Flexoelectric Engineering of Bulk Photovoltaic Photodetector.

The bulk photovoltaic effect (BPVE) offers an interesting approach to generate a steady photocurrent in a single-phase material under homogeneous illumination, and it has been extensively investigated in ferroelectrics exhibiting spontaneous polarization that breaks inversion symmetry. Flexoelectricity breaks inversion symmetry via a strain gradient in the otherwise nonpolar materials, enabling manipulation of ferroelectric order without an electric field. Combining these two effects, we demonstrate active mechanical control of BPVE in suspended 2-dimensional CuInP2S6 (CIPS) that is ferroelectric yet sensitive to electric field, which enables practical photodetection with an order of magnitude enhancement in performance. The suspended CIPS exhibits a 20-fold increase in photocurrent, which can be continuously modulated by either mechanical force or light polarization. The flexoelectrically engineered photodetection device, activated by air pressure and without any optimization, possesses a responsivity of 2.45 × 10-2 A/W and a detectivity of 1.73 × 1011 jones, which are superior to those of ferroelectric-based photodetection and comparable to those of the commercial Si photodiode.

Integrated transcriptomic and metabolomic analyses reveals anthocyanin biosynthesis in leaf coloration of quinoa (Chenopodium quinoa Willd.).

BACKGROUND: Quinoa leaves demonstrate a diverse array of colors, offering a potential enhancement to landscape aesthetics and the development of leisure-oriented sightseeing agriculture in semi-arid regions. This study utilized integrated transcriptomic and metabolomic analyses to investigate the mechanisms underlying anthocyanin synthesis in both emerald green and pink quinoa leaves. RESULTS: Integrated transcriptomic and metabolomic analyses indicated that both flavonoid biosynthesis pathway (ko00941) and anthocyanin biosynthesis pathway (ko00942) were significantly associated with anthocyanin biosynthesis. Differentially expressed genes (DEGs) and differentially accumulated metabolites (DAMs) were analyzed between the two germplasms during different developmental periods. Ten DEGs were verified using qRT-PCR, and the results were consistent with those of the transcriptomic sequencing. The elevated expression of phenylalanine ammonia-lyase (PAL), chalcone synthase (CHS), 4-coumarate CoA ligase (4CL) and Hydroxycinnamoyltransferase (HCT), as well as the reduced expression of flavanone 3-hydroxylase (F3H) and Flavonol synthase (FLS), likely cause pink leaf formation. In addition, bHLH14, WRKY46, and TGA indirectly affected the activities of CHS and 4CL, collectively regulating the levels of cyanidin 3-O-(3'', 6''-O-dimalonyl) glucoside and naringenin. The diminished expression of PAL, 4CL, and HCT decreased the formation of cyanidin-3-O-(6"-O-malonyl-2"-O-glucuronyl) glucoside, leading to the emergence of emerald green leaves. Moreover, the lowered expression of TGA and WRKY46 indirectly regulated 4CL activity, serving as another important factor in maintaining the emerald green hue in leaves N1, N2, and N3. CONCLUSION: These findings establish a foundation for elucidating the molecular regulatory mechanisms governing anthocyanin biosynthesis in quinoa leaves, and also provide some theoretical basis for the development of leisure and sightseeing agriculture.

Allergens induce upregulated IL-18 and IL-18Rα expression in blood Th2 and Th17 cells of patients with allergic asthma.

Allergic asthma (AA) is closely associated with the polarization of T helper (Th)2 and Th17 cells. Interleukin (IL)-18 acts as an inducer of Th2 and Th17 cell responses. However, expressions of IL-18 and IL-18 receptor alpha (IL-18Rα) in blood Th2 and Th17 cells of patients with AA remain unclear. We therefore investigated their expressions in Th2 and Th17 cells using flow cytometric analysis, quantitative real-time PCR (qPCR), and murine AA model. We observed increased proportions of Th2, Th17, IL-18+, IL-18+ Th2, and IL-18+ Th17 cells in blood CD4+ T cells of patients with AA. Additionally, house dust mite seemed to upregulate further IL-18 expression in Th2 and Th17, and upregulate IL-18Rα expression in CD4+ T, Th2, and Th17 cells of AA patients. It was also found that the plasma levels of IL-4, IL-17A, and IL-18 in AA patients were elevated, and they were correlated between each other. In ovalbumin (OVA)-induced asthma mouse (AM), we observed that the percentages of blood CD4+ T, Th2, and Th17 cells were increased. Moreover, OVA-induced AM expressed higher level of IL-18Rα in blood Th2 cells, which was downregulated by IL-18. Increased IL-18Rα expression was also observed in blood Th2 cells of OVA-induced FcεRIα-/- mice. Collectively, our findings suggest the involvement of Th2 cells in AA by expressing excessive IL-18 and IL-18Rα in response to allergen, and that IL-18 and IL-18Rα expressing Th2 cells are likely to be the potential targets for AA therapy.

Towards two-dimensional van der Waals ferroelectrics.

The discovery of ferroelectricity in two-dimensional (2D) van der Waals (vdW) materials has brought important functionalities to the 2D materials family, and may trigger a revolution in next-generation nanoelectronics and spintronics. In this Perspective, we briefly review recent progress in the field of 2D vdW ferroelectrics, focusing on the mechanisms that drive spontaneous polarization in 2D systems, unique properties brought about by the reduced lattice dimensionality and promising applications of 2D vdW ferroelectrics. We finish with an outlook for challenges that need to be addressed and our view on possible future research directions.

First-in-human validation of enzymolysis clearance strategy for decreasing renal radioactivity using modified [68Ga]Ga-HER2 Affibody.

PURPOSE: Enzymolysis clearance strategy, characterized by releasing the non-reabsorbable radioactive fragment under the specific cleavage of enzymes, is confirmed to be a safe and effective way to reduce the renal radioactivity accumulation in mice. However, the effectiveness of this strategy in humans remains unknown. Human epidermal growth factor receptor 2 (HER2) is overexpressed in various types of tumors, and radiolabeled HER2 Affibody is believed to be an attractive tool for HER2-targeted theranostics. However, its wide application is limited by the high and persistent renal uptake. In this study, we intend to validate the effectiveness of enzymolysis clearance strategy in reducing renal accumulation by using a modified HER2 Affibody. MATERIALS AND METHODS: A new HER2 Affibody ligand, NOTA-MVK-ZHER2:2891, containing a cleavable Met-Val-Lys (MVK) linker was synthesized and labeled with 68Ga. The microPET imaging study was performed in SKOV-3 tumor mice to assess the uptakes of the control ligand and the MVK one in tumors and kidneys. Seven healthy volunteers were included for biodistribution and dosimetric studies with both the control and MVK ligands performed 1 week apart. Urine and blood samples from healthy volunteers were collected for in vivo metabolism study of the two ligands. Four HER2-positive and two HER2-negative patients were recruited for [68Ga]Ga-NOTA-MVK-ZHER2:2891 PET/CT imaging at 2 and 4 h post-injection (p.i.). RESULTS: [68Ga]Ga-NOTA-MVK-ZHER2:2891 was stable both in PBS and in mouse serum. MicroPET images showed that the tumor uptake of [68Ga]Ga-NOTA-MVK-ZHER2:2891 was comparable to that of [68Ga]Ga-NOTA-ZHER2:2891 at all the time points, while the kidney uptake was significantly reduced 40 min p.i. (P < 0.05). The biodistribution study in healthy volunteers showed that the kidney uptake of MVK ligand was significantly lower than that of the control ligand at 1 h p.i. (P < 0.05), with the SUVmean of 34.3 and 45.8, respectively, while the uptakes of the two ligands in the other organs showed negligible difference. The effective doses of the MVK ligand and the control one were 26.1 and 28.7 µSv/MBq, respectively. The enzymolysis fragment of [68Ga]Ga-NOTA-Met-OH was observed in the urine samples of healthy volunteers injected with the MVK ligand, indicating that the enzymolysis clearance strategy worked in humans. The PET/CT study of patients showed that the range of SUVmax of HER2-positive lesions was 9.4-21, while that of HER2-negative lesions was 2.7-6.2, which suggested that the MVK modification did not affect the ability of ZHER2:2891 structure to bind with HER2. CONCLUSION: We for the first time demonstrated that enzymolysis clearance strategy can effectively reduce renal radioactivity accumulation in humans. This strategy is expected to decrease renal radiation dose of peptide and small protein-based radiotracers, especially in the field of radionuclide therapy.

Effects of polycyclic aromatic hydrocarbons on the gut-testis axis.

Polycyclic aromatic hydrocarbons (PAHs) are a large group of organic compounds which are comprised of two or more fused benzene rings. As a typical environmental pollutant, PAHs are widely distributed in water, soil, atmosphere and food. Despite extensive researches on the mechanisms of health damage caused by PAHs, especially their carcinogenic and mutagenic toxicity, there is still a lack of comprehensive summarization and synthesis regarding the mechanisms of PAHs on the gut-testis axis, which represents an intricate interplay between the gastrointestinal and reproductive systems. Thus, this review primarily focuses on the potential forms of interaction between PAHs and the gut microbiota and summarizes their adverse outcomes that may lead to gut microbiota dysbiosis, then compiles the possible mechanistic pathways on dysbiosis of the gut microbiota impairing the male reproductive function, in order to provide valuable insights for future research and guide further exploration into the intricate mechanisms underlying the impact of gut microbiota dysbiosis caused by PAHs on male reproductive function.

Naringenin mitigates cadmium-induced cell death, oxidative stress, mitochondrial dysfunction, and inflammation in KGN cells by regulating the expression of sirtuin-1.

The objective of this study was to examine the potential protective role of naringenin against the harmful effects induced by cadmium in KGN cell line. Cell viability was evaluated by cell counting kit-8 assay. Caspase-3/-9 activities were determined by caspase-3/-9 activity assay kits, respectively. Intracellular reactive oxygen species (ROS) level was detected by ROS-Glo™ H2O2 Assay, antioxidant capacity was determined by a total antioxidant capacity assay kit. Mitochondrial membrane potential (MMP), ATP level, and ATP synthase activity were determined by JC-1, ATP assay kit, and ATP synthase activity assay kit, respectively. The mRNA expression was determined by qRT-PCR. Cadmium reduced cell viability and increased caspase-3/-9 activities in a concentration-dependent manner. Naringenin improved cell viability and reduced caspase-3/-9 activities in cadmium-stimulated KGN cells in a concentration-dependent manner. Cadmium diminished the antioxidant capacity, increased ROS production, and induced mitochondrial dysfunction in KGN cells. These effects were ameliorated by naringenin treatment in a concentration-dependent manner. Furthermore, naringenin reduced the levels of pro-inflammatory cytokines in KGN cells exposed to cadmium. SIRT1 knockdown downregulated its expression in KGN cells and compromised the protective effects of naringenin on cell viability and caspase-3/-9 activities in cadmium-stimulated KGN cells. Naringenin prevented the reduction of MMP, ATP levels, and ATP synthase activity in cadmium-stimulated KGN cells in a concentration-dependent manner. However, these protective effects were significantly reversed by SIRT1 knockdown. In conclusion, this study suggests that naringenin protects against cadmium-induced damage by regulating oxidative stress, mitochondrial function, and inflammation in KGN cells, with SIRT1 playing a potential mediating role.

Sodium arsenite impairs sperm quality via downregulating the ZMYND15 and ZMYND10.

Zinc finger MYND-type containing 15 (ZMYND15) has been documented to play important roles in spermatogenesis, and mutants contribute to recessive azoospermia, severe oligozoospermia, non-obstructive azoospermia, teratozoospermia, even male infertility. ZMYND10 is involved in sperm motility. Whether environmental pollutants impair male fertility via regulating the expression of ZMYND15 and ZMYND10 has not been studied. Arsenic exposure results in poor sperm quality and male infertility. In order to investigate whether arsenic-induced male reproductive toxicity is related to the expression of ZMYND15, ZMYND10 and their target genes, we established a male rat model of sodium arsenite exposure-induced reproductive injury, measured sperm quality, serum hormone levels, mRNA and protein expressions of intratesticular ZMYND15 and ZMYND10 as well as their target genes. The results showed that, in addition to the increased mRNA expression of Tnp1, sodium arsenite exposure reduced sperm quality, serum hormone levels, and mRNA and protein expression of intratesticular ZMYND15 and ZMYND10 and their target genes in male rats compared with the control group (p < .05). Therefore, our study first showed that the environmental pollutant arsenic impairs sperm quality in male rats by reducing the expression of ZMYND10 and ZMYND15 and their regulatory genes, which provides a possible diagnostic marker for environmental pollutants-induced male infertility.

The effects of medication therapy management on medication utilization among Medicare beneficiaries with HIV/AIDS.

BACKGROUND: Medicare Part D plans are required to provide medication therapy management (MTM) programs to eligible beneficiaries to optimize medication utilization. MTM programs' effects on medication utilization among older persons living with HIV/AIDS (PLWHs) remain unclear. OBJECTIVE: This study examined the effects of the Medicare MTM programs on medication utilization among PLWHs. METHODS: This study analyzed 2017 Medicare databases linked to the Area Health Resources Files. Recipients and nonrecipients of the MTM services were compared on their medication utilization: adherence to antiretroviral medications, drug-drug interactions (DDI), and concurrent use of opioids and benzodiazepines. The intervention group comprised recipients of the MTM services, and the control group was nonrecipients meeting the eligibility criteria. A propensity score with a ratio of 1:2 between the intervention and control groups was used to identify study groups with balanced characteristics. A logistic regression was used to control for patient/community characteristics. RESULTS: After matching, the intervention and comparison groups comprised 3298 and 6596 beneficiaries for the antiretroviral adherence measure, 809 and 1618 for the DDI measure, and 691 and 1382 for the concurrent use of opioids and benzodiazepines measure. The intervention was associated with higher odds of adherence to antiretroviral medications (adjusted odds ratio = 1.15, 95% CI = 1.04-1.26), and no concurrent use of opioids and benzodiazepines (adjusted odds ratio = 1.255, 95% CI = 1.005-1.568). The study groups did not differ on no DDI (adjusted odds ratio = 0.95, 95% CI = 0.74-1.20). CONCLUSIONS: Medicare MTM programs effectively improved medication utilization among PLWHs. Future studies should explore the long-term effects of the program.

A detection model of cognitive impairment via the integrated gait and eye movement analysis from a large Chinese community cohort.

INTRODUCTION: Whether the integration of eye-tracking, gait, and corresponding dual-task analysis can distinguish cognitive impairment (CI) patients from controls remains unclear. METHODS: One thousand four hundred eighty-one participants, including 724 CI and 757 controls, were enrolled in this study. Eye movement and gait, combined with dual-task patterns, were measured. The LightGBM machine learning models were constructed. RESULTS: A total of 105 gait and eye-tracking features were extracted. Forty-six parameters, including 32 gait and 14 eye-tracking features, showed significant differences between two groups (P < 0.05). Of these, the Gait_3Back-TurnTime and Dual-task cost-TurnTime patterns were significantly correlated with plasma phosphorylated tau 181 (p-tau181) level. A model based on dual-task gait, dual-task smooth pursuit, prosaccade, and anti-saccade achieved the best area under the receiver operating characteristics curve (AUC) of 0.987 for CI detection, while combined with p-tau181, the model discriminated mild cognitive impairment from controls with an AUC of 0.824. DISCUSSION: Combining dual-task gait and dual-task eye-tracking analysis is feasible for the detection of CI. HIGHLIGHTS: This is the first study to report the efficiency of integrated parameters of dual-task gait and eye-tracking for cognitive impairment (CI) detection in a large cohort. We identified 46 gait and eye-tracking features associated with CI, and two were correlated to plasma phosphorylated tau 181. We constructed the model based on dual-task gait, smooth pursuit, prosaccade, and anti-saccade, achieving the best area under the curve of 0.987 for CI detection.

Clinical nursing mentors' motivation, attitude, and practice for mentoring and factors associated with them.

OBJECTIVE: To investigate the motivation, attitude, and practice toward mentoring and related factors among clinical nursing mentors. METHODS: This cross-sectional study included clinical nursing mentors from 30 hospitals in Zhejiang Province between August and September 2023. Demographic information, motivation, attitude, and practice were collected through a self-administered questionnaire. RESULTS: A total of 495 valid questionnaires were collected, and most of the participants were 30-39 years old (68.7%). Average motivation, attitude, and practice scores were 29 [26, 32] (possible range: 8-40), 87 (82, 94) (possible range: 22-110), and 41 (38, 45) (possible range: 11-55), respectively. Correlation analyses showed that the motivation scores were positively correlated with attitude scores (r = 0.498, P < 0.001) and practice scores (r = 0.408, P = 0.001), while attitude scores were positively correlated with practice scores (r = 0.554, P < 0.001). Multivariate logistic regression showed that intermediate and senior nursing mentors (OR = 0.638, 95% CI: [0.426-0.956], P = 0.030) and different hospitals (OR = 1.627, 95% CI: [1.054-2.511], P = 0.028) were independently associated with motivation. The hospital's frequency of psychological care was a significant factor associated with nursing mentoring motivation, attitude, and practice. Participation in training (OR = 2.908, 95% CI: [1.430, 5.913], P = 0.003) and lower frequency of job evaluation in hospital ("Often": OR = 0.416, 95% CI: [0.244-0.709], P = 0.001 and "Sometimes": OR = 0.346, 95% CI: [0.184-0.650], P = 0.001) were independently associated with practice. CONCLUSION: Clinical nursing mentors had adequate motivation, positive attitude, and proactive practice towards mentoring and associated factors. Clinical nursing mentorship should be enhanced by prioritizing mentor training, fostering a supportive environment with consistent psychological care, and promoting structured mentorship activities.

Dysconnectivity of the parafascicular nucleus in Parkinson's disease: A dynamic causal modeling analysis.

BACKGROUND: Recent animal model studies have suggested that the parafascicular nucleus has the potential to be an effective deep brain stimulation target for Parkinson's disease. However, our knowledge on the role of the parafascicular nucleus in Parkinson's disease patients remains limited. OBJECTIVE: We aimed to investigate the functional alterations of the parafascicular nucleus projections in Parkinson's disease patients. METHODS: We enrolled 72 Parkinson's disease patients and 60 healthy controls, then utilized resting-state functional MRI and spectral dynamic causal modeling to explore the effective connectivity of the bilateral parafascicular nucleus to the dorsal putamen, nucleus accumbens, and subthalamic nucleus. The associations between the effective connectivity of the parafascicular nucleus projections and clinical features were measured with Pearson partial correlations. RESULTS: Compared with controls, the effective connectivity from the parafascicular nucleus to dorsal putamen was significantly increased, while the connectivity to the nucleus accumbens and subthalamic nucleus was significantly reduced in Parkinson's disease patients. There was a significantly positive correlation between the connectivity of parafascicular nucleus-dorsal putamen projection and motor deficits. The connectivity from the parafascicular nucleus to the subthalamic nucleus was negatively correlated with motor deficits and apathy, while the connectivity from the parafascicular nucleus to the nucleus accumbens was negatively associated with depression. CONCLUSION: The present study demonstrates that the parafascicular nucleus-related projections are damaged and associated with clinical symptoms of Parkinson's disease. Our findings provide new insights into the impaired basal ganglia-thalamocortical circuits and give support for the parafascicular nucleus as a potential effective neuromodulating target of the disease.

Downregulation of TOP2 modulates neurodegeneration caused by GGGGCC expanded repeats.

GGGGCC repeats in a non-coding region of the C9orf72 gene have been identified as a major genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. We previously showed that the GGGGCC expanded repeats alone were sufficient to cause neurodegeneration in Drosophila. Recent evidence indicates that GGGGCC expanded repeats can modify various gene transcriptomes. To determine the role of these genes in GGGGCC-mediated neurotoxicity, we screened an established Drosophila model expressing GGGGCC expanded repeats in this study. Our results showed that knockdown of the DNA topoisomerase II (Top2) gene can specifically modulate GGGGCC-associated neurodegeneration of the eye. Furthermore, chemical inhibition of Top2 or siRNA-induced Top2 downregulation could alleviate the GGGGCC-mediated neurotoxicity in Drosophila assessed by eye neurodegeneration and locomotion impairment. By contrast, upregulated Top2 levels were detected in Drosophila strains, and moreover, TOP2A level was also upregulated in Neuro-2a cells expressing GGGGCC expanded repeats, as well as in the brains of Sod1G93A model mice. This indicated that elevated levels of TOP2A may be involved in a pathway common to the pathophysiology of distinct ALS forms. Moreover, through RNA-sequencing, a total of 67 genes, involved in the pathways of intracellular signaling cascades, peripheral nervous system development, and others, were identified as potential targets of TOP2A to modulate GGGGCC-mediated neurodegeneration.

Common and unique dysconnectivity profiles of dorsal and median raphe in Parkinson's disease.

The serotonergic (5-HT) system, which undergoes degeneration in Parkinson's disease (PD), is involved in the pathogenesis of motor and nonmotor symptoms. The dorsal raphe (DR) and median raphe (MR) nuclei are the main source of 5-HT neurons, however, brain connectivity changes in these two nuclei have not been delineated in PD. Here we used resting-state fMRI (rs-fMRI) to characterize functional connectivity profiles of DR and MR and further examine the associations between dysconnectivity of raphe nuclei and clinical phenotypes of PD. We found that DR and MR commonly hypo-connected with the sensorimotor, temporal, and occipital cortex, limbic system, left thalamus, putamen, and cerebellum in PD. DR had unique decreased connectivity with the bilateral prefrontal and cingulate cortices, while MR had lower connectivity with the pons. Moreover, reduced connectivity of DR correlated with depression, drowsiness, and anxiety, whereas dysconnectivity of MR correlated with depression, cognitive deficits, sleep disturbances, and pain. Our findings highlight the complex roles of raphe nuclei in motor and nonmotor symptoms, providing novel insights into the neurophysiological mechanisms underlying pathogenesis of PD.

Interleukin-17 Receptor E and C-C Motif Chemokine Receptor 10 Identify Heterogeneous T Helper 17 Subsets in a Mouse Dry Eye Disease Model.

Dry eye disease (DED) features the inflammatory response of the ocular surface. Pro-inflammatory T helper 17 (Th17) cells are important for the pathogenesis of DED. In the present study a mouse DED model was used to discover two Th17 subsets in draining lymph nodes and conjunctivae based on the expression of IL-17 receptor E (IL-17RE) and CCR10: IL-17RElowCCR10- Th17 and IL-17REhighCCR10+ Th17. IL-17REhighCCR10+ Th17 expressed more retinoic acid-related orphan receptor gamma t but fewer T-box-expressed-in-T-cells than IL-17RElowCCR10- Th17. In addition, the former expressed higher IL-17A, IL-21, and IL-22 but fewer IFN-γ than the latter. Further analysis showed that IL-17REhighCCR10+ Th17 did not express IFN-γ in vivo, whereas IL-17RElowCCR10- Th17 contained IFN-γ-expressing Th17/Th1 cells. Moreover, IL-17REhighCCR10+ Th17 possessed more phosphorylated p38 mitogen-activated protein kinase (MAPK) and Jnk than IL-17RElowCCR10- Th17, suggesting higher activation of MAPK signaling in IL-17REhighCCR10+ Th17. In vitro treatment with IL-17C effectively maintained IL-17A expression in Th17 cells through p38 MAPK rather than Jnk MAPK. Furthermore, the adoptive transfer of the two Th17 subpopulations indicated their equivalent pathogenicity in DED. Interestingly, IL-17REhighCCR10+ Th17 cells were able to phenotypically polarize to IL-17RElowCCR10- Th17 cells in vivo. In conclusion, the current study revealed novel Th17 subsets with differential phenotypes, functions, and signaling status in DED, thus deepening the understanding of Th17 pathogenicity, and exhibited Th17 heterogeneity in DED.

Compound heterozygous variants of THG1L result in autosomal recessive cerebellar ataxia.

tRNA-histidine guanyltransferase 1-like protein (THG1L), located in the mitochondria, plays a crucial role in the tRNA maturation process. Dysfunction of THG1L results in abnormal mitochondrial tRNA modification and neurodevelopmental disorders. To date, few studies have focused on THG1L-related cerebellar ataxia. Whole-exome sequencing revealed compound heterozygous variants NM_017872.5: [c.224A > G]; [c.369-8T > G] in THG1L in a 6-year-old boy with moderate cerebellar ataxia. The variant c.224A > G was demonstrated to downregulate its RNA and protein expression, and c.369-8 T > G resulted in a 7 bp insertion before exon 3. Our case expanded the gene variation and clinical spectrum of THG1L-related cerebellar ataxia.

Leigh Syndrome: A Study of 209 Patients at the Beijing Children's Hospital.

OBJECTIVE: Leigh syndrome (LS) is a heterogeneous neurodegenerative disease and the most frequent pediatric manifestation of mitochondrial disease. In the largest patient collection to date, this study aimed to provide new insights into the clinical and genetic spectrum of LS, defect-specific associations, and predictors of disease course and survival. METHODS: Clinical, metabolic, neuroimaging, onset, and survival data were collected from the medical records of 209 patients referred to the Beijing Children's Hospital with symmetrical basal ganglia and/or brainstem neuroimaging changes indicative of LS by 30 centers from the Chinese network of mitochondrial disease (mitoC-NET) between January 2013 and July 2021 for exploratory analysis. RESULTS: Pathogenic variants were identified in 52 genes, most frequently MT-ATP6, SURF1, and PDHA1. Maternally inherited variants accounted for 42% (heteroplasmy level ≥90% in 64%). Phenotypes spanned 92 Human Phenotype Ontology terms. Elevated serum lactate (144/195), global developmental delay (142/209), and developmental regression (103/209) were most frequent. Discriminating neuroimaging and/or clinical features were identified for MT-ATP6 (m.9176T>C), MT-ND5, PDHA1, SUCLG1, and SURF1. Poorest survival was associated with MT-ND5, MT-ATP6 (m.8993T>C and m.9176T>C), SURF1, and ALDH5A1 (≤50% 3 year's survival), in contrast to milder defects with specific treatment (ECHS1 and SLC19A3, 100% 3 year's survival). INTERPRETATION: Our data define phenotype, onset, and survival of LS in a defect-specific manner, identifying features discriminating between genetic defects and predictive of disease outcome. These findings are essential to early diagnosis, in optimizing family counseling, and to the design and monitoring of future clinical trials, the next frontier of LS research. ANN NEUROL 2022;91:466-482.

GSN gene frameshift mutations in Alzheimer's disease.

BACKGROUND: The pathogenic missense mutations of the gelsolin (GSN) gene lead to familial amyloidosis of the Finnish type (FAF); however, our previous study identified GSN frameshift mutations existed in patients with Alzheimer's disease (AD). The GSN genotype-phenotype heterogeneity and the role of GSN frameshift mutations in patients with AD are unclear. METHOD: In total, 1192 patients with AD and 1403 controls were screened through whole genome sequencing, and 884 patients with AD were enrolled for validation. Effects of GSN mutations were evaluated in vitro. GSN, Aß42, Aß40 and Aß42/40 were detected in both plasma and cerebrospinal fluid (CSF). RESULTS: Six patients with AD with GSN P3fs and K346fs mutations (0.50%, 6/1192) were identified, who were diagnosed with AD but not FAF. In addition, 13 patients with AD with GSN frameshift mutations were found in the validation cohort (1.47%, 13/884). Further in vitro experiments showed that both K346fs and P3fs mutations led to the GSN loss of function in inhibiting Aß-induced toxicity. Moreover, a higher level of plasma (p=0.001) and CSF (p=0.005) GSN was observed in AD cases than controls, and a positive correlation was found between the CSF GSN and CSF Aß42 (r=0.289, p=0.009). Besides, the GSN level was initially increasing and then decreasing with the disease course and cognitive decline. CONCLUSIONS: GSN frameshift mutations may be associated with AD. An increase in plasma GSN is probably a compensatory reaction in AD, which is a potential biomarker for early AD.

Synaptic Loss in Spinocerebellar Ataxia Type 3 Revealed by SV2A Positron Emission Tomography.

BACKGROUND: Severe reduced synaptic density was observed in spinocerebellar ataxia (SCA) in postmortem neuropathology, but in vivo assessment of synaptic loss remains challenging. OBJECTIVE SPINOCEREBELLAR ATAXIA TYPE 3: The objective of this study was to assess in vivo synaptic loss and its clinical correlates in spinocerebellar ataxia type 3 (SCA3) patients by synaptic vesicle glycoprotein 2A (SV2A)-positron emission tomography (PET) imaging. METHODS: We recruited 74 SCA3 individuals including preataxic and ataxic stages and divided into two cohorts. All participants received SV2A-PET imaging using 18 F-SynVesT-1 for synaptic density assessment. Specifically, cohort 1 received standard PET procedure and quantified neurofilament light chain (NfL), and cohort 2 received simplified PET procedure for exploratory purpose. Bivariate correlation was performed between synaptic loss and clinical as well as genetic assessments. RESULTS: In cohort 1, significant reductions of synaptic density were observed in cerebellum and brainstem in SCA3 ataxia stage compared to preataxic stage and controls. Vermis was found significantly involved in preataxic stage compared to controls. Receiver operating characteristic (ROC) curves highlighted SV2A of vermis, pons, and medulla differentiating preataxic stage from ataxic stage, and SV2A combined with NfL improved the performance. Synaptic density was significantly negatively correlated with disease severity in cerebellum and brainstem (International Co-operative Ataxia Rating Scale: ρ ranging from -0.467 to -0.667, P ≤ 0.002; Scale of Assessment and Rating of Ataxia: ρ ranging from -0.465 to -0.586, P ≤ 0.002). SV2A reduction tendency of cerebellum and brainstem identified in cohort 1 was observed in cohort 2 with simplified PET procedure. CONCLUSIONS: We first identified in vivo synaptic loss was related to disease severity of SCA3, suggesting SV2A PET could be a promising clinical biomarker for disease progression of SCA3. © 2023 International Parkinson and Movement Disorder Society.

Heat-induced antigen retrieval utilizing modified Tris-EDTA buffer for reprobing of Western blots on nitrocellulose paper.

The development of heat-induced antigen retrieval technologies with Tris-EDTA buffer has dramatically improved immunostaining of specific antigens for routine immunohistochemical detection (Krenacs et al., 2010) [1]. However, little evidence exists on whether heat-Induced antigen retrieval utilizing Tris-EDTA buffer can strip western blot (WB) membranes and allow sequential reprobing. Here, we serendipitously discover that ∼95 °C Tris-EDTA buffer with 0.01% Tween 20 could repeatedly strip the Nitrocellulose membranes (NC). After electroblotting, NC blots were soaked into Tris-EDTA stripping buffer (∼95 °C, 10-25min) and we could perform at least five rounds (the following antibodies used: Vinculin, Atg7, Caspase-3, UBA5, JNK and ERK1/2) stripping in sequential chemiluminescent detections. The NC membranes also show clear western signals and background without losing transferred proteins during the reprobing process of WB. Hence, this study report additional new roles of the heat-Induced antigen retrieval Tris-EDTA buffer with 0.01% Tween 20. The method is simpler, more affordable and harmless for the nitrocellulose paper, which will be helpful for effective reprobing in western blotting applications.