Loss of Katnal2 leads to ependymal ciliary hyperfunction and autism-related phenotypes in mice.

Autism spectrum disorders (ASD) frequently accompany macrocephaly, which often involves hydrocephalic enlargement of brain ventricles. Katnal2 is a microtubule-regulatory protein strongly linked to ASD, but it remains unclear whether Katnal2 knockout (KO) in mice leads to microtubule- and ASD-related molecular, synaptic, brain, and behavioral phenotypes. We found that Katnal2-KO mice display ASD-like social communication deficits and age-dependent progressive ventricular enlargements. The latter involves increased length and beating frequency of motile cilia on ependymal cells lining ventricles. Katnal2-KO hippocampal neurons surrounded by enlarged lateral ventricles show progressive synaptic deficits that correlate with ASD-like transcriptomic changes involving synaptic gene down-regulation. Importantly, early postnatal Katnal2 re-expression prevents ciliary, ventricular, and behavioral phenotypes in Katnal2-KO adults, suggesting a causal relationship and a potential treatment. Therefore, Katnal2 negatively regulates ependymal ciliary function and its deletion in mice leads to ependymal ciliary hyperfunction and hydrocephalus accompanying ASD-related behavioral, synaptic, and transcriptomic changes.

Gas Evolution Kinetics in Overlithiated Positive Electrodes and its Impact on Electrode Design.

Increasing lithium contents within the lattice of positive electrode materials is projected in pursuit of high-energy-density batteries. However, it intensifies the release of lattice oxygen and subsequent gas evolution during operations. This poses significant challenges for managing internal pressure of batteries, particularly in terms of the management of gas evolution in composite electrodes-an area that remains largely unexplored. Conventional assumptions postulate that the total gas evolution is estimated by multiplying the total particle count by the quantities of gas products from an individual particle. Contrarily, this investigation on overlithiated materials-a system known to release the lattice oxygen-demonstrates that loading densities and inter-particle spacing in electrodes significantly govern gas evolution rates, leading to distinct extents of gas formation despite of an equivalent quantity of released lattice oxygen. Remarkably, this study discoveres that O2 and CO2 evolution rates are proportional to 1O2 concentration by the factor of second and first-order, respectively. This indicates an exceptionally greater change in the evolution rate of O2 compared to CO2 depending on local 1O2 concentration. These insights pave new routes for more sophisticated approaches to manage gas evolution within high-energy-density batteries.

Investigating perceptions and attitude toward telenursing among undergraduate nursing students for the future of nursing education: a cross-sectional study.

BACKGROUND: Telenursing is poised to emerge as a novel healthcare delivery system in the digital age. Hence, understanding nursing students' perspectives and readiness is pivotal for its effective implementation. This study investigated nursing students' perceptions regarding, and attitudes toward, telenursing and the factors that influenced their attitudes based on the technology acceptance model. METHODS: This study used a cross-sectional descriptive approach. The participants consisted of 188 nursing students (first to fourth year) enrolled in the College of Nursing in Korea. Differences in attitudes toward telenursing were analyzed using independent t-test and one-way analysis of variance. Pearson's correlation coefficient was used to examine the correlations between the main variables. Factors that influenced attitudes toward telenursing were analyzed using multiple regression. RESULTS: Of the participants, 65.4% lacked substantial awareness of telenursing and 19.1% had prior telenursing experience. Although prospects on telenursing indicated that 90.4% had an optimistic view, face-to-face nursing was heavily preferred for both satisfactory and favored healthcare delivery. Many cited the Internet as their source of knowledge, and only 18.6% had received telenursing education. Attitude toward telenursing was significantly more positive among those with experience of telenursing, telenursing observation in clinical practice, and telenursing education exposure. The regression model was statistically significant (F = 67.445, p < .000). Factors, such as perceived usefulness, social influence, innovativeness, and self-efficacy, influenced attitudes toward telenursing. CONCLUSIONS: Nursing students exhibited a lack of substantial awareness of telenursing; however, they simultaneously displayed a positive outlook. This lack of comprehensive understanding could stem from the absence of formal education in telenursing. Understanding and utilizing the potential of telenursing could be significantly aided by nursing students' education and knowledge. Thus, it is necessary to include telenursing education in the nursing curriculum. The skills and knowledge required for telenursing clinical practice can be developed through telenursing education. Such preparedness will affect nurses' attitudes and intentions and the quality of telenursing offered to patients in the future.

PCSK9 stimulates Syk, PKCδ, and NF-κB, leading to atherosclerosis progression independently of LDL receptor.

Proprotein convertase subtilisin/kexin type-9 (PCSK9) binds to and degrades low-density lipoprotein (LDL) receptor, leading to increase of LDL cholesterol in blood. Its blockers have emerged as promising therapeutics for cardiovascular diseases. Here we show that PCSK9 itself directly induces inflammation and aggravates atherosclerosis independently of the LDL receptor. PCSK9 exacerbates atherosclerosis in LDL receptor knockout mice. Adenylyl cyclase-associated protein 1 (CAP1) is the main binding partner of PCSK9 and indispensable for the inflammatory action of PCSK9, including induction of cytokines, Toll like receptor 4, and scavenger receptors, enhancing the uptake of oxidized LDL. We find spleen tyrosine kinase (Syk) and protein kinase C delta (PKCδ) to be the key mediators of inflammation after PCSK9-CAP1 binding. In human peripheral blood mononuclear cells, serum PCSK9 levels are positively correlated with Syk, PKCδ, and p65 phosphorylation. The CAP1-fragment crystallizable region (CAP1-Fc) mitigates PCSK9-mediated inflammatory signal transduction more than the PCSK9 blocking antibody evolocumab does.

Navigating the Landscape of Telemedicine Research: A Topic Modeling Approach for the Present and Future.

Introduction: Telemedicine, which is the provision of remote clinical services via telecommunication technology, has undergone an upsurge since the COVID-19 pandemic. To capture this paradigm, this study surveyed telemedicine literature, including postpandemic publications, to identify dominant research themes and temporal trends and suggest directions for future research. Methods: A corpus of 56,445 telemedicine studies is sourced from PubMed. Latent Dirichlet allocation (LDA) topic modeling performed using the Konstanz Information Miner platform. The textual data for topic modeling were processed by following standard procedures for natural language processing. Moreover, the term frequency-inverse document frequency approach was used to capture the importance of words within the corpus. We assessed perplexity, coherence, and the elbow method to determine the optimal number of topics for modeling. Results: The findings confirm the surge in telemedicine research after 2020, signifying its prominence. LDA topic modeling reveals seven distinct research themes, with the most prominent topic being "patient satisfaction" (21.38%) followed by "perspectives and challenges" (17.95%), and "smartphone apps" (14.32%). Furthermore, the results demonstrate a noticeable shift in topics from screening to therapeutic applications of telemedicine. Conclusions: This study serves as a guide for a broad range of telemedicine research topics. This synthesis of themes reflects the commitment of scholars to address the changing dynamics and health care needs, such as the COVID-19 pandemic, aging in place, smartphone usage, and technological advancement. The analysis also reveals flexible research responses to policy and contextual shifts, highlighting the collective drive to broaden the application of telemedicine in community health care.

Single-Walled Carbon Nanotube-Guided Topical Skin Delivery of Tyrosinase to Prevent Photoinduced Damage.

When the skin is exposed to ultraviolet radiation (UV), it leads to the degradation of the extracellular matrix (ECM) and results in inflammation. Subsequently, melanocytes are triggered to induce tyrosinase-mediated melanin synthesis, protecting the skin. Here, we introduce a proactive approach to protect the skin from photodamage via the topical delivery of Streptomyces avermitilis-derived tyrosinase (SaTy) using single-walled carbon nanotube (SWNT). Utilizing a reverse electrodialysis (RED) battery, we facilitated the delivery of SaTy-SWNT complexes up to depths of approximately 300 µm, as analyzed by using confocal Raman microscopy. When applied to ex vivo porcine skin and in vivo albino mouse skin, SaTy-SWNT synthesized melanin, resulting in 4-fold greater UV/vis absorption at 475 nm than in mice without SaTy-SWNT. The synthesized melanin efficiently absorbed UV light and alleviated skin inflammation. In addition, the densification of dermal collagen, achieved through SaTy-mediated cross-linking, reduced photoinduced wrinkles by 66.3% in the affected area. Our findings suggest that SWNT-mediated topical protein delivery holds promise in tissue engineering applications.

Double Emulsion-Mediated Delivery of Polyphenol Mixture Alleviates Atopic Dermatitis.

Although the polyphenols have been studied to alleviate inflammation, there are still challenges to delivering the polyphenols with stabilized formulation due to their low water solubility and susceptibility to oxidation. Herein, the transdermal delivery system of polyphenol mixture (PM), including quercetin (Q), phloretin (P), and ellagic acid (E), is developed using double emulsion for applying to atopic dermatitis (AD). Through the in vitro anti-degranulation assay, the optimal molar ratio of each polyphenol (Q:P:E = 5:1:1) is obtained, and the PM shows at most a 43.6% reduction of degranulation of immune cells, which is the primary factor of AD. Moreover, the water-in-oil-in-water double emulsion (W/O/W) enhances the PM's stability and has a higher anti-degranulation effect than the oil-in-water emulsion (O/W). In the in vivo 1-chloro-2,4-dinitrobenzene (DNCB)-induced mice AD model, PM reduces more AD symptoms than every single polyphenol. The PM-encapsulated W/O/W (PM_W/O/W) shows the most effectiveness in AD by decreasing dermatitis score, i.e., skin/ear thickness, mast cells, and serum IgE level. Finally, this suggests that the findings on the optimal ratio of PM and double emulsion-based delivery would be beneficial in treating AD and can be applied to other allergic diseases.

5-Methylthiopentyl Isothiocyanate, a Sulforaphane Analogue, Inhibits Pro-inflammatory Cytokines by Regulating LPS/ATP-mediated NLRP3 Inflammasome Activation.

BACKGROUND: Pro-inflammatory cytokines secreted from activated macrophages and astrocytes are crucial mediators of inflammation for host defense. Among them, the secretion of IL-1ß, a major pro-inflammatory cytokine, is especially mediated by the activation of NLRP3 inflammasome. Pro-IL-1ß, which is produced in response to the invaded pathogens, such as LPS, is cleaved and matured in the NLRP3 inflammasome by the recognition of ATP. Excessively activated IL-1ß induces other immune cells, resulting in the up-regulation of inflammation. Therefore, regulation of NLRP3 inflammasome can be a good strategy for alleviating inflammation. OBJECTIVE: Our study aimed to examine whether 5-methylthiopentyl isothiocyanate, a sulforaphane analogue (berteroin), has an anti-inflammatory effect on the NLRP3 inflammasome activation induced by LPS and ATP. METHODS: Primary bone marrow-derived macrophages (BMDMs) and astrocytes were stimulated by LPS and ATP with the treatment of 5-methylthiopentyl isothiocyanate, a sulforaphane analogue. The secretion of pro-inflammatory cytokines was measured by ELISA, and the expression level of NLRP3 inflammasome-associated proteins was detected by western blot. The association of NLRP3 inflammasome was assessed by co-immunoprecipitation, and the formation of ASC specks was evaluated by fluorescent microscope. RESULTS: 5-Methylthiopentyl isothiocyanate, a sulforaphane analogue (berteroin), decreased the release of pro-inflammatory cytokines, IL-1ß, and IL-6 in the BMDMs. Berteroin notably prevented the formation of both NLRP3 inflammasome and ASC specks, which reduced the secretion of IL-1ß. Additionally, berteroin reduced the IL-1ß secretion and cleaved IL-1ß expression in the primary astrocytes. DISCUSSION AND CONCLUSION: These results indicated the anti-inflammatory effects of 5-methylthiopentyl isothiocyanate (berteroin) by regulating NLRP3 inflammasome activation, suggesting that berteroin could be the potential natural drug candidate for the regulation of inflammation.

The Molecular Mechanisms of Neuroinflammation in Alzheimer's Disease, the Consequence of Neural Cell Death.

Alzheimer's disease (AD) is accompanied by neural cell loss and memory deficit. Neural cell death, occurring via apoptosis and autophagy, is widely observed in the AD brain in addition to neuroinflammation mediated by necroptosis and the NLRP3 inflammasome. Neurotoxicity induced by amyloid-beta (Aß) and tau aggregates leads to excessive neural cell death and neuroinflammation in the AD brain. During AD progression, uncontrolled neural cell death results in the dysregulation of cellular activity and synaptic function. Apoptosis mediated by pro-apoptotic caspases, autophagy regulated by autophagy-related proteins, and necroptosis controlled by the RIPK/MLKL axis are representative of neural cell death occurred during AD. Necroptosis causes the release of cellular components, contributing to the pro-inflammatory environment in the AD brain. Inordinately high levels of neural cell death and pro-inflammatory events lead to the production of pro-inflammatory cytokines and feed-forward hyper neuroinflammation. Thus, neural cell death and neuroinflammation cause synaptic dysfunction and memory deficits in the AD brain. In this review, we briefly introduce the mechanisms of neural cell death and neuroinflammation observed in the AD brain. Combined with a typical strategy for targeting Aß and tau, regulation of neural cell death and neuroinflammation may be effective for the amelioration of AD pathologies.

The Derivatives of Cromolyn Ameliorate the Abnormal Misfolding of Amyloid Proteins and Neuroinflammation in the Neural Cells.

BACKGROUND: The representative symptom of Alzheimer's Disease (AD) has mainly been mentioned to be misfolding of amyloid proteins, such as amyloid-beta (Aß) and tau protein. In addition, the neurological pathology related to neuroinflammatory signaling has recently been raised as an important feature in AD. Currently, numerous drug candidates continue to be investigated to reduce symptoms of AD, including amyloid proteins misfolding and neuroinflammation. OBJECTIVE: Our research aimed to identify the anti-AD effects of two chemical derivatives modified from cromoglicic acid, CNU 010 and CNU 011. METHODS: CNU 010 and CNU 011 derived from cromoglicic acid were synthesized. The inhibitory effects of Aß and tau were identified by thioflavin T assay. Moreover, western blots were conducted with derivates CNU 010 and CNU 011 to confirm the effects on inflammation. RESULTS: CNU 010 and CNU 011 significantly inhibited the aggregation of Aß and tau proteins. Moreover, they reduced the expression levels of mitogen-activated protein (MAP) kinase and nuclear factor kappa-light-chain-enhancer of activated B cells (NF- κB) signaling proteins, which are representative early inflammatory signaling markers. Also, the inhibitory effects on the lipopolysaccharide (LPS)-induced cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS) expression referring to late inflammation were confirmed. CONCLUSION: Our results showing multiple beneficial effects of cromolyn derivatives against abnormal aggregation of amyloid proteins and neuroinflammatory signaling provide evidence that CNU 010 and CNU 011 could be further developed as potential drug candidates for AD treatment.

Solid-State Reaction Heterogeneity During Calcination of Lithium-Ion Battery Cathode.

During solid-state calcination, with increasing temperature, materials undergo complex phase transitions with heterogeneous solid-state reactions and mass transport. Precise control of the calcination chemistry is therefore crucial for synthesizing state-of-the-art Ni-rich layered oxides (LiNi1-x-y Cox Mny O2 , NRNCM) as cathode materials for lithium-ion batteries. Although the battery performance depends on the chemical heterogeneity during NRNCM calcination, it has not yet been elucidated. Herein, through synchrotron-based X-ray, mass spectrometry microscopy, and structural analyses, it is revealed that the temperature-dependent reaction kinetics, the diffusivity of solid-state lithium sources, and the ambient oxygen control the local chemical compositions of the reaction intermediates within a calcined particle. Additionally, it is found that the variations in the reducing power of the transition metals (i.e., Ni, Co, and Mn) determine the local structures at the nanoscale. The investigation of the reaction mechanism via imaging analysis provides valuable information for tuning the calcination chemistry and developing high-energy/power density lithium-ion batteries.

A digital pathway for genetic testing in UK NHS patients with cancer: BRCA-DIRECT randomised study internal pilot.

BACKGROUND: Germline genetic testing affords multiple opportunities for women with breast cancer, however, current UK NHS models for delivery of germline genetic testing are clinician-intensive and only a minority of breast cancer cases access testing. METHODS: We designed a rapid, digital pathway, supported by a genetics specialist hotline, for delivery of germline testing of BRCA1/BRCA2/PALB2 (BRCA-testing), integrated into routine UK NHS breast cancer care. We piloted the pathway, as part of the larger BRCA-DIRECT study, in 130 unselected patients with breast cancer and gathered preliminary data from a randomised comparison of delivery of pretest information digitally (fully digital pathway) or via telephone consultation with a genetics professional (partially digital pathway). RESULTS: Uptake of genetic testing was 98.4%, with good satisfaction reported for both the fully and partially digital pathways. Similar outcomes were observed in both arms regarding patient knowledge score and anxiety, with <5% of patients contacting the genetics specialist hotline. All progression criteria established for continuation of the study were met. CONCLUSION: Pilot data indicate preliminary demonstration of feasibility and acceptability of a fully digital pathway for BRCA-testing and support proceeding to a full powered study for evaluation of non-inferiority of the fully digital pathway, detailed quantitative assessment of outcomes and operational economic analyses. TRIAL REGISTRATION NUMBER: ISRCTN87845055.

Reclassification of clinically-detected sequence variants: Framework for genetic clinicians and clinical scientists by CanVIG-UK (Cancer Variant Interpretation Group UK).

PURPOSE: Variant classifications may change over time, driven by emergence of fresh or contradictory evidence or evolution in weighing or combination of evidence items. For variant classifications above the actionability threshold, which is classification of likely pathogenic or pathogenic, clinical actions may be irreversible, such as risk-reducing surgery or prenatal interventions. Variant reclassification up or down across the actionability threshold can therefore have significant clinical consequences. Laboratory approaches to variant reinterpretation and reclassification vary widely. METHODS: Cancer Variant Interpretation Group UK is a multidisciplinary network of clinical scientists and genetic clinicians from across the 24 Molecular Diagnostic Laboratories and Clinical Genetics Services of the United Kingdom (NHS) and Republic of Ireland. We undertook surveys, polls, and national meetings of Cancer Variant Interpretation Group UK to evaluate opinions about clinical and laboratory management regarding variant reclassification. RESULTS: We generated a consensus framework on variant reclassification applicable to cancer susceptibility genes and other clinical areas, which provides explicit recommendations for clinical and laboratory management of variant reclassification scenarios on the basis of the nature of the new evidence, the magnitude of evidence shift, and the final classification score. CONCLUSION: In this framework, clinical and laboratory resources are targeted for maximal clinical effect and minimal patient harm, as appropriate to all resource-constrained health care settings.

Association between Olfactory Receptors and Skin Physiology.

Olfactory receptors are chemosensory receptors that detect odorants and function in the initial perception of a smell. Intriguingly, olfactory receptors are also expressed in cells other than olfaction sensory cells, an expression pattern termed ectopic expression. Ectopically expressed olfactory receptors have a distinct role depending on the type of tissues or cells in which they are expressed. This review introduces current research on the ectopic expression and function of olfactory receptors in skin and provides insight into directions for future research.

Templated synthesis of microparticles with carbonaceous skeletal structures using polymer cubosomes as templates.

Polymer cubosomes (PCs) are bicontinuous mesoporous colloidal particles that feature high surface areas and an extremely ordered crystalline pore network. PCs have attracted tremendous attention because of their potential applications in many fields. Herein, we obtained new microparticles with carbonaceous reticulated networks via templated synthesis using PCs as templates. The water-channel networks of the PCs were translated into a carbonaceous skeletal cubic structure. Carbon precursors were polymerized inside the water-channel networks of the PCs under acidic conditions without collapsing the internal crystalline mesophases. The carbonaceous interconnected networks created by the templated synthesis exhibited cubic crystalline skeletal networks similar to those of the PCs. These cubic-ordered mesoporous carbon (cOMC) microparticles exhibited several properties in electrochemical experiments. In addition, the nanoscopic structures and surfaces of these microparticles sustain electrochemically perturbing environments, and thus retain more than 90% capacitance after 1000 charge-discharge cycles.

A chemical tool for blue light-inducible proximity photo-crosslinking in live cells.

We developed a proximity photo-crosslinking method (Spotlight) with a 4-azido-N-ethyl-1,8-naphthalimide (AzNP) moiety that can be converted to reactive aryl nitrene species using ambient blue light-emitting diode light. Using an AzNP-conjugated HaloTag ligand (VL1), blue light-induced photo-crosslinked products of various HaloTag-conjugated proteins of interest were detected in subcellular spaces in live cells. Chemical or heat stress-induced dynamic changes in the proteome were also detected, and photo-crosslinking in the mouse brain tissue was enabled. Using Spotlight, we further identified the host interactome of SARS-CoV-2 nucleocapsid (N) protein, which is essential for viral genome assembly. Mass analysis of the VL1-crosslinked product of N-HaloTag in HEK293T cells showed that RNA-binding proteins in stress granules were exclusively enriched in the cross-linked samples. These results tell that our method can reveal the interactome of protein of interest within a short distance in live cells.

Metabolomic analysis of amino acids and organic acids in aging mouse eyes using gas chromatography-tandem mass spectrometry.

This is a metabolomics study for monitoring altered amino acid (AA) and organic acid (OA) metabolism of in eyes from aging an mouse model at 8 and 18 weeks and 18 months. Simultaneous metabolic profiling analysis of OAs and AAs was performed as ethoxycarbonyl/methoxime/tert-butyldimethylsilyl derivatives by gas chromatography-tandem mass spectrometry. A total of 42 metabolites-24 AAs and 18 OAs-were determined and their composition values were normalized to the corresponding mean values of 8-week-old mice as the control group. Then their normalized values were plotted as star graphs, which were distorted and readily distinguishable for each age-related group. Among the 42 metabolites, 18 AAs and 11 OAs were age dependent and significantly different (p < 0.05). Principal component analysis and partial least squares discriminant analysis showed unclear separation between 8- and 18-week-old mice but clear separation between these and 18-month-old mice. In particular, the variable importance in projection scores of 4-hydroxyproline, cis-aconitic acid, glycine, isocitric acid, leucine, pipecolic acid and lysine from partial least-squares-discriminant analysis were higher than 1.3. A heatmap for the classification and visualization of 42 metabolites showed differences in metabolite changes with aging. Altered AA and OA profiles were monitored, which may explain the metabolic disturbance of AA and OA. These findings are related to mitochondrial dysfunctions related to energy metabolism and the impaired antioxidant system in the aging eye. Therefore, the present metabolomics results of the association between physiological states and altered metabolism of AA and OA will be useful for understanding the aging eye and related diseases.

Quantifying prediction of pathogenicity for within-codon concordance (PM5) using 7541 functional classifications of BRCA1 and MSH2 missense variants.

PURPOSE: Conditions and thresholds applied for evidence weighting of within-codon concordance (PM5) for pathogenicity vary widely between laboratories and expert groups. Because of the sparseness of available clinical classifications, there is little evidence for variation in practice. METHODS: We used as a truthset 7541 dichotomous functional classifications of BRCA1 and MSH2, spanning 311 codons of BRCA1 and 918 codons of MSH2, generated from large-scale functional assays that have been shown to correlate excellently with clinical classifications. We assessed PM5 at 5 stringencies with incorporation of 8 in silico tools. For each analysis, we quantified a positive likelihood ratio (pLR, true positive rate/false positive rate), the predictive value of PM5-lookup in ClinVar compared with the functional truthset. RESULTS: pLR was 16.3 (10.6-24.9) for variants for which there was exactly 1 additional colocated deleterious variant on ClinVar, and the variant under examination was equally or more damaging when analyzed using BLOSUM62. pLR was 71.5 (37.8-135.3) for variants for which there were 2 or more colocated deleterious ClinVar variants, and the variant under examination was equally or more damaging than at least 1 colocated variant when analyzed using BLOSUM62. CONCLUSION: These analyses support the graded use of PM5, with potential to use it at higher evidence weighting where more stringent criteria are met.

Quantifying evidence toward pathogenicity for rare phenotypes: The case of succinate dehydrogenase genes, SDHB and SDHD.

PURPOSE: The weight of the evidence to attach to observation of a novel rare missense variant in SDHB or SDHD in individuals with the rare neuroendocrine tumors, pheochromocytomas and paragangliomas (PCC/PGL), is uncertain. METHODS: We compared the frequency of SDHB and SDHD very rare missense variants (VRMVs) in 6328 and 5847 cases of PCC/PGL, respectively, with that of population controls to generate a pan-gene VRMV likelihood ratio (LR). Via windowing analysis, we measured regional enrichments of VRMVs to calculate the domain-specific VRMV-LR (DS-VRMV-LR). We also calculated subphenotypic LRs for variant pathogenicity for various clinical, histologic, and molecular features. RESULTS: We estimated the pan-gene VRMV-LR to be 76.2 (54.8-105.9) for SDHB and 14.8 (8.7-25.0) for SDHD. Clustering analysis revealed an SDHB enriched region (ɑɑ 177-260, P = .001) for which the DS-VRMV-LR was 127.2 (64.9-249.4) and an SDHD enriched region (ɑɑ 70-114, P = .000003) for which the DS-VRMV-LR was 33.9 (14.8-77.8). Subphenotypic LRs exceeded 6 for invasive disease (SDHB), head-and-neck disease (SDHD), multiple tumors (SDHD), family history of PCC/PGL, loss of SDHB staining on immunohistochemistry, and succinate-to-fumarate ratio >97 (SDHB, SDHD). CONCLUSION: Using methodology generalizable to other gene-phenotype dyads, the LRs relating to rarity and phenotypic specificity for a single observation in PCC/PGL of a SDHB/SDHD VRMV can afford substantial evidence toward pathogenicity.

Suppressing High-Current-Induced Phase Separation in Ni-Rich Layered Oxides by Electrochemically Manipulating Dynamic Lithium Distribution.

Understanding the cycling rate-dependent kinetics is crucial for managing the performance of batteries in high-power applications. Although high cycling rates may induce reaction heterogeneity and affect battery lifetime and capacity utilization, such phase transformation dynamics are poorly understood and uncontrollable. In this study, synchrotron-based operando X-ray diffraction is performed to monitor the high-current-induced phase transformation kinetics of LiNi0.6 Co0.2 Mn0.2 O2 . The sluggish Li diffusion at high Li content induces different phase transformations during charging and discharging, with strong phase separation and homogeneous phase transformation during charging and discharging, respectively. Moreover, by exploiting the dependence of Li diffusivity on the Li content and electrochemically tuning the initial Li content and distribution, phase separation pathway can be redirected to solid solution kinetics at a high charging rate of 7 C. Finite element analysis further elucidates the effect of the Li-content-dependent diffusion kinetics on the phase transformation pathway. The findings suggest a new direction for optimizing fast-cycling protocols based on the intrinsic properties of the materials.