.

The NOTCH-RIPK4-IRF6-ELOVL4 Axis Suppresses Squamous Cell Carcinoma.

Receptor-interacting serine/threonine protein kinase 4 (RIPK4) and its kinase substrate the transcription factor interferon regulatory factor 6 (IRF6) play critical roles in the development and maintenance of the epidermis. In addition, ourselves and others have previously shown that RIPK4 is a NOTCH target gene that suppresses the development of cutaneous and head and neck squamous cell carcinomas (HNSCCs). In this study, we used autochthonous mouse models, where the expression of Pik3caH1047R oncogene predisposes the skin and oral cavity to tumor development, and show that not only loss of Ripk4, but also loss of its kinase substrate Irf6, triggers rapid SCC development. In vivo rescue experiments using Ripk4 or a kinase-dead Ripk4 mutant showed that the tumor suppressive function of Ripk4 is dependent on its kinase activity. To elucidate critical mediators of this tumor suppressive pathway, we performed transcriptional profiling of Ripk4-deficient epidermal cells followed by multiplexed in vivo CRISPR screening to identify genes with tumor suppressive capabilities. We show that Elovl4 is a critical Notch-Ripk4-Irf6 downstream target gene, and that Elovl4 loss itself triggers SCC development. Importantly, overexpression of Elovl4 suppressed tumor growth of Ripk4-deficient keratinocytes. Altogether, our work identifies a potent Notch1-Ripk4-Irf6-Elovl4 tumor suppressor axis.

Rosmarinic acid alleviates ultraviolet-mediated skin aging via attenuation of mitochondrial and ER stress responses.

Chronic exposure to Ultraviolet B radiation (UV-B) evokes a myriad of toxic signalling events in the irradiated skin. One of such response is ER stress, which is known to exacerbate photodamage responses. Also, recent literature has highlighted the adverse impact of environmental toxicants on mitochondrial dynamics and mitophagy. Impaired mitochondrial dynamics escalates oxidative damage and causes apoptosis. There have been evidences that support crosstalk between ER stress and mitochondrial dysfunction. However, mechanistic clarification is still needed to verify the interactions between UPR responses and mitochondrial dynamics impairment in UV-B-induced photodamage models. Lastly, plant-based natural agents have garnered attention as therapeutic agents against skin photodamage. Thus, gaining mechanistic insights of plant-based natural agents is required for their application and feasibility in clinical settings. With this aim in view, this study was performed in primary human dermal fibroblasts (HDFs) and Balb/C mice. Different parameters regarding mitochondrial dynamics, ER stress, intracellular damage and histological damage were analyzed using western blot, rt-PCR and microscopy. We demonstrated that UV-B exposure leads to induction of UPR responses, upregulation of Drp-1 and inhibition of mitophagy. Further, 4-PBA treatment leads to reversal of these noxious stimuli in irradiated HDF cells, thereby, indicating an upstream role of UPR induction in mitophagy inhibition. Also, we explored the therapeutic effect of Rosmarinic acid (RA) against ER stress and impaired mitophagy in photodamage models. RA prevents intracellular damage via alleviation of ER stress and mitophagic responses in HDFs and irradiated Balb/C mice skin. The current study summarizes the mechanistic insights into UVB-mediated intracellular damage and role of natural plant-based agent (RA) in ameliorating these toxic responses.

Control of Ionic Conductivity by Lithium Distribution in Cubic Oxide Argyrodites Li6+xP1-xSixO5Cl.

Argyrodite is a key structure type for ion-transporting materials. Oxide argyrodites are largely unexplored despite sulfide argyrodites being a leading family of solid-state lithium-ion conductors, in which the control of lithium distribution over a wide range of available sites strongly influences the conductivity. We present a new cubic Li-rich (>6 Li+ per formula unit) oxide argyrodite Li7SiO5Cl that crystallizes with an ordered cubic (P213) structure at room temperature, undergoing a transition at 473 K to a Li+ site disordered F4̅3m structure, consistent with the symmetry adopted by superionic sulfide argyrodites. Four different Li+ sites are occupied in Li7SiO5Cl (T5, T5a, T3, and T4), the combination of which is previously unreported for Li-containing argyrodites. The disordered F4̅3m structure is stabilized to room temperature via substitution of Si4+ with P5+ in Li6+xP1-xSixO5Cl (0.3 < x < 0.85) solid solution. The resulting delocalization of Li+ sites leads to a maximum ionic conductivity of 1.82(1) × 10-6 S cm-1 at x = 0.75, which is 3 orders of magnitude higher than the conductivities reported previously for oxide argyrodites. The variation of ionic conductivity with composition in Li6+xP1-xSixO5Cl is directly connected to structural changes occurring within the Li+ sublattice. These materials present superior atmospheric stability over analogous sulfide argyrodites and are stable against Li metal. The ability to control the ionic conductivity through structure and composition emphasizes the advances that can be made with further research in the open field of oxide argyrodites.

A noncoding single-nucleotide polymorphism at 8q24 drives IDH1-mutant glioma formation.

Establishing causal links between inherited polymorphisms and cancer risk is challenging. Here, we focus on the single-nucleotide polymorphism rs55705857, which confers a sixfold greater risk of isocitrate dehydrogenase (IDH)-mutant low-grade glioma (LGG). We reveal that rs55705857 itself is the causal variant and is associated with molecular pathways that drive LGG. Mechanistically, we show that rs55705857 resides within a brain-specific enhancer, where the risk allele disrupts OCT2/4 binding, allowing increased interaction with the Myc promoter and increased Myc expression. Mutating the orthologous mouse rs55705857 locus accelerated tumor development in an Idh1R132H-driven LGG mouse model from 472 to 172 days and increased penetrance from 30% to 75%. Our work reveals mechanisms of the heritable predisposition to lethal glioma in ~40% of LGG patients.