Femtogram-Sensitive Cantilever Platform for Dynamic Graphene Oxide Nanosheet Monitoring.

This study introduces a new approach to optimizing graphene oxide (GO) properties using liquid-phase plasma treatment in a microenvironment. Our innovation exploits atomic force microscopy (AFM) cantilever frequency tracking to monitor mass variations in GO, which are indicative of surface oxidation-reduction processes or substituent doping (boron/nitrogen). Complementary in situ Raman spectroscopy has observed D/G band shifts, and X-ray photoelectron spectroscopy (XPS) determined the C/O ratio and B/N doping levels pre- and post-treatment, confirming chemical tuning to GO. We can achieve femtogram-level precision in detecting nanomaterial mass changes by correlating elemental ratios with AFM cantilever frequency measurements. This multifaceted approach not only enhances our understanding of the chemical properties of GO but also establishes a new, versatile method for monitoring, modifying, and optimizing the properties of nanomaterials.

Dynamic changes in quality of life in older patients with chronic obstructive pulmonary disease: a 7-year follow up.

PURPOSES: Chronic obstructive pulmonary disease (COPD) is a major cause of the rapid decline of health-related quality of life (HRQoL), associated with accelerated frailty in older populations. This study aimed to analyse the long-term dynamic changes of HRQoL and the predictive factors for the rapid decline of HRQoL in older patients with COPD. METHODS: Overall 244 patients with COPD, aged ≧ 65 years from one medical centre were enrolled between March 2012 and July 2020. Further, we prospectively assessed HRQoL scores with utility values, using EuroQol Five-Dimension (EQ-5D) questionnaires. Additionally, long-term dynamic changes in HRQoL were analysed using the Kernel smoothing method and examined the factors contributing to the deterioration of HRQoL using a linear mixed effects model. RESULTS: Older patients with COPD with forced expiration volume (FEV1) < 50% of prediction entered the phase of rapid and continuous decline of HRQoL ~ 2 years after enrolment, but patients with FEV1 ≥ 50% of prediction without rapidly declined HRQoL during 7 years follow up. Therefore, FEV1 < 50% of prediction is a novel predictor for the rapid decline of HRQoL. The course of rapidly declining HRQoL occurred, initially in the usual activities and pain/discomfort domains, followed by the morbidity, self-care, and depression/anxiety domains ~ 2 and 4 years after enrolment, respectively. The mixed effects model indicated that both FEV1 < 50% of prediction and a history of severe acute exacerbation (SAE) requiring hospitalisation were contributing factors for deterioration in HRQoL . CONCLUSIONS: Both FEV1 < 50% of prediction and exacerbations requiring hospitalisation were contributing factors for the deterioration of HRQoL in long-term follow up. Additionally, FEV1 < 50% of prediction was a novel predictor for patients entering the phase of rapid decline of HRQoL.

Purkinje Cell Dendritic Swellings: A Postmortem Study of Essential Tremor and Other Cerebellar Degenerative Disorders.

Under stress, Purkinje cells (PCs) undergo a variety of reactive morphological changes. These can include swellings of neuronal processes. While axonal swellings, "torpedoes", have been well-studied, dendritic swellings (DS) have not been the centerpiece of study. Surprisingly little is known about their frequency or relationship to other morphological changes in degenerating PCs. Leveraging a large brain bank, we (1) examined the morphology of DS, (2) quantified DS, and (2) examined correlations between counts of DS versus 16 other PC morphological changes in a broad range of cerebellar degenerative disorders. There were 159 brains - 100 essential tremor (ET), 13 Friedreich's ataxia, and 46 spinocerebellar ataxia (SCA) (14 SCA1, 7 SCA2, 13 SCA3, 5 SCA6, 5 SCA7, and 2 SCA8). DS were a feature of PCs across all these disorders, with varying morphologies and changes elsewhere in the dendritic arbor. On Luxol fast blue/hematoxylin and eosin-stained sections, the median number of DS per PC ranged from 0.001 in ET to 0.025 in SCA8. Bielschowsky-stained sections yielded higher counts, from 0.003 in ET to 0.042 in SCA6. Torpedo counts exceeded DS counts by one order of magnitude. DS counts were more robustly correlated with torpedo counts than with counts for any of the other PC morphological changes. In summary, DS ranged in prevalence across cerebellar degenerative disorders, from 1/1,000 to 42/1,000 PCs. Across disorders of cerebellar degeneration, these swellings of the dendritic compartment were most robustly correlated with swellings of the axonal compartment, suggesting a similar type of cellular response to duress.

Effects of Low-Frequency Deep Brain Stimulation in Bilateral Zona Incerta for a Patient With Tremor and Cerebellar Ataxia.

Background: Whether low-frequency deep brain stimulation (DBS) in the caudal zona incerta (cZi) can improve cerebellar ataxia symptoms remains unexplored. Case Report: We report a 66-year-old man initially diagnosed with essential tremor and subsequently developed cerebellar ataxia after bilateral cZi DBS implantation. We tested the effects of low-frequency DBS stimulations (sham, 10 Hz, 15 Hz, 30 Hz) on ataxia severity. Discussion: Low-frequency cZi DBS improves ataxic speech at 30 Hz, but not at 10 Hz or 15 Hz in this patient. Low-frequency DBS did not improve gait or stance. Therefore, low-frequency stimulation may play a role in treating ataxic speech. Highlights: The finding of this case study suggests that bilateral low-frequency DBS at 30 Hz in the caudal zona incerta has the potential to improve ataxic speech but has limited impact on gait and stance. The involvement of zona incerta in speech warrants further investigation.

The cerebellum computes frequency dynamics for motions with numerical precision and cross-individual uniformity.

Cross-individual variability is considered the essence of biology, preventing precise mathematical descriptions of biological motion1-7 like the physics law of motion. Here we report that the cerebellum shapes motor kinematics by encoding dynamic motor frequencies with remarkable numerical precision and cross-individual uniformity. Using in-vivo electrophysiology and optogenetics in mice, we confirmed that deep cerebellar neurons encoded frequencies via populational tuning of neuronal firing probabilities, creating cerebellar oscillations and motions with matched frequencies. The mechanism was consistently presented in self-generated rhythmic and non-rhythmic motions triggered by a vibrational platform, or skilled tongue movements of licking in all tested mice with cross-individual uniformity. The precision and uniformity allowed us to engineer complex motor kinematics with designed frequencies. We further validated the frequency-coding function of the human cerebellum using cerebellar electroencephalography recordings and alternating-current stimulation during voluntary tapping tasks. Our findings reveal a cerebellar algorithm for motor kinematics with precision and uniformity, the mathematical foundation for brain-computer interface for motor control.

Hepatic and metabolic outcomes induced by sub-chronic exposure to polystyrene microplastics in mice.

Microplastics (MPs) have attracted significant attention due to their global distribution in living environments. Although some studies have reported MP-induced hepatotoxicity in mouse models, a systematic approach to MP-mediated liver toxicity was still lacking. Therefore, we used a mouse model to study the sub-chronic effects of MP exposure on the liver. Female C57BL/6 mice, aged 6 weeks, received an oral administration of 0.3 mg of Nile Red-labeled polystyrene (PS) microplastics, with particle sizes of 0.5 µm (submicron) and 5 µm (micron), via gavage, while control mice received vehicle only. Each mouse was exposed to MPs twice a week for 12 weeks. After sacrifice, the levels of MP accumulation, oxidative stress, inflammation, and pathological changes were measured in the mouse liver, and blood samples were collected for serum biochemistry analysis. Our results demonstrated that 0.5 µm PS-MPs were accumulated in mouse livers post-MP exposure, but not in the 5 µm MP exposure group. Simultaneously, increased levels of glucose, triglyceride, alanine transaminase (ALT), aspartate transaminase (AST), superoxide dismutase, 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA), interleukin-6, and lipid droplets were found in the 0.5 µm MP exposure group, while the fewer responses, including elevated liver weight index, glucose, high-density lipoprotein, AST, and decreased HNE-MA were observed in 5 µm MP exposure group. These results indicate that sub-chronic exposure to submicron MPs causes MP deposition in mouse livers, which further induces oxidative stress, increases inflammatory cytokines and perturbs glucose and lipid homeostasis, which might trigger more severe metabolic dysfunction or non-alcoholic steatohepatitis-like hepatotoxicity.

Clinical Predictors of Medication Compliance in Patients With Acute Herpetic Neuralgia.

PURPOSE: Pain is one of the most common and harmful symptoms experienced by individuals with acute herpetic neuralgia (AHN). In this population, studies to determine the causes that affect patients taking medications compliance are rare. This study aimed to construct a predictive model for medication compliance of patients with AHN and to verify its performance. DESIGN AND METHODS: In this prospective study of 398 patients with AHN who were discharged from a tertiary hospital with medications from July 2020 to October 2022, we used logistic regression analysis to explore the predictive factors of medication compliance of patients with AHN and to construct a nomogram. The area under the curve was used to evaluate the predictive effect of the model. RESULTS: A predictive model of drug compliance of patients with AHN was constructed based on the following four factors: disease duration, pain severity before treatment, medication beliefs, and comorbidity of chronic diseases. The area under the curve of the model was 0.766 (95% confidence interval [0.713, 0.819]), with a maximum Youden's index of 0.431, sensitivity of 0.776, and specificity of 0.655. A linear calibration curve was found with a slope close to 1. CONCLUSIONS: The prediction model constructed in this study had good predictive performance and provided a reference for early clinical screening of independent factors that affected the medication compliance of patients with AHN.

Oxygen Switchable Photo-Hydrovoltaic Effect along the Silicon-Water Interface.

Moving boundaries of electrical double layers have shown promising capability in driving directional electron flows in solids, leading to a range of hydrovoltaic effects. The recent discovery of a photohydrovoltaic phenomenon utilizes a moving illumination zone to generate moving boundaries with different properties at the solid-water interface, referred to as the kinetic photovoltaic effect. Here, oxygen was found to act as a chemical switch to turn on and off the kinetic photovoltaic effect. Introducing oxygen would rapidly diminish the kinetic photovoltage in p-Si. On the contrary, degassing oxygen leads to a gradual recovery, whose rate can be facilely speeded up by more than one order through electrostatic gating. Mechanistic investigations of the oxygen switch behavior uncovered a dependence of surface band bending intensity of silicon on oxygen adsorption, which highlights the role of gas molecules, often overlooked, in applications based on semiconductor-liquid interfaces, such as photoelectrochemistry.

SARA captures disparate progression and responsiveness in spinocerebellar ataxias.

BACKGROUND: The Scale for Assessment and Rating of Ataxia (SARA) is a widely used clinical scale to assess cerebellar ataxia but faces some criticisms about the relevancy of all its items. OBJECTIVES: To prepare for future clinical trials, we analyzed the progression of SARA and its items in several polyQ spinocerebellar ataxias (SCA) from various cohorts. METHODS: We included data from patients with SCA1, SCA2, SCA3, and SCA6 from four cohorts (EUROSCA, RISCA, CRC-SCA, and SPATAX) for a total of 850 carriers and 3431 observations. Longitudinal progression of the SARA and its items was measured. Cohort, stage and genetic effects were tested. We looked at the respective contribution of each item to the total scale. Sensitivity to change of the scale and the impact of item removal was evaluated by calculating sample sizes needed in various scenarios. RESULTS: Longitudinal progression was significantly different between cohorts in SCA1, SCA2 and SCA3, the EUROSCA cohort having the fastest progression. Advanced-stage patients were progressing slower in SCA2 and SCA6. Items were not contributing equally to the full scale through ataxia severity: gait, stance, hand movement, and heel-shin contributed the most in the early stage, and finger-chase, nose-finger, and sitting in later stages. Few items drove the sensitivity to the change of SARA, but changes in the scale structure could not improve its sensitivity in all populations. CONCLUSION: SARA and its item's progression pace showed high heterogeneity across cohorts and SCAs. However, no combinations of items improved the responsiveness in all SCAs or populations taken separately.

Content Validity of the Modified Functional Scale for the Assessment and Rating of Ataxia (f-SARA) Instrument in Spinocerebellar Ataxia.

The functional Scale for the Assessment and Rating of Ataxia (f-SARA) assesses Gait, Stance, Sitting, and Speech. It was developed as a potentially clinically meaningful measure of spinocerebellar ataxia (SCA) progression for clinical trial use. Here, we evaluated content validity of the f-SARA. Qualitative interviews were conducted among individuals with SCA1 (n = 1) and SCA3 (n = 6) and healthcare professionals (HCPs) with SCA expertise (USA, n = 5; Europe, n = 3). Interviews evaluated symptoms and signs of SCA and relevance of f-SARA concepts for SCA. HCP cognitive debriefing was conducted. Interviews were recorded, transcribed, coded, and analyzed by ATLAS.TI software. Individuals with SCA1 and 3 reported 85 symptoms, signs, and impacts of SCA. All indicated difficulties with walking, stance, balance, speech, fatigue, emotions, and work. All individuals with SCA1 and 3 considered Gait, Stance, and Speech relevant f-SARA concepts; 3 considered Sitting relevant (42.9%). All HCPs considered Gait and Speech relevant; 5 (62.5%) indicated Stance was relevant. Sitting was considered a late-stage disease indicator. Most HCPs suggested inclusion of appendicular items would enhance clinical relevance. Cognitive debriefing supported clarity and comprehension of f-SARA. Maintaining current abilities on f-SARA items for 1 year was considered meaningful for most individuals with SCA1 and 3. All HCPs considered meaningful changes as stability in f-SARA score over 1-2 years, 1-2-point change in total f-SARA score, and deviation from natural history. These results support content validity of f-SARA for assessing SCA disease progression in clinical trials.

Reduced sensitivity to future consequences underlies gambling decision in cerebellar ataxia.

INTRODUCTION: Previous research has identified that people with cerebellar ataxia (CA) showed impaired reward-related decision-making in the Iowa Gambling Task (IGT). To investigate the mechanisms underlying this impairment, we examined CA participants' combination of performance in the IGT, which predominantly tests reward seeking, and the modified IGT (mIGT), which mainly assesses punishment avoidance. METHODS: Fifty participants with CA and one hundred controls completed the IGT and mIGT. Task performance in each of the five twenty-trial blocks was compared between groups and the learning rates were assessed with simple linear regressions. Each participant's IGT score and mIGT score were compared. RESULTS: CA participants performed worse than controls in both the IGT and the mIGT, especially in the last block (IGT: -0.24 ± 10.05 vs. 3.88 ± 10.31, p = 0.041; mIGT: 2.72 ± 7.62 vs. 8.65 ± 8.64, p < 0.001). In contrast to the controls, those with CA did not significantly improve their scores over time in either task. Controls performed better in the mIGT than the IGT, while CA participants' scores in the two tasks showed no significant difference. IGT and mIGT performance did not correlate with ataxia severity or depressive symptoms. CONCLUSION: Individuals with CA showed impaired performance in both the IGT and mIGT, which indicates disruption in both short-term reward seeking and short-term punishment avoidance. Therefore, these results suggest that reduced sensitivity to long-term consequences drives the risky decision-making in CA.

Validation of a New Patient-Reported Outcome Measure of the Functional Impact of Essential Tremor on Activities of Daily Living.

Background: The Essential Tremor Rating Assessment Scale (TETRAS) is a popular scale for essential tremor (ET), but its activities of daily living (ADL) and performance (P) subscales are based on a structured interview and physical exam. No patient-reported outcome (PRO) scale for ET has been developed according to US regulatory guidelines. Objective: Develop and validate a TETRAS PRO subscale. Methods: Fourteen items, rated 0-4, were derived from TETRAS ADL and structured cognitive interviews of 18 ET patients. Convergent validity analyses of TETRAS PRO versus TETRAS ADL, TETRAS-P, and the Quality of Life in Essential Tremor Questionnaire (QUEST) were computed for 67 adults with ET or ET plus. Test-retest reliability was computed at intervals of 1 and 30 days. The influence of mood (Hospital Anxiety and Depression Scale, HADS) and coping behaviors (Essen Coping Questionnaire, ECQ) was examined with multiple linear regression. Results: TETRAS PRO was strongly correlated (r > 0.7) with TETRAS ADL, TETRAS-P, and QUEST and exhibited good to excellent reliability (Cronbach alpha 95%CI = 0.853-0.926; 30-day test-retest intraclass correlation 95%CI = 0.814-0.921). The 30-day estimate of minimum detectable change (MDC) was 6.6 (95%CI 5.2-8.0). TETRAS-P (rsemipartial = 0.607), HADS depression (rsemipartial = 0.384), and the coping strategy of information seeking and exchange of experiences (rsemipartial = 0.176) contributed statistically to TETRAS PRO in a multiple linear regression (R2 = 0.67). Conclusions: TETRAS PRO is a valid and reliable scale that is influenced strongly by tremor severity, moderately by mood (depression), and minimally by coping skills. The MDC for TETRAS PRO is probably sufficient to detect clinically important change.

Consensus Paper: Cerebellum and Reward.

Cerebellum is a key-structure for the modulation of motor, cognitive, social and affective functions, contributing to automatic behaviours through interactions with the cerebral cortex, basal ganglia and spinal cord. The predictive mechanisms used by the cerebellum cover not only sensorimotor functions but also reward-related tasks. Cerebellar circuits appear to encode temporal difference error and reward prediction error. From a chemical standpoint, cerebellar catecholamines modulate the rate of cerebellar-based cognitive learning, and mediate cerebellar contributions during complex behaviours. Reward processing and its associated emotions are tuned by the cerebellum which operates as a controller of adaptive homeostatic processes based on interoceptive and exteroceptive inputs. Lobules VI-VII/areas of the vermis are candidate regions for the cortico-subcortical signaling pathways associated with loss aversion and reward sensitivity, together with other nodes of the limbic circuitry. There is growing evidence that the cerebellum works as a hub of regional dysconnectivity across all mood states and that mental disorders involve the cerebellar circuitry, including mood and addiction disorders, and impaired eating behaviors where the cerebellum might be involved in longer time scales of prediction as compared to motor operations. Cerebellar patients exhibit aberrant social behaviour, showing aberrant impulsivity/compulsivity. The cerebellum is a master-piece of reward mechanisms, together with the striatum, ventral tegmental area (VTA) and prefrontal cortex (PFC). Critically, studies on reward processing reinforce our view that a fundamental role of the cerebellum is to construct internal models, perform predictions on the impact of future behaviour and compare what is predicted and what actually occurs.

Neuronal population activity in the olivocerebellum encodes the frequency of essential tremor in mice and patients.

Essential tremor (ET) is the most prevalent movement disorder, characterized primarily by action tremor, an involuntary rhythmic movement with a specific frequency. However, the neuronal mechanism underlying the coding of tremor frequency remains unexplored. Here, we used in vivo electrophysiology, optogenetics, and simultaneous motion tracking in the Grid2dupE3 mouse model to investigate whether and how neuronal activity in the olivocerebellum determines the frequency of essential tremor. We report that tremor frequency was encoded by the temporal coherence of population neuronal firing within the olivocerebellums of these mice, leading to frequency-dependent cerebellar oscillations and tremors. This mechanism was precise and generalizable, enabling us to use optogenetic stimulation of the deep cerebellar nuclei to induce frequency-specific tremors in wild-type mice or alter tremor frequencies in tremor mice. In patients with ET, we showed that deep brain stimulation of the thalamus suppressed tremor symptoms but did not eliminate cerebellar oscillations measured by electroencephalgraphy, indicating that tremor-related oscillations in the cerebellum do not require the reciprocal interactions with the thalamus. Frequency-disrupting transcranial alternating current stimulation of the cerebellum could suppress tremor amplitudes, confirming the frequency modulatory role of the cerebellum in patients with ET. These findings offer a neurodynamic basis for the frequency-dependent stimulation of the cerebellum to treat essential tremor.

Advances in precision therapy of low-grade serous ovarian cancer: A review.

Low-grade serous ovarian carcinoma (LGSOC) is a rare subtype of ovarian cancer that accounts for approximately 6% to 10% of serous ovarian cancers. The clinical treatment of LGSOC is similar to that of high-grade serous ovarian carcinoma, however, its clinical and molecular characteristics are different from those of high-grade serous ovarian carcinoma. This article reviews the research on gene diagnosis, surgical treatment, chemotherapy, and biological therapy of LGSOC, providing reference for clinical diagnosis and treatment of LGSOC. Surgery is the cornerstone of LGSOC treatment and maximum effort must be made to achieve R0 removal. Although LGSOC is not sensitive to chemotherapy, postoperative platinum-based combination chemotherapy remains the first-line treatment option for LGSOC. Additional clinical trials are needed to confirm the clinical benefits of chemotherapy and explore new chemotherapy protocols. Hormone and targeted therapies may also play important roles. Some patients, particularly those with residual lesions after treatment, may benefit from hormone maintenance therapy after chemotherapy. Targeted therapies, such as MEKi, show good application prospects and are expected to change the treatment pattern of LGSOC. Continuing to further study the genomics of LGSOC, identify its specific gene changes, and combine traditional treatment methods with precision targeted therapy based on second-generation sequencing may be the direction for LGSOC to overcome the treatment bottleneck. In future clinical work, comprehensive genetic testing should be carried out for LGSOC patients to accumulate data for future scientific research, in order to find more effective methods and drugs for the treatment of LGSOC.

Lipid responses to perfluorooctane sulfonate exposure for multiple rat organs.

Perfluorooctane sulfonate (PFOS) is a persistent chemical that has long been a threat to human health. However, the molecular effects of PFOS on various organs are not well studied. In this study, male Sprague-Dawley rats were treated with various doses of PFOS through gavage for 21 days. Subsequently, the liver, lung, heart, kidney, pancreas, testis, and serum of the rats were harvested for lipid analysis. We applied a focusing lipidomic analytical strategy to identify key lipid responses of phosphorylcholine-containing lipids, including phosphatidylcholines and sphingomyelins. Partial least squares discriminant analysis revealed that the organs most influenced by PFOS exposure were the liver, kidney, and testis. Changes in the lipid profiles of the rats indicated that after exposure, levels of diacyl-phosphatidylcholines and 22:6-containing phosphatidylcholines in the liver, kidney, and testis of the rats decreased, whereas the level of 20:3-containing phosphatidylcholines increased. Furthermore, levels of polyunsaturated fatty acids-containing plasmenylcholines decreased. Changes in sphingomyelin levels indicated organ-dependent responses. Decreased levels of sphingomyelins in the liver, nonmonotonic dose responses in the kidney, and irregular responses in the testis after PFOS exposure are observed. These lipid responses may be associated with alterations pertaining to phosphatidylcholine synthesis, fatty acid metabolism, membrane properties, and oxidative stress in the liver, kidney, and testis. Lipid responses in the liver could have contributed to the observed increase in liver to body weight ratios. The findings suggest potential toxicity and possible mechanisms associated with PFOS in multiple organs.

Pathologically based criteria to distinguish essential tremor from controls: analyses of the human cerebellum.

OBJECTIVE: Essential tremor is among the most prevalent neurological diseases. Diagnosis is based entirely on neurological evaluation. Historically, there were few postmortem brain studies, hindering attempts to develop pathologically based criteria to distinguish essential tremor from control brains. However, an intensive effort to bank essential tremor brains over recent years has resulted in postmortem studies involving >200 brains, which have identified numerous degenerative changes in the essential tremor cerebellar cortex. Although essential tremor and controls have been compared with respect to individual metrics of pathology, there has been no overarching analysis to derive a combination of metrics to distinguish essential tremor from controls. We asked whether there is a constellation of pathological findings that separates essential tremor from controls, and how well that constellation performs. METHODS: Analyses included 100 essential tremor brains from the essential tremor centralized brain repository and 50 control brains. A standard tissue block from the cerebellar cortex was used to quantify 11 metrics of pathological change. Three supervised classification algorithms were investigated, with data divided into training and validation samples. RESULTS: Using three different algorithms, we illustrate the ability to correctly predict a diagnosis of essential tremor, with sensitivity and specificity >87%, and in the majority of situations, >90%. We also provide a web-based application that uses these metric values, and based on specified cutoffs, determines the likely diagnosis. INTERPRETATION: These analyses set the stage for use of pathologically based criteria to distinguish clinically diagnosed essential tremor cases from controls, at the time of postmortem.

Ni-catalyzed enantioconvergent deoxygenative reductive cross-coupling of unactivated alkyl alcohols and aryl bromides.

Transition metal-catalyzed enantioconvergent cross-coupling of an alkyl precursor presents a promising method for producing enantioenriched C(sp3) molecules. Because alkyl alcohol is a ubiquitous and abundant family of feedstock in nature, the direct reductive coupling of alkyl alcohol and aryl halide enables efficient access to valuable compounds. Although several strategies have been developed to overcome the high bond dissociation energy of the C - O bond, the asymmetric pattern remains unknown. In this report, we describe the realization of an enantioconvergent deoxygenative reductive cross-coupling of unactivated alkyl alcohol (ß-hydroxy ketone) and aryl bromide in the presence of an NHC activating agent. The approach can accommodate substituents of various sizes and functional groups, and its synthetic potency is demonstrated through a gram scale reaction and derivatizations into other compound families. Finally, we apply our convergent method to the efficient asymmetric synthesis of four ß-aryl ketones that are natural products or bioactive compounds.

Pancreas-directed AAV8-hSPINK1 gene therapy safely and effectively protects against pancreatitis in mice.

OBJECTIVE: Currently, there is no cure for chronic pancreatitis (CP). Germline loss-of-function variants in SPINK1 (encoding trypsin inhibitor) are common in patients with CP and are associated with acute attacks and progression of the disease. This preclinical study was conducted to explore the potential of adeno-associated virus type 8 (AAV8)-mediated overexpression of human SPINK1 (hSPINK1) for pancreatitis therapy in mice. DESIGN: A capsid-optimised AAV8-mediated hSPINK1 expression vector (AAV8-hSPINK1) to target the pancreas was constructed. Mice were treated with AAV8-hSPINK1 by intraperitoneal injection. Pancreatic transduction efficiency and safety of AAV8-hSPINK1 were dynamically evaluated in infected mice. The effectiveness of AAV8-hSPINK1 on pancreatitis prevention and treatment was studied in three mouse models (caerulein-induced pancreatitis, pancreatic duct ligation and Spink1 c.194+2T>C mouse models). RESULTS: The constructed AAV8-hSPINK1 vector specifically and safely targeted the pancreas, had low organ tropism for the heart, lungs, spleen, liver and kidneys and had a high transduction efficiency (the optimal expression dose was 2×1011 vg/animal). The expression and efficacy of hSPINK1 peaked at 4 weeks after injection and remained at significant level for up to at least 8 weeks. In all three mouse models, a single dose of AAV8-hSPINK1 before disease onset significantly alleviated the severity of pancreatitis, reduced the progression of fibrosis, decreased the levels of apoptosis and autophagy in the pancreas and accelerated the pancreatitis recovery process. CONCLUSION: One-time injection of AAV8-hSPINK1 safely targets the pancreas with high transduction efficiency and effectively ameliorates pancreatitis phenotypes in mice. This approach is promising for the prevention and treatment of CP.