Structural insights into the Caprin-2 HR1 domain in canonical Wnt signaling.

The canonical Wnt signaling pathway plays crucial roles in cell fate decisions as well as in pathogenesis of various diseases. Previously, we reported Caprin-2 as a new regulator of canonical Wnt signaling through a mechanism of facilitating LRP5/6 phosphorylation. Here, we resolved the crystal structure of the N-terminal homologous region 1 (HR1) domain of human Caprin-2 (hCap2_HR1). HR1 domain is so far only observed in Caprin-2 and its homologous protein Caprin-1, and the function of this domain remains largely mysterious. Here, the structure showed that hCap2_HR1 forms a homo-dimer and exhibits an overall structure roughly resembling the appearance of a pair of scissors. Moreover, we found that residues R200 and R201, which located at a basic cluster within the N-terminal "blades" region, are critical for Caprin-2's localization to the plasma membrane. In line with this, mutations targeting these two residues decrease Caprin-2's activity in the canonical Wnt signaling. Overall, we characterized a previously unknown "scissors"-like structure of the full-length HR1 domain, and revealed its function in mediating Caprin-2's localization to the plasma membrane.

LncRNA HOTAIRM1 functions in DNA double-strand break repair via its association with DNA repair and mRNA surveillance factors.

The eukaryotic exon junction complex component Y14 participates in double-strand break (DSB) repair via its RNA-dependent interaction with the non-homologous end-joining (NHEJ) complex. Using immunoprecipitation-RNA-seq, we identified a set of Y14-associated long non-coding RNAs (lncRNAs). The lncRNA HOTAIRM1 serves as a strong candidate that mediates the interaction between Y14 and the NHEJ complex. HOTAIRM1 localized to near ultraviolet laser-induced DNA damage sites. Depletion of HOTAIRM1 delayed the recruitment of DNA damage response and repair factors to DNA lesions and compromised the efficiency of NHEJ-mediated DSB repair. Identification of the HOTAIRM1 interactome revealed a large set of RNA processing factors including mRNA surveillance factors. The surveillance factors Upf1 and SMG6 localized to DNA damage sites in a HOTAIRM1-dependent manner. Depletion of Upf1 or SMG6 increased the level of DSB-induced non-coding transcripts at damaged sites, indicating a pivotal role for Upf1/SMG6-mediated RNA degradation in DNA repair. We conclude that HOTAIRM1 serves as an assembly scaffold for both DNA repair and mRNA surveillance factors that act in concert to repair DSBs.

A phase 2 trial exploring the significance of homologous recombination status in patients with platinum sensitive or platinum resistant relapsed ovarian cancer receiving combination cediranib and olaparib.

OBJECTIVE: Combination cediranib/olaparib has reported activity in relapsed ovarian cancer. This phase 2 trial investigated the activity of cediranib/olaparib in relapsed ovarian cancer and its association with homologous recombination deficiency (HRD). METHODS: Seventy patients were enrolled to cohorts of either platinum-sensitive or platinum-resistant ovarian cancer and received olaparib tablets 200 mg twice daily and cediranib tablets 30 mg once daily under a continuous dosing schedule. HRD testing was performed on pre-treatment, on-treatment and archival biopsies by sequencing key homologous recombination repair (HRR) genes and by genomic LOH analysis. The primary objective for the platinum-sensitive cohort was the association of HRD, defined as presence of HRR gene mutation, with progression-free survival (PFS). The primary objective for the platinum-resistant cohort was objective response rate (ORR), with a key secondary endpoint evaluating the association of HRD status with activity. RESULTS: In platinum-sensitive ovarian cancer (N = 35), ORR was 77.1% (95% CI 59.9-89.6%) and median PFS was 16.4 months (95% CI 13.2-18.6). Median PFS in platinum-sensitive HRR-HRD cancers (N = 22) was 16.8 months (95% CI 11.3-18.6), and 16.4 months (95% CI 9.4-NA) in HRR-HR proficient cancers (N = 13; p = 0.57). In platinum-resistant ovarian cancer (N = 35), ORR was 22.9% (95% CI 10.4-40.1%) with median PFS 6.8 months (95% CI 4.2-9.1). Median PFS in platinum-resistant HRR-HRD cancers (N = 7) was 10.5 months (95% CI 3.6-NA) and 5.6 months (95% CI 3.6-7.6) in HRR-HR proficient cancers (N = 18; p = 0.23). CONCLUSIONS: Cediranib/olaparib had clinical activity in both platinum-sensitive and -resistant ovarian cancer. Presence of HRR gene mutations was not associated with cediranib/olaparib activity in either setting.

Molecular-weight effects of a homopolymer on the AB- and ABC-stacks of perforations in block copolymer/homopolymer films.

We have demonstrated the molecular-weight effects of adding homopolystyrene (hPS) on the evolution of perforated layers and double gyroids in polystyrene-block-poly(methyl methacrylate)-based films during isothermal annealing. Two homopolystyrenes of 2.8 and 17 kg mol-1 were used. To prepare blend films, PS-b-PMMA and hPSx (x: 2.8 or 17) were mixed at a weight-fraction ratio of 75/25 in toluene and then spin-coated at SiOx/Si. Spin coating inevitably produced films with thick edges at the periphery of the substrate. The structural evolution of the spun films was in situ characterized by grazing incidence small-angle X-ray scattering (GISAXS). The annealed films were then characterized using a scanning electron microscope (SEM). We found that thin middle regions behaved differently from thick beads for the films. The middle of the blend films mainly formed perforated layers with different spatial orders and orientations, depending on the molecular weight of added hPS chains. Hexagonally perforated layers quickly formed at 205 °C for PS-b-PMMA/hPS2.8 films. However, when hPS17 was used instead of hPS2.8, perforated layers formed with defects in PS-b-PMMA/hPS17 films annealed at 205 °C. Annealing at 240 °C improved the spatial order and orientation of perforated layers for a PS-b-PMMA/hPS17 film. Nevertheless, annealing at 240 °C inversely depressed the in-plane spatial order of perforated layers for a PS-b-PMMA/hPS2.8 film. The depression in the in-plane spatial order is ascribed to a dilution effect of added short chains. Compared to the middle regions, the thick beads went through several metastable phases, such as perpendicularly oriented perforated layers and double gyroids.

Self-improving dystrophic epidermolysis bullosa with a novel heterozygous missense variant in the COL7A1 gene in a Taiwanese family.

Self-improving dystrophic epidermolysis bullosa (DEB) is a genodermatosis that is inherited autosomal dominantly or recessively, and its clinical symptoms may improve or subside spontaneously. Herein, we report a case of self-improving DEB with COL7A1 p.Gly2025Asp variant. The diagnosis was made through histopathological, electron microscopic examination, and genetic testing. The same variant is also noted on his father, who presents with dystrophic toenails without any blisters. This study highlights that idiopathic nail dystrophy could be linked to congenital or hereditary disease. Furthermore, we conducted a review of the literature on the characteristics of reported cases of self-improving DEB with a personal or family history of nail dystrophy. The results supported our findings that nail dystrophy may be the sole manifestation in some family members. We suggest that individuals suffering from idiopathic nail dystrophy may seek genetic counselling when planning pregnancy to early evaluate the potential risk of hereditary diseases.

Vascular endothelial dysfunction induced by 3-bromofluoranthene via MAPK-mediated-NFκB pro-inflammatory pathway and intracellular ROS generation.

3-Bromofluoranthene (3-BrFlu) is the secondary metabolite of fluoranthene, which is classified as a polycyclic aromatic hydrocarbon, through bromination and exists in the fine particulate matter of air pollutants. Endothelial dysfunction plays a critical role in the pathogenesis of cardiovascular and vascular diseases. Little is known about the molecular mechanism of 3-BrFlu on endothelial dysfunction in vivo and in vitro assay. In the present study, 3-BrFlu included concentration-dependent changes in ectopic angiogenesis of the sub-intestinal vein and dilation of the dorsal aorta in zebrafish. Disruption of vascular endothelial integrity and up-regulation of vascular endothelial permeability were also induced by 3-BrFlu in a concentration-dependent manner through pro-inflammatory responses in vascular endothelial cells, namely, SVEC4-10 cells. Generation of pro-inflammatory mediator PGE2 was induced by 3-BrFlu through COX2 expression. Expression of COX2 and generation of pro-inflammatory cytokines, including TNFα and IL-6, were induced by 3-BrFlu through phosphorylation of NF-κB p65, which was mediated by phosphorylation of MAPK, including p38 MAPK, ERK and JNK. Furthermore, generation of intracellular ROS was induced by 3-BrFlu, which is associated with the down-regulated activities of the antioxidant enzyme (AOE), including SOD and catalase. We also found that 3-BrFlu up-regulated expression of the AOE and HO-1 induced by 3-BrFlu through Nrf-2 expression. However, the 3-BrFlu-induced upregulation of AOE and HO-1 expression could not be revised the responses of vascular endothelial dysfunction. In conclusion, 3-BrFlu is a hazardous substance that results in vascular endothelial dysfunction through the MAPK-mediated-NFκB pro-inflammatory pathway and intracellular ROS generation.

Prognostic impact of caspase-8 mutation in oral cavity squamous cell carcinoma.

OBJECTIVE: Identifying the drive genes and inhibiting their significant signals were persistently the main concepts in cancer treatment. However, for oral cavity squamous cell carcinoma (OCSCC), the most influential genes for overall survival (OS) remain unclear. METHODS: A total of 120 OCSCC patients with corresponding pathologic specimens were collected in Taiwan. Whole-exome sequencing was done and the prognostic impact of each gene was analyzed. TCGA database was used to validate. RESULTS: The incidences of caspase-8 mutation were 22.1% and 10.9% in the Taiwan and TCGA cohort, respectively. In the Taiwan cohort, caspase-8 mutation was the most significant independent for OS with an adjusted hazard ratio (HR) ([95% CI]: 3.83 [1.84-7.99]). It was validated by the TCGA database (HR [95% CI]: 1.51 [1.00-2.29]). The 5-year OSs of the patients with or without caspase-8 mutation were 38.1% vs. 75.3% (p < 0.001) (HR [95% CI]: 3.264 [1.645-6.438]) in the Taiwan cohort, and 26.1% vs. 49.0% (p = 0.048) (1.513 [1.001-2.288]) in the TCGA cohorts, respectively. Caspase-8 mutation was also individually associated with poor prognosis for TNM stage I/II/III/IV, respectively. CASP8 R127* and R494*, defined as pathogenic mutations in ClinVar, were presented in both cohorts. CONCLUSIONS: Caspase-8 mutation was the most significant genetic alteration impacting prognosis.

Association between obstructive sleep apnea severity and depression risk: a systematic review and dose-response meta-analysis.

Obstructive sleep apnea (OSA) has received considerable attention as a potential risk factor for depressive symptoms. The systematic review was conducted to confirm the dose‒response connection between OSA severity and depression risk. A systematic literature search of English and Chinese articles published in PubMed, EMBASE, Scopus, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI), and SinoMed databases from their inception to 28 August 2023 was conducted. An evaluation using the Newcastle‒Ottawa Scale was performed. A meta-analysis was used to evaluate the impact of OSA severity. A random-effects dose‒response model was conducted to evaluate the linear and nonlinear dose‒response connections. We evaluated publication bias by funnel plots, and symmetry by Egger's test. We identified 18 cross-sectional researches. 3143 participants which were involved in the dose‒response meta-analysis. Contrasted with mild OSA, individuals with severe OSA had a higher adjusted risk of depression (rate ratio: 1.34, 95% confidence interval = 1.05-1.70), with substantial heterogeneity (I2 = 70.9%, Pheterogeneity<0.001). There is a significant linear connection between OSA severity and depression risk. The depression risk increased by 0.4% for every 1 event per hour increase in the apnea-hypopnea index (AHI). The protocol for this unfunded research was drafted and registered at PROSPERO (ID CRD42023474097).

Wireless, soft electronics for rapid, multisensor measurements of hydration levels in healthy and diseased skin.

Precise, quantitative measurements of the hydration status of skin can yield important insights into dermatological health and skin structure and function, with additional relevance to essential processes of thermoregulation and other features of basic physiology. Existing tools for determining skin water content exploit surrogate electrical assessments performed with bulky, rigid, and expensive instruments that are difficult to use in a repeatable manner. Recent alternatives exploit thermal measurements using soft wireless devices that adhere gently and noninvasively to the surface of the skin, but with limited operating range (∼1 cm) and high sensitivity to subtle environmental fluctuations. This paper introduces a set of ideas and technologies that overcome these drawbacks to enable high-speed, robust, long-range automated measurements of thermal transport properties via a miniaturized, multisensor module controlled by a long-range (∼10 m) Bluetooth Low Energy system on a chip, with a graphical user interface to standard smartphones. Soft contact to the surface of the skin, with almost zero user burden, yields recordings that can be quantitatively connected to hydration levels of both the epidermis and dermis, using computational modeling techniques, with high levels of repeatability and insensitivity to ambient fluctuations in temperature. Systematic studies of polymers in layered configurations similar to those of human skin, of porcine skin with known levels of hydration, and of human subjects with benchmarks against clinical devices validate the measurement approach and associated sensor hardware. The results support capabilities in characterizing skin barrier function, assessing severity of skin diseases, and evaluating cosmetic and medication efficacy, for use in the clinic or in the home.

Artificial intelligence interpretation of touch print smear cytology of testicular specimen from patients with azoospermia.

PURPOSE: Identification of mature sperm at microdissection testicular sperm extraction (mTESE) is a crucial step of sperm retrieval to help patients with non-obstructive azoospermia (NOA) proceed to intracytoplasmic sperm injection. Touch print smear (TPS) cytology allows immediate interpretation and prompt sperm identification intraoperatively. In this study, we leverage machine learning (ML) to facilitate TPS reading and conquer the learning curve for new operators. MATERIALS AND METHODS: One hundred seventy-six microscopic TPS images from the testicular specimen of patients with azoospermia at Taipei Veterans General Hospital were retrospectively collected, including categories of Sertoli cell, primary spermatocytes, round spermatids, elongated spermatids, immature sperm, and mature sperm. Among them, 118 images were assigned as the training set and 29 images as the validation set. RetinaNet (Lin et al. in IEEE Trans Pattern Anal Mach Intell. 42:318-327, 2020), a one-stage detection framework, was adopted for cell detection. The performance was evaluated at the cell level with average precision (AP) and recall, and the precision-recall (PR) curve was displayed among an independent testing set that contains 29 images that aim to assess the model. RESULTS: The training set consisted of 4772 annotated cells, including 1782 Sertoli cells, 314 primary spermatocytes, 443 round spermatids, 279 elongated spermatids, 504 immature sperm, and 1450 mature sperm. This study demonstrated the performance of each category and the overall AP and recall on the validation set, which were 80.47% and 96.69%. The overall AP and recall were 79.48% and 93.63% on the testing set, while increased to 85.29% and 93.80% once the post-meiotic cells were merged into one category. CONCLUSIONS: This study proposed an innovative approach that leveraged ML methods to facilitate the diagnosis of spermatogenesis at mTESE for patients with NOA. With the assistance of ML techniques, surgeons could determine the stages of spermatogenesis and provide timely histopathological diagnosis for infertile males.

Effect of different exit-site care dressings on preventing peritoneal dialysis related infection from nontropical area: a systematic review and network meta-analysis.

OBJECT: This study aims to conduct a systematic review and network meta-analysis to comprehensively evaluate the efficacy of various dressings in preventing exit-site infection (ESI) and peritonitis. METHODS: We searched PubMed, Embase, Web of Science, CINAHL Plus with Full Text (EBSCO), Sino Med, Wan Fang Data, China National Knowledge Infrastructure (CNKI) from 1 January 1999 to 10 July 2023. The language restrictions were Chinese and English. Randomized controlled trials, non-randomized controlled trials, and self-controlled trials were included in this study. We used ROB 2 tool to evaluate the quality of the included literature. Two authors independently extracted the data according to the Cochrane Handbook. A Frequentist network meta-analysis was performed using Stata17.0 according to PRISAMA with a random effects model. RESULTS: From 2092 potentially eligible studies, thirteen studies were selected for analysis, including nine randomized controlled studies, three quasi-experimental studies and one self-controlled trial. A total of 1229 patients were included to compare five types of exit site care dressings, named disinfection dressings, antibacterial dressings, non-antibacterial occlusive dressings, sterile gauze, and no-particular dressings. The outcome of prevention ESI is antibacterial dressings (SUCRA = 97.6) >non-antibacterial occlusive dressings (SUCRA = 68.3) >disinfection dressings (SUCRA = 50.6) >no-particular dressings (SUCRA = 23.9) >sterile gauze (SUCRA = 9.5). The antibacterial dressings were more effective than sterile gauze (OR = 0.13, 95%CI 0.04∼0.44), and no-particular dressing (OR = 0.18, 95%CI 0.07∼0.50) in preventing ESI; the non-antibacterial occlusive dressings were effective than sterile gauze (OR:0.30, 95%CI 0.16∼0.57). There is no statistical significance between no-particular dressings and other types of dressings in preventing the mature ESI. There is no statistical significance in the effectiveness of five types of dressings in preventing peritonitis. CONCLUSIONS: The no-particular dressings maybe more cost-effective for preventing mature ESI. None of the dressings was more effective than another in preventing peritonitis. Then, none of the different types of dressing is strongly recommended for preventing ESI or peritonitis.RegistrationCRD42022366756.

Dietary nutrient intake and nutritional status in maintenance hemodialysis patients: a multicenter cross-sectional survey.

PURPOSE: To investigate the dietary nutrient intake of Maintenance hemodialysis (MHD) patients, identify influencing factors, and explore the correlation between dietary nutrient intake and nutritional and disease control indicators. METHODS: This was a multicenter cross-sectional study. A dietary survey was conducted using a three-day dietary record method, and a self-designed diet management software was utilized to calculate the daily intake of dietary nutrients. The nutritional status and disease control indicators were assessed using subjective global assessment, handgrip strength, blood test indexes, and dialysis adequacy. RESULTS: A total of 382 MHD patients were included in this study. Among them, 225 (58.9%) and 233 (61.0%) patients' protein and energy intake did not meet the recommendations outlined in the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative Clinical Practice Guideline for Nutrition in Chronic Kidney Disease (2020 update). The average protein and energy intake for these patients were 0.99 ± 0.32 g/kg/d and 29.06 ± 7.79 kcal/kg/d, respectively. Multiple linear regression analysis showed that comorbidity-diabetes had a negative influence on normalized daily energy intake (nDEI = DEI / ideal body weight) (B = -2.880, p = 0.001) and normalized daily protein intake (nDPI = DPI / ideal body weight) (B = -0.109, p = 0.001). Pearson correlation analysis revealed that dietary DPI (r = -0.109, p < 0.05), DEI (r = -0.226, p < 0.05) and phosphorus (r = -0.195, p < 0.001) intake were statistically correlated to Kt/V; dietary nDPI (r = 0.101, p < 0.05) and sodium (r = -0.144, p < 0.001) intake were statistically correlated to serum urea nitrogen; dietary DPI (r = 0.200, p < 0.001), DEI (r = 0.241, p < 0.001), potassium (r = 0.129, p < 0.05), phosphorus (r = 0.199, p < 0.001), and fiber (r = 0.157, p < 0.001) intake were statistically correlated to serum creatinine; dietary phosphorus (r = 0.117, p < 0.05) and fiber (r = 0.142, p < 0.001) intake were statistically correlated to serum phosphorus; dietary nDPI (r = 0.125, p < 0.05), DPI (r = 0.135, p < 0.05), nDEI (r = 0.116, p < 0.05), DEI (r = 0.125, p < 0.05), potassium (r = 0.148, p < 0.001), and phosphorus (r = 0.156, p < 0.001) intake were statistically correlated to subjective global assessment scores; dietary nDPI (r = 0.215, p < 0.001), DPI (r = 0.341, p < 0.001), nDEI (r = 0.142, p < 0.05), DEI (r = 0.241, p < 0.001), potassium (r = 0.166, p < 0.05), phosphorus (r = 0.258, p < 0.001), and fiber (r = 0.252, p < 0.001) intake were statistically correlated to handgrip strength in males; dietary fiber (r = 0.190, p < 0.05) intake was statistically correlated to handgrip strength in females. CONCLUSIONS: The dietary nutrient intake of MHD patients need improvement. Inadequate dietary nutrient intake among MHD patients could have a detrimental effect on their blood test indexes and overall nutritional status. It is crucial to address and optimize the dietary intake of nutrients in this patient population to enhance their health outcomes and well-being.

Free Latissimus Dorsi Flaps in Head and Neck Reconstruction at a Modern High-Volume Microsurgery Center.

BACKGROUND: Over the past two decades, with the introduction of the perforator flap concept and advances in flap dissections, lower extremities have emerged as the preferred soft tissue flap donor sites. As a modern and high-volume microsurgical center, and the senior author being one of the pioneers and advocates for the use of lower extremity flap donor sites, we aim to investigate the role of latissimus dorsi (LD) free flap in head and neck reconstruction within our current practice. METHODS: All free LD flaps used for head and neck reconstruction performed by a single surgeon between January 2010 and June 2023 were reviewed for their indications and immediate and short-term outcomes. RESULTS: A total of 1,586 head and neck free flap reconstructions were performed, and 33 free LD flaps were identified. The patients' median age was 53 (interquartile range [IQR] 48.5-63.5) years. Twenty-nine (87.9%) flaps were used to reconstruct oro-maxillo-facial and four (12.1%) flaps were used to reconstruct scalp defects. Most patients had prior radiation (n = 28, 84.8%), neck dissection (n = 24, 72.7%), and multiple previous head and neck flap reconstructions with a median of 3.0 (IQR 3.0-3.5) previous flaps. Six (18.2%) LD flaps were used to replace failed flaps from other donor sites. No major complications such as total flap failure or takebacks, and no need for vein grafts but three (9.1%) had flap marginal necrosis. Other complications included one flap dehiscence (3.0%), one orocutaneous fistula (3.0%), two wound infections (6.1%), three plate exposures (9.1%), and three patients who developed local recurrence (9.1%). The median patient follow-up time was 16 (IQR 5-27) months. CONCLUSION: This retrospective study demonstrates the role of LD free flap in head and neck reconstruction as a reliable and versatile backup soft tissue flap when workhorse flaps from lower extremity donor sites are either unavailable or unsuitable.

2024 Guidelines of the Taiwan Society of Cardiology on the Primary Prevention of Atherosclerotic Cardiovascular Disease --- Part I.

Atherosclerotic cardiovascular disease (ASCVD) is one of the leading causes of death worldwide and in Taiwan. It is highly prevalent and has a tremendous impact on global health. Therefore, the Taiwan Society of Cardiology developed these best-evidence preventive guidelines for decision-making in clinical practice involving aspects of primordial prevention including national policies, promotion of health education, primary prevention of clinical risk factors, and management and control of clinical risk factors. These guidelines cover the full spectrum of ASCVD, including chronic coronary syndrome, acute coronary syndrome, cerebrovascular disease, peripheral artery disease, and aortic aneurysm. In order to enhance medical education and health promotion not only for physicians but also for the general public, we propose a slogan (2H2L) for the primary prevention of ASCVD on the basis of the essential role of healthy dietary pattern and lifestyles: "Healthy Diet and Healthy Lifestyles to Help Your Life and Save Your Lives". We also propose an acronym of the modifiable risk factors/enhancers and relevant strategies to facilitate memory: " ABC2D2EFG-I'M2 ACE": Adiposity, Blood pressure, Cholesterol and Cigarette smoking, Diabetes mellitus and Dietary pattern, Exercise, Frailty, Gout/hyperuricemia, Inflammation/infection, Metabolic syndrome and Metabolic dysfunction-associated fatty liver disease, Atmosphere (environment), Chronic kidney disease, and Easy life (sleep well and no stress). Some imaging studies can be risk enhancers. Some risk factors/clinical conditions are deemed to be preventable, and healthy dietary pattern, physical activity, and body weight control remain the cornerstone of the preventive strategy.

Anastasis Drives Senescence and Non-Cell Autonomous Neurodegeneration in the Astrogliopathy Alexander Disease.

Anastasis is a recently described process in which cells recover after late-stage apoptosis activation. The functional consequences of anastasis for cells and tissues are not clearly understood. Using Drosophila, rat and human cells and tissues, including analyses of both males and females, we present evidence that glia undergoing anastasis in the primary astrogliopathy Alexander disease subsequently express hallmarks of senescence. These senescent glia promote non-cell autonomous death of neurons by secreting interleukin family cytokines. Our findings demonstrate that anastasis can be dysfunctional in neurologic disease by inducing a toxic senescent population of astroglia.SIGNIFICANCE STATEMENT Under some conditions cells otherwise destined to die can be rescued just before death in a process called anastasis, or "rising from the dead." The fate and function of cells undergoing a near death experience is not well understood. Here, we find that in models and patient cells from Alexander disease, an important brain disorder in which glial cells promote neuronal dysfunction and death, anastasis of astrocytic glia leads to secretion of toxic signaling molecules and neurodegeneration. These studies demonstrate a previously unexpected deleterious consequence of rescuing cells on the brink of death and suggest therapeutic strategies for Alexander disease and related disorders of glia.

Analysis of MUC6 polymorphisms on the clinicopathologic characteristics of Asian patients with oral squamous cell carcinoma.

Head and neck squamous cell carcinomas (HNSCCs) are generally associated with tobacco consumption, alcohol abuse or both. Mucins (MUCs) are high-molecular-weight glycoproteins produced by many epithelial tissues. Many studies have indicated that MUCs play an important role in cancer metastasis. MUC6 expression has been observed in gastric and oncocytic phenotypes and plays an important role during cancer progression. We found that levels of MUC6 are lower in Asian HNCC patients and affect the disease-free survival of HNCC patients. Next, we investigated the combined effect of MUC6 polymorphisms and exposure to environmental carcinogens on the susceptibility to and clinicopathological characteristics of HNCC. Three single-nucleotide polymorphisms (SNPs) of MUC6 (rs7481521, rs6597947 and rs61869016) were analysed using real-time PCR. After adjusting for other co-variants, we found that carrying a CC genotype at MUC6 rs6597947 led to a lower risk of developing oral squamous cell carcinoma (OSCC) than wild-type carriers among non-betel-quid chewers. Moreover, male oral cancer patients who carried the AA + CC genotype at MUC6 rs6597947 had a lower risk of lymph node metastasis than other genotypes, suggesting a significant functional compromise and decompensated disease. Therefore, our findings suggest that genetic variations in MUC6 may correlate to OSCC and indicate the progression in OSCC patients.

Hispolon induces apoptosis in oral squamous cell carcinoma cells through JNK/HO-1 pathway activation.

Oral squamous cell carcinoma (OSCC) has a high recurrence rate and poor prognosis. Hispolon, a polyphenolic compound with antiviral, antioxidant, and anticancer activities, is a potential chemotherapy agent. However, few studies have investigated the anti-cancer mechanism of hispolon in oral cancer. This present study used the cell viability assay, clonogenic assay, fluorescent nuclear staining, and flow cytometry assay to analyse the apoptosis-inducing effects of hispolon in OSCC cells. After hispolon treatment, the apoptotic initiators, cleaved caspase-3, -8, and - 9, were upregulated, whereas the cellular inhibitor of apoptosis protein-1 (cIAP1) was downregulated. Furthermore, a proteome profile analysis using a human apoptosis array revealed the overexpression of heme oxygenase-1 (HO-1) by hispolon, which was determined to be involved in caspase-dependent apoptosis. Moreover, cotreatment with hispolon and mitogen-activated protein kinase (MAPK) inhibitors revealed that hispolon induces apoptosis in OSCC cells through activation of the c-Jun N-terminal kinase (JNK) pathway and not the extracellular signal-regulated kinase (ERK) or p38 pathway. These findings indicate that hispolon may exert an anticancer effect on oral cancer cells by upregulating HO-1 and inducing caspase-dependent apoptosis by activating the JNK pathway.

Controllable Black-to-Yellow Phase Transition by Tuning the Lattice Symmetry in Perovskite Quantum Dots.

The black-to-yellow phase transition in perovskite quantum dots (QDs) is more complex than in bulk perovskites, regarding the role of surface energy. Here, with the assistance of in situ grazing-incidence wide-angle and small-angle X-ray scattering (GIWAXS/GISAXS), distinct phase behaviors of cesium lead iodide (CsPbI3 ) QD films under two different temperature profiles-instant heating-up (IHU) and slow heating-up (SHU) is investigated. The IHU process can cause the phase transition from black phase to yellow phase, while under the SHU process, the majority remains in black phase. Detailed studies and structural refinement analysis reveal that the phase transition is triggered by the removal of surface ligands, which switches the energy landscape. The lattice symmetry determines the transition rate and the coexistence black-to-yellow phase ratio. The SHU process allows longer relaxation time for a more ordered QD packing, which helps sustain the lattice symmetry and stabilizes the black phase. Therefore, one can use the lattice symmetry as a general index to monitor the CsPbI3 QD phase transition and finetune the coexistence black-to-yellow phase ratio for niche applications.

Critical Influence of Organic A'-Site Ligand Structure on 2D Perovskite Crystallization.

Organic A'-site ligand structure plays a crucial role in the crystal growth of 2D perovskites, but the underlying mechanism has not been adequately understood. This problem is tackled by studying the influence of two isomeric A'-site ligands, linear-shaped n-butylammonium (n-BA+ ) and branched iso-butylammonium (iso-BA+ ), on 2D perovskites from precursor to device, with a combination of in situ grazing-incidence wide-angle X-ray scattering and density functional theory. It is found that branched iso-BA+ , due to the lower aggregation enthalpies, tends to form large-size clusters in the precursor solution, which can act as pre-nucleation sites to expedite the crystallization of vertically oriented 2D perovskites. Furthermore, iso-BA+ is less likely to be incorporated into the MAPbI3 lattice than n-BA+ , suppressing the formation of unwanted multi-oriented perovskites. These findings well explain the better device performance of 2D perovskite solar cells based on iso-BA+ and elucidate the fundamental mechanism of ligand structural impact on 2D perovskite crystallization.

Real-time trajectory guide tracking for intraoperative MRI-guided neurosurgery.

PURPOSE: In current intraoperative MRI (IMRI) methods, an iterative approach is used to aim trajectory guides at intracerebral targets: image MR-visible features, determine current aim by fitting model to image, manipulate device, repeat. Infrequent updates are produced by such methods, compared to rapid optically tracked stereotaxy used in the operating room. Our goal was to develop a real-time interactive IMRI method for aiming. METHODS: The current trajectory was computed from two points along the guide's central axis, rather than by imaging the entire device. These points were determined by correlating one-dimensional spokes from a radial sequence with the known cross-sectional projection of the guide. The real-time platform RTHawk was utilized to control MR sequences and data acquisition. On-screen updates were viewed by the operator while simultaneously manipulating the guide to align it with the planned trajectory. Accuracy was quantitated in a phantom, and in vivo validation was demonstrated in nonhuman primates undergoing preclinical gene ( n = 5 $$ n=5 $$ ) and cell ( n = 4 $$ n=4 $$ ) delivery surgeries. RESULTS: Updates were produced at 5 Hz In 10 phantom experiments at a depth of 48 mm, the cannula tip was placed with radial error of (min, mean, max) = (0.16, 0.29, 0.68) mm. Successful in vivo delivery of payloads to all 14 targets was demonstrated across nine surgeries with depths of (min, mean, max) = (33.3, 37.9, 42.5) mm. CONCLUSION: A real-time interactive update rate was achieved, reducing operator fatigue without compromising accuracy. Qualitative interpretation of images during aiming was rendered unnecessary by objectively computing device alignment.