Enhanced Homogeneity in Perovskite Photovoltaic Films via Antisolvent Extraction of a Methylamine-Based Gel Precursor.

Solution-processed perovskite solar cells (PSCs) are at the forefront of next-generation photovoltaics, exhibiting outstanding photoelectric performance and cost-effective manufacturing. However, the prevalent use of polar aprotic solvents such as N,N-dimethylformamide and dimethyl sulfoxide in the preparation of perovskite precursor solution hinders complete solvent removal during film formation. Their high boiling points and strong coordinating abilities lead to solvated intermediates and heterogeneous perovskite crystal nucleation, particularly in the absence of the antisolvent-assisted crystallization. To address this, we developed a methylamine (MA)-based gel dispersion system that significantly improves the uniformity of perovskite films. By employing ethyl acetate (EA) antisolvent extraction, the gel precursor is extracted from a solution of MAI and PbI2 in MA ethanol, which is then diluted in pure acetonitrile (ACN) solvent to form a clear perovskite precursor solution. Benefiting from the highly volatile nature of the ACN-based gel perovskite precursor solution and its rich concentration of high-valent PbIn2-n coordination compounds, this approach enables the fabrication of high-quality MAPbI3 perovskite films, yielding PCEs of 21.34% for PSC and 19.77% for a 5 × 5 cm2 mini-module. This MA-based gel perovskite precursor strategy offers a promising avenue for potential applications in the scalable manufacture of PSCs.

The evolution of public attention in acute kidney injury and continuous renal replacement therapy: trends analysis from 2004 to 2024.

Background: Acute kidney injury (AKI) and the need for Continuous Renal Replacement Therapy (CRRT) are critically important health concerns. This study analyzes global and regional Internet search queries to understand public attention in AKI and CRRT over time. Methods: We used Google Trends™ to analyze search queries for AKI and CRRT from January 2004 to March 2024. The study examined global trends and detailed insights from the United States, including state-by-state breakdowns. We identified patterns, peaks of attention, and temporal trends in public attention, comparing regional variations across the US and top-ranking countries worldwide. Results: Global attention in AKI peaked in October 2022, with Portugal, Zambia, and Spain showing the highest regional attention. Within the United States, peak attention was in February 2008. Tennessee, Pennsylvania, and West Virginia were the top states that paid attention to AKI. Attention in CRRT peaked globally in March 2024. South Korea, Saudi Arabia, and Bahrain have led the global attention to CRRT. In the United States, peak attention was in April 2020. West Virginia, Tennessee, and Kentucky showed the highest state-specific attention in CRRT. Conclusions: This study reveals significant temporal and geographical variations in online search patterns for AKI and CRRT, suggesting evolving public attention to these critical health issues. This knowledge can guide the development of targeted public health initiatives, enhance medical education efforts, and help healthcare systems tailor their approach to improving awareness and outcomes in kidney health across diverse populations.

Benzo(a)anthracene Targeting SLC1A5 to Synergistically Enhance PAH Mixture Toxicity.

Human exposure to polycyclic aromatic hydrocarbons (PAHs) as mutagenic and carcinogenic pollutants in the environment often occurs in the form of mixtures. Although the mixture effects of PAHs have been previously recognized, the toxicological mechanisms to explain them still remain quite unclear. This study combined metabolomics and chemical proteomics methods to comprehensively understand the mixture effects of a PAH mixture including benzo(a)anthracene (BaA), benzo(b)fluoranthene (BbF), benzo(a)pyrene (BaP), and chrysene (CHR). Among them, BaA has shown a strong synergistic effect with other PAHs. Interestingly, BaA alone is not a potent oxidative stress inducer in liver cells but dose-dependently amplifies oxidative damage caused by the PAH mixture. Global metabolomics analysis results revealed damage to the antioxidant glutathione synthesis, which was caused by the glutamine depletion caused by BaA in the mixture. Subsequently, the label-free chemical proteomics and cellular thermal shift analysis (CETSA) demonstrated that the PAH mixture altered the thermal shift of glutamine transporter SLC1A5. Furthermore, Western blotting and the isothermal titration calorimetry (ITC) interaction measurements showed nanomolar KD values between BaA and SLC1A5. Overall, this study showed that BaA synergistically contributed to PAH mixture induced oxidative damage by targeting SLC1A5 to inhibit glutamate transport into cells, resulting in the inhibition of glutathione synthesis.

Clinical characteristics of megaloblastic anemia with pancytopenia.

OBJECTIVES: In this study, we aimed to explore the clinical characteristics of patients with megaloblastic anemia and pancytopenia. METHODS: Data on patient characteristics, laboratory examinations, clinical manifestations, and associated diseases were collected from Changzhou Hospital of Traditional Chinese Medicine. The participants were divided into two groups according to routine blood test results: megaloblastic anemia patients with pancytopenia (Group A) and megaloblastic anemia patients with simple anemia (Group B). RESULTS: The number of patients with fever and bleeding in Group A was much higher than that in Group B. Inpatient days and hospitalization costs in Group A were higher than those in Group B. White blood cell count, red blood cell count, haemoglobin level, and platelet count in Group A were lower than those in Group B. There were no significant differences in mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), and serum levels of lactate dehydrogenase (LDH), total bilirubin (TBIL), direct bilirubin (DBIL), indirect bilirubin (IBIL), albumin (ALB), vitamin B12, folic acid, and ferritin between the two groups. The incidence of associated diseases, particularly pulmonary infections, was significantly higher in Group A than in Group B. There was no significant difference in the degree of bone marrow hyperplasia between the two groups. CONCLUSION: Patients with pancytopenia and megaloblastic anemia often developed infection and bleeding, which caused more severe anemia, higher hospitalization costs, and longer inpatient days. Early diagnosis and active treatment are required to reduce patient complications and costs.

Navigating Nephrology's Decline Through a GPT-4 Analysis of Internal Medicine Specialties in the United States: Qualitative Study.

Background: The 2024 Nephrology fellowship match data show the declining interest in nephrology in the United States, with an 11% drop in candidates and a mere 66% (321/488) of positions filled. Objective: The study aims to discern the factors influencing this trend using ChatGPT, a leading chatbot model, for insights into the comparative appeal of nephrology versus other internal medicine specialties. Methods: Using the GPT-4 model, the study compared nephrology with 13 other internal medicine specialties, evaluating each on 7 criteria including intellectual complexity, work-life balance, procedural involvement, research opportunities, patient relationships, career demand, and financial compensation. Each criterion was assigned scores from 1 to 10, with the cumulative score determining the ranking. The approach included counteracting potential bias by instructing GPT-4 to favor other specialties over nephrology in reverse scenarios. Results: GPT-4 ranked nephrology only above sleep medicine. While nephrology scored higher than hospice and palliative medicine, it fell short in key criteria such as work-life balance, patient relationships, and career demand. When examining the percentage of filled positions in the 2024 appointment year match, nephrology's filled rate was 66%, only higher than the 45% (155/348) filled rate of geriatric medicine. Nephrology's score decreased by 4%-14% in 5 criteria including intellectual challenge and complexity, procedural involvement, career opportunity and demand, research and academic opportunities, and financial compensation. Conclusions: ChatGPT does not favor nephrology over most internal medicine specialties, highlighting its diminishing appeal as a career choice. This trend raises significant concerns, especially considering the overall physician shortage, and prompts a reevaluation of factors affecting specialty choice among medical residents.

Digital health tools in nephrology: A comparative analysis of AI and professional opinions via online polls.

Background: Professional opinion polling has become a popular means of seeking advice for complex nephrology questions in the #AskRenal community on X. ChatGPT is a large language model with remarkable problem-solving capabilities, but its ability to provide solutions for real-world clinical scenarios remains unproven. This study seeks to evaluate how closely ChatGPT's responses align with current prevailing medical opinions in nephrology. Methods: Nephrology polls from X were submitted to ChatGPT-4, which generated answers without prior knowledge of the poll outcomes. Its responses were compared to the poll results (inter-rater) and a second set of responses given after a one-week interval (intra-rater) using Cohen's kappa statistic (κ). Subgroup analysis was performed based on question subject matter. Results: Our analysis comprised two rounds of testing ChatGPT on 271 nephrology-related questions. In the first round, ChatGPT's responses agreed with poll results for 163 of the 271 questions (60.2%; κ = 0.42, 95% CI: 0.38-0.46). In the second round, conducted to assess reproducibility, agreement improved slightly to 171 out of 271 questions (63.1%; κ = 0.46, 95% CI: 0.42-0.50). Comparison of ChatGPT's responses between the two rounds demonstrated high internal consistency, with agreement in 245 out of 271 responses (90.4%; κ = 0.86, 95% CI: 0.82-0.90). Subgroup analysis revealed stronger performance in the combined areas of homeostasis, nephrolithiasis, and pharmacology (κ = 0.53, 95% CI: 0.47-0.59 in both rounds), compared to other nephrology subfields. Conclusion: ChatGPT-4 demonstrates modest capability in replicating prevailing professional opinion in nephrology polls overall, with varying performance levels between question topics and excellent internal consistency. This study provides insights into the potential and limitations of using ChatGPT in medical decision making.

Identification of kidney-related medications using AI from self-captured pill images.

INTRODUCTION: ChatGPT, a state-of-the-art large language model, has shown potential in analyzing images and providing accurate information. This study aimed to explore ChatGPT-4 as a tool for identifying commonly prescribed nephrology medications across different versions and testing dates. METHODS: 25 nephrology medications were obtained from an institutional pharmacy. High-quality images of each medication were captured using an iPhone 13 Pro Max and uploaded to ChatGPT-4 with the query, 'What is this medication?' The accuracy of ChatGPT-4's responses was assessed for medication name, dosage, and imprint. The process was repeated after 2 weeks to evaluate consistency across different versions, including GPT-4, GPT-4 Legacy, and GPT-4.Ø. RESULTS: ChatGPT-4 correctly identified 22 out of 25 (88%) medications across all versions. However, it misidentified Hydrochlorothiazide, Nifedipine, and Spironolactone due to misreading imprints. For instance, Nifedipine ER 90 mg was mistaken for Metformin Hydrochloride ER 500 mg because 'NF 06' was misread as 'NF 05'. Hydrochlorothiazide 50 mg was confused with the 25 mg version due to imprint errors, and Spironolactone 25 mg was misidentified as Naproxen Sodium or Diclofenac Sodium. Despite these errors, ChatGPT-4 showed 100% consistency when retested, correcting misidentifications after receiving feedback on the correct imprints. CONCLUSION: ChatGPT-4 shows strong potential in identifying nephrology medications from self-captured images, though challenges with difficult-to-read imprints remain. Providing feedback improved accuracy, suggesting ChatGPT-4 could be a valuable tool in digital health for medication identification. Future research should enhance the model's ability to distinguish similar imprints and explore broader integration into digital health platforms.

AI integration in nephrology: evaluating ChatGPT for accurate ICD-10 documentation and coding.

Background: Accurate ICD-10 coding is crucial for healthcare reimbursement, patient care, and research. AI implementation, like ChatGPT, could improve coding accuracy and reduce physician burden. This study assessed ChatGPT's performance in identifying ICD-10 codes for nephrology conditions through case scenarios for pre-visit testing. Methods: Two nephrologists created 100 simulated nephrology cases. ChatGPT versions 3.5 and 4.0 were evaluated by comparing AI-generated ICD-10 codes against predetermined correct codes. Assessments were conducted in two rounds, 2 weeks apart, in April 2024. Results: In the first round, the accuracy of ChatGPT for assigning correct diagnosis codes was 91 and 99% for version 3.5 and 4.0, respectively. In the second round, the accuracy of ChatGPT for assigning the correct diagnosis code was 87% for version 3.5 and 99% for version 4.0. ChatGPT 4.0 had higher accuracy than ChatGPT 3.5 (p = 0.02 and 0.002 for the first and second round respectively). The accuracy did not significantly differ between the two rounds (p > 0.05). Conclusion: ChatGPT 4.0 can significantly improve ICD-10 coding accuracy in nephrology through case scenarios for pre-visit testing, potentially reducing healthcare professionals' workload. However, the small error percentage underscores the need for ongoing review and improvement of AI systems to ensure accurate reimbursement, optimal patient care, and reliable research data.

Large language model triaging of simulated nephrology patient inbox messages.

Background: Efficient triage of patient communications is crucial for timely medical attention and improved care. This study evaluates ChatGPT's accuracy in categorizing nephrology patient inbox messages, assessing its potential in outpatient settings. Methods: One hundred and fifty simulated patient inbox messages were created based on cases typically encountered in everyday practice at a nephrology outpatient clinic. These messages were triaged as non-urgent, urgent, and emergent by two nephrologists. The messages were then submitted to ChatGPT-4 for independent triage into the same categories. The inquiry process was performed twice with a two-week period in between. ChatGPT responses were graded as correct (agreement with physicians), overestimation (higher priority), or underestimation (lower priority). Results: In the first trial, ChatGPT correctly triaged 140 (93%) messages, overestimated the priority of 4 messages (3%), and underestimated the priority of 6 messages (4%). In the second trial, it correctly triaged 140 (93%) messages, overestimated the priority of 9 (6%), and underestimated the priority of 1 (1%). The accuracy did not depend on the urgency level of the message (p = 0.19). The internal agreement of ChatGPT responses was 92% with an intra-rater Kappa score of 0.88. Conclusion: ChatGPT-4 demonstrated high accuracy in triaging nephrology patient messages, highlighting the potential for AI-driven triage systems to enhance operational efficiency and improve patient care in outpatient clinics.

AI-Driven Patient Education in Chronic Kidney Disease: Evaluating Chatbot Responses against Clinical Guidelines.

Chronic kidney disease (CKD) patients can benefit from personalized education on lifestyle and nutrition management strategies to enhance healthcare outcomes. The potential use of chatbots, introduced in 2022, as a tool for educating CKD patients has been explored. A set of 15 questions on lifestyle modification and nutrition, derived from a thorough review of three specific KDIGO guidelines, were developed and posed in various formats, including original, paraphrased with different adverbs, incomplete sentences, and misspellings. Four versions of AI were used to answer these questions: ChatGPT 3.5 (March and September 2023 versions), ChatGPT 4, and Bard AI. Additionally, 20 questions on lifestyle modification and nutrition were derived from the NKF KDOQI guidelines for nutrition in CKD (2020 Update) and answered by four versions of chatbots. Nephrologists reviewed all answers for accuracy. ChatGPT 3.5 produced largely accurate responses across the different question complexities, with occasional misleading statements from the March version. The September 2023 version frequently cited its last update as September 2021 and did not provide specific references, while the November 2023 version did not provide any misleading information. ChatGPT 4 presented answers similar to 3.5 but with improved reference citations, though not always directly relevant. Bard AI, while largely accurate with pictorial representation at times, occasionally produced misleading statements and had inconsistent reference quality, although an improvement was noted over time. Bing AI from November 2023 had short answers without detailed elaboration and sometimes just answered "YES". Chatbots demonstrate potential as personalized educational tools for CKD that utilize layman's terms, deliver timely and rapid responses in multiple languages, and offer a conversational pattern advantageous for patient engagement. Despite improvements observed from March to November 2023, some answers remained potentially misleading. ChatGPT 4 offers some advantages over 3.5, although the differences are limited. Collaboration between healthcare professionals and AI developers is essential to improve healthcare delivery and ensure the safe incorporation of chatbots into patient care.

A novel model based on serum N-glycan markers for evaluating stage of liver necroinflammation in treatment-naïve chronic hepatitis B patients.

This study aimed to establish a novel noninvasive model based on the serum N-glycan spectrum for providing an objective value for determining the stage of liver necroinflammation related to chronic hepatitis B (CHB) patients. N-glycan profiles of the sera of 295 treatment-naïve CHB patients were analyzed. N-glycan profiles were tested for different liver necroinflammation stages using DNA sequence-assisted fluorophore-assisted carbohydrate electrophoresis. A serum N-glycan model named N-glycan-LI (NGLI) using support vector machine was selected to evaluate the classification of liver necroinflammation (G < 2 and G ≥ 2). The area under the receiver operating characteristic curves (AUROCs) was 0.898 (training set, n = 236) and 0.911 (validation set, n = 59) regardless of the stage of liver fibrosis (AUROC = 0.886 and 0.926, respectively, in S < 2 and S ≥ 2 group). The NGLI correspondingly had the highest specificity (SP) of 90.79% and negative predictive value of 92.00% in an inactive stage (including immune-tolerant [IT] and inactive-carrier [IC] stage), had the highest positive predictive value of 95.18% in stage immune-active, and had the highest SP of 93.94% in grey zone IT + IC. N-glycan profiles appear to correlate well with hepatic necroinflammation in CHB when compared with liver biopsy. The newly developed model appears to reliably predict liver damage in naïve-treatment patients with CHB.

Effects of hesperidin on the histological structure, oxidative stress, and apoptosis in the liver and kidney induced by NiCl2.

The aim of this study was to investigate the effect of hesperidin on the liver and kidney dysfunctions induced by nickel. The mice were divided into six groups: nickel treatment with 80 mg/kg, 160 mg/kg, 320 mg/kg hesperidin groups, 0.5% CMC-Na group, nickel group, and blank control group. Histopathological techniques, biochemistry, immunohistochemistry, and the TUNEL method were used to study the changes in structure, functions, oxidative injuries, and apoptosis of the liver and kidney. The results showed that hesperidin could alleviate the weight loss and histological injuries of the liver and kidney induced by nickel, and increase the levels of lactate dehydrogenase (LDH), alanine aminotransferase (GPT), glutamic oxaloacetic transaminase (GOT) in liver and blood urea nitrogen (BUN), creatinine (Cr) and N-acetylglucosidase (NAG) in kidney. In addition, hesperidin could increase the activities of superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and glutathione peroxidase (GSH-Px) in the liver and kidney, decrease the content of malondialdehyde (MDA) and inhibit cell apoptosis. It is suggested that hesperidin could help inhibit the toxic effect of nickel on the liver and kidney.

An novel effective and safe model for the diagnosis of nonalcoholic fatty liver disease in China: gene excavations, clinical validations, and mechanism elucidation.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases. NAFLD leads to liver fibrosis and hepatocellular carcinoma, and it also has systemic effects associated with metabolic diseases, cardiovascular diseases, chronic kidney disease, and malignant tumors. Therefore, it is important to diagnose NAFLD early to prevent these adverse effects. METHODS: The GSE89632 dataset was downloaded from the Gene Expression Omnibus database, and then the optimal genes were screened from the data cohort using lasso and Support Vector Machine Recursive Feature Elimination (SVM-RFE). The ROC values of the optimal genes for the diagnosis of NAFLD were calculated. The relationship between optimal genes and immune cells was determined using the DECONVOLUTION algorithm CIBERSORT. Finally, the specificity and sensitivity of the diagnostic genes were verified by detecting the expression of the diagnostic genes in blood samples from 320 NAFLD patients and liver samples from 12 mice. RESULTS: Through machine learning we identified FOSB, GPAT3, RGCC and RNF43 were the key diagnostic genes for NAFLD, and they were further demonstrated by a receiver operating characteristic curve analysis. We found that the combined diagnosis of the four genes identified NAFLD samples well from normal samples (AUC = 0.997). FOSB, GPAT3, RGCC and RNF43 were strongly associated with immune cell infiltration. We also experimentally examined the expression of these genes in NAFLD patients and NAFLD mice, and the results showed that these genes are highly specific and sensitive. CONCLUSIONS: Data from both clinical and animal studies demonstrate the high sensitivity, specificity and safety of FOSB, GPAT3, RGCC and RNF43 for the diagnosis of NAFLD. The relationship between diagnostic key genes and immune cell infiltration may help to understand the development of NAFLD. The study was reviewed and approved by Ethics Committee of Tianjin Second People's Hospital in 2021 (ChiCTR1900024415).

Paraprotein-Mediated Glomerular Diseases.

Paraproteinemias are a group of complex diseases associated with an overproduction of a monoclonal immunoglobulin that can cause a diversity of kidney disorders and end-organ damage. In this review, we focus on paraprotein-mediated glomerular diseases. Kidney biopsy plays a crucial role in diagnosing these disorders, enabling the identification of specific histological patterns. These lesions are categorized into organized (such as amyloidosis, immunotactoid glomerulopathy, fibrillary glomerulonephritis, cryoglobulinemic glomerulonephritis, and monoclonal crystalline glomerulopathies) and nonorganized deposits (such as monoclonal Ig deposition disease and proliferative glomerulonephritis with monoclonal Ig deposits) based on the characteristics of immunofluorescence findings and the ultrastructural appearance of deposits on electron microscopy. This review aims to provide an update, highlight, and discuss clinicopathological aspects such as definition, epidemiology, clinical manifestations, mechanisms of kidney injury, histological features, and diagnostic procedures.

Increased adrenal steroidogenesis and suppressed corticosteroid responsiveness in critical COVID-19.

BACKGROUND: The effect of coronavirus disease 2019 (COVID-19) on adrenal endocrine metabolism in critically ill patients remains unclear. This study aimed to investigate the alterations in adrenal steroidogenic activity, elucidate underlying mechanisms, provide in situ histopathological evidence, and examine the clinical implications. METHODS: The comparative analyses of the adrenal cortices from 24 patients with fatal COVID-19 and 20 matched controls were performed, excluding patients previously treated with glucocorticoids. SARS-CoV-2 and its receptors were identified and pathological alterations were examined. Furthermore, histological examinations, immunohistochemical staining and ultrastructural analyses were performed to assess corticosteroid biosynthesis. The zona glomerulosa (ZG) and zona fasciculata (ZF) were then dissected for proteomic analyses. The biological processes that affected steroidogenesis were analyzed by integrating histological, proteomic, and clinical data. Finally, the immunoreactivity and responsive genes of mineralocorticoid and glucocorticoid receptors in essential tissues were quantitatively measured to evaluate corticosteroid responsiveness. FINDINGS: The demographic characteristics of COVID-19 patients were comparable with those of controls. SARS-CoV-2-like particles were identified in the adrenocortical cells of three patients; however, these particles did not affect cellular morphology or steroid synthesis compared with SARS-CoV-2-negative specimens. Although the adrenals exhibited focal necrosis, vacuolization, microthrombi, and inflammation, widespread degeneration was not evident. Notably, corticosteroid biosynthesis was significantly enhanced in both the ZG and ZF of COVID-19 patients. The increase in the inflammatory response and cellular differentiation in the adrenal cortices of patients with critical COVID-19 was positively correlated with heightened steroidogenic activity. Additionally, the appearance of more dual-ZG/ZF identity cells in COVID-19 adrenals was in accordance with the increased steroidogenic function. However, activated mineralocorticoid and glucocorticoid receptors and their responsive genes in vital tissues were markedly reduced in patients with critical COVID-19. INTERPRETATION: Critical COVID-19 was characterized by potentiated adrenal steroidogenesis, associated with increased inflammation, enhanced differentiation and elevated dual-ZG/ZF identity cells, alongside suppressed corticosteroid responsiveness. These alterations implied the reduced effectiveness of conventional corticosteroid therapy and underscored the need for evaluation of the adrenal axis and corticosteroid sensitivity.

Synthesis and Preclinical Evaluation of Novel 68Ga-DOTA-RBB as Potential PET Radiotracer for Imaging CDK4/6 in Tumors.

Many malignant tumors, including breast cancer, exhibit amplification and overexpression of cyclin-dependent kinase 4 and 6 (CDK4/6). Ribociclib, approved and used in clinical treatment, acts as a highly selective CDK4/6 inhibitor for ER+/HER2- breast cancer. By modifying ribociclib with the chelator DOTA, we designed and synthesized a novel CDK4/6-positive PET imaging agent, which was radiolabeled by 68Ga for radioactive tagging. The radiotracer demonstrates high radiochemical purity, excellent stability in vitro and in vivo, and favorable pharmacokinetic characteristics. Cell uptake experiments using MCF-7 cells indicate that an excess of ribociclib (RBB) can inhibit cellular uptake of 68Ga-DOTA-RBB. Imaging and biodistribution experiments in MCF-7 tumor-bearing nude mice show significant radioactive accumulation in the tumor. However, preadministration of excess ribociclib results in a substantial reduction in radioactive accumulation within the tumor. On the basis of our explorations, 68Ga-DOTA-RBB, as a targeted imaging agent for CDK4/6-positive tumors, holds significant potential application values.

A clade of receptor-like cytoplasmic kinases and 14-3-3 proteins coordinate inositol hexaphosphate accumulation.

Inositol hexaphosphate (InsP6) is the major storage form of phosphorus in seeds. Reducing seed InsP6 content is a breeding objective in agriculture, as InsP6 negatively impacts animal nutrition and the environment. Nevertheless, how InsP6 accumulation is regulated remains largely unknown. Here, we identify a clade of receptor-like cytoplasmic kinases (RLCKs), named Inositol Polyphosphate-related Cytoplasmic Kinases 1-6 (IPCK1-IPCK6), deeply involved in InsP6 accumulation. The InsP6 concentration is dramatically reduced in seeds of ipck quadruple (T-4m/C-4m) and quintuple (C-5m) mutants, accompanied with the obviously increase of phosphate (Pi) concentration. The plasma membrane-localized IPCKs recruit IPK1 involved in InsP6 synthesis, and facilitate its binding and activity via phosphorylation of GRF 14-3-3 proteins. IPCKs also recruit IPK2s and PI-PLCs required for InsP4/InsP5 and InsP3 biosynthesis respectively, to form a potential IPCK-GRF-PLC-IPK2-IPK1 complex. Our findings therefore uncover a regulatory mechanism of InsP6 accumulation governed by IPCKs, shedding light on the mechanisms of InsP biosynthesis in eukaryotes.

Urinary Oxalate Excretion During Pregnancy in Primary Hyperoxaluria Type 1: A Report of 4 Cases.

Primary hyperoxaluria (PH) is a rare genetic disorder characterized by excessive oxalate production because of specific gene defects. PH1 is the most prevalent type, causing recurrent kidney stone disease and often leading to chronic kidney disease and kidney failure. Our previous study suggested that pregnancy did not adversely affect kidney function in female patients with PH. In this study, we identified 4 PH1 cases with urinary oxalate (UOx) measurements during pregnancy from the Rare Kidney Stone Consortium and Oxalosis and Hyperoxaluria Foundation PH registry to investigate UOx levels during pregnancy in patients with PH1. The PH Registry is approved by the Institutional Review Board of Mayo Clinic (Rochester, MN). All 4 showed a decrease in UOx during pregnancy when compared with before pregnancy and after delivery. These findings contrast with those of the general population, in which the UOx tends to increase during pregnancy because of a simultaneous physiological increase in the glomerular filtration rate. Elucidating the mechanism underlying reduced UOx during pregnancy in PH1 could suggest novel PH therapies. These findings could also affect the clinical management and have implications regarding the safety of withholding novel PH1-directed molecular therapies that currently have uncertain safety profiles during pregnancy. We highlight the need for additional data on urinary changes in patients with PH and other populations while pregnant to clarify changes in UOx throughout pregnancy.