Alzheimer's disease-linked risk alleles elevate microglial cGAS-associated senescence and neurodegeneration in a tauopathy model.

The strongest risk factors for late-onset sporadic Alzheimer's disease (AD) include the ε4 allele of apolipoprotein E (APOE), the R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2), and female sex. Here, we combine APOE4 and TREM2R47H (R47H) in female P301S tauopathy mice to identify the pathways activated when AD risk is the strongest, thereby highlighting detrimental disease mechanisms. We find that R47H induces neurodegeneration in 9- to 10-month-old female APOE4 tauopathy mice. The combination of APOE4 and R47H (APOE4-R47H) worsened hyperphosphorylated tau pathology in the frontal cortex and amplified tauopathy-induced microglial cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling and downstream interferon response. APOE4-R47H microglia displayed cGAS- and BAX-dependent upregulation of senescence, showing association between neurotoxic signatures and implicating mitochondrial permeabilization in pathogenesis. By uncovering pathways enhanced by the strongest AD risk factors, our study points to cGAS-STING signaling and associated microglial senescence as potential drivers of AD risk.

Lignans from Sambucus williamsii Protect Bone Via Microbiome.

PURPOSE OF REVIEW: Traditional Chinese Medicine has a unique system to diagnose and treat bone diseases with symptoms similar to those of osteoporosis. Sambucus williamsii Hance (SWH), a folk medicine in northern part of China for fractures healing and pain alleviation, has been demonstrated to exert bone anabolic effects in ovariectomized (OVX) rat and mice models in our previous studies. Lignans were identified to be the main bioactive fractions of SWH. However, pharmacokinetics study showed that the levels of lignan were too low to be detected in rat serum even upon taking 15 times of the effective dose of lignan-rich fraction from SWH. We hypothesize that lignans from SWH might exert its bone protective effect via the gut microbiome. RECENT FINDINGS: Our study revealed that the lignan-rich fraction of SWH did not influence the diversity of gut microbiota in OVX rats, but significantly increased the abundance of a few phyla, in particular, the restoration of the abundance of several genera that was directly correlated with bone mineral density (BMD). In addition, a subsequent metabolomic study indicated that serotonin, a neurotransmitter synthesized in the intestine and influenced by gut microbiota, may be involved in mediating the bone protective action of the lignans. Gut-derived serotonin is thought to inhibit bone growth. Based on this finding, several inhibitors that suppressed the synthesis of serotonin were identified from the lignans of SWH. Our studies suggested that microbiome is an indispensable factor for lignans derived from S. willimasii to exert bone beneficial effects.

Consecutive chirality transfer: efficient synthesis of chiral C,O-chelated BINOL/gold(iii) complexes for asymmetric catalysis and chiral resolution of disubstituted BINOLs.

A novel approach for efficient synthesis of chiral C,O-chelated BINOL/gold(iii) complexes by diastereomeric resolution using enantiopure BINOL as a chiral resolving agent was demonstrated. The BINOL/gold(iii) diastereomers with different solubility were separated by simple filtration, providing optically pure BINOL/gold(iii) complexes with up to >99 : 1 dr. By combining this with an efficient BINOL ligand dissociation process, a simple and column-free method for chiral resolution of racemic gold(iii) dichloride complexes on a gram scale was established, affording their enantiopure forms in good yields. Conversely, the resolved enantiopure gold(iii) dichloride complexes could serve as chiral resolving agents to resolve disubstituted BINOL derivatives, achieving both BINOLs and gold(iii) complexes in good to excellent yields (overall 77-96% and 76-95%, respectively) with a high optical purity of up to 99% ee. Through a consecutive chirality transfer process, the chiral information from an inexpensive chiral source was transferred to highly valuable gold(iii) complexes, followed by sterically bulky BINOL derivatives. This work would open a new synthetic strategy facilitating the development of structurally diverse chiral gold(iii) complexes and gold(iii)-mediated chiral resolution of BINOL derivatives. In addition, this new class of C,O-chelated BINOL/gold(iii) complexes achieved asymmetric carboalkoxylation of ortho-alkynylbenzaldehydes with an excellent enantioselectivity of up to 99% ee.

Synthesis of satellite and ground data provide unique perspectives for discovering the air pollution patterns: A case study in Guangdong Province, China.

Existing studies have analyzed the spatio-temporal patterns of air pollutants by combining ground and satellite measurements, primarily for cross-validation purposes. However, the unique characteristics and discrepancies between satellite and ground measurements have rarely been leveraged to understand pollution patterns and identify air pollution sources. To our best knowledge, this study is the first to utilize these discrepancies to holistically analyze the spatial and temporal patterns and investigate local biomass-burning effects on the five typical air pollutants: particulate matter (PM2.5)/aerosol optical depth (AOD), carbon monoxide (CO), nitrogen dioxide (NO2), sulphur dioxide (SO2), and ozone (O3). Guangdong (GD) province was selected as a case study due to its complex air pollution sources and patterns. Ground-based analysis from 2015 to 2023 shows significant decreases in PM2.5, CO, NO2, and SO2, and a significant increase in O3 in urban areas, indicating the efficacy of stringent air pollution control policies. However, satellite analysis shows significant downtrend only in AOD, while the trends of other pollutants are almost negligible, which are likely to be evidence of industrial migration. Both measurements exhibit regular seasonal patterns for all air pollutants. In-depth time-series comparisons between ground and satellite data reveal seasonal consistency for NO2 but noticeable discrepancies for both AOD and CO, which could be attributed to urban-rural differences and local versus transported pollution sources. Spatially, AOD and NO2 exhibits the most significant regional discrepancies, followed by SO2 and CO, with higher values observed over Pearl River Delta (PRD) compared to non-PRD regions. O3 is more evenly distributed, showing more pronounced seasonal variations than regional differences. The synergetic use of satellite and ground measurements collectively verifies the significant local biomass-burning effects on the five pollutants. These findings can aid in developing more targeted air pollution control policies.

Safety and Efficacy Comparison of Tenecteplase and Alteplase for Clinically Suspected Large Vessel Occlusion Strokes without Thrombectomy.

INTRODUCTION: Tenecteplase is a thrombolytic with higher fibrin affinity and is potentially better in clot lysis. A higher spontaneous recanalisation rate for large vessel occlusion (LVO) strokes had been shown in comparison studies with alteplase. Results of the LVO studies reflect the composite effect of the thrombolytic and thrombectomy, as patients would be treated by thrombectomy had they not been recanalised by intravenous thrombolysis alone. Thrombectomy is not readily available in many parts of the world. Our study aimed to compare the outcomes of suspected LVO patients treated with tenecteplase versus alteplase only, without the confounding effect of thrombectomy. METHODS: This is a retrospective review. Data of patients given tenecteplase from May 2020 to August 2023 and those given alteplase 0.9 mg/kg from January 2019 to August 2023 were retrieved. Due to fluctuation in supply of tenecteplase during the COVID pandemic, some LVO patients were given alteplase. Patients with anterior circulation, clinically suspected LVO strokes (defined as National Institutes of Health Stroke Scale (NIHSS) score ≥6, plus cortical signs or hyperdense vessel sign), with thrombolysis given within 4.5 h of stroke onset were analysed. Patients with thrombectomy done were excluded. Safety and efficacy outcomes were compared. RESULTS: There were 245 tenecteplase-treated patients treated between May 1, 2020, and August 31, 2023, and 732 patients were treated with alteplase between January 1, 2019, to August 31, 2023. Out of these, 148 tenecteplase patients and 138 alteplase 0.9 mg/kg patients fulfilled the study criteria. The symptomatic intracerebral haemorrhage rate was non-significantly lower in the tenecteplase group (2.1% vs. 5.8%, p = 0.13). There were no significant differences in the rate of ≥8-point NIHSS improvement (23.6% vs. 23.7%, p = 1) or the ≥4-point improvement (40.5% vs. 40.7%, p = 1) at 24 h. At 3 months, 21.6% of tenecteplase patients had good functional outcome (modified Rankin scale [mRS] 0-2), compared to 26.3% in the alteplase group (p = 0.40). CONCLUSION: In this pragmatic study of clinically suspected anterior circulation LVO patients without thrombectomy, outcome solely reflects the effects of tenecteplase. Tenecteplase showed comparable safety and efficacy to alteplase, but the result should be interpreted with caution in view of its small sample size and non-randomised study design.

Automated 3D Cobb Angle Measurement Using U-Net in CT Images of Preoperative Scoliosis Patients.

To propose a deep learning framework "SpineCurve-net" for automated measuring the 3D Cobb angles from computed tomography (CT) images of presurgical scoliosis patients. A total of 116 scoliosis patients were analyzed, divided into a training set of 89 patients (average age 32.4 ± 24.5 years) and a validation set of 27 patients (average age 17.3 ± 5.8 years). Vertebral identification and curve fitting were achieved through U-net and NURBS-net and resulted in a Non-Uniform Rational B-Spline (NURBS) curve of the spine. The 3D Cobb angles were measured in two ways: the predicted 3D Cobb angle (PRED-3D-CA), which is the maximum value in the smoothed angle map derived from the NURBS curve, and the 2D mapping Cobb angle (MAP-2D-CA), which is the maximal angle formed by the tangent vectors along the projected 2D spinal curve. The model segmented spinal masks effectively, capturing easily missed vertebral bodies. Spoke kernel filtering distinguished vertebral regions, centralizing spinal curves. The SpineCurve Network method's Cobb angle (PRED-3D-CA and MAP-2D-CA) measurements correlated strongly with the surgeons' annotated Cobb angle (ground truth, GT) based on 2D radiographs, revealing high Pearson correlation coefficients of 0.983 and 0.934, respectively. This paper proposed an automated technique for calculating the 3D Cobb angle in preoperative scoliosis patients, yielding results that are highly correlated with traditional 2D Cobb angle measurements. Given its capacity to accurately represent the three-dimensional nature of spinal deformities, this method shows potential in aiding physicians to develop more precise surgical strategies in upcoming cases.

The application of machine learning methods for predicting the progression of adolescent idiopathic scoliosis: a systematic review.

Predicting curve progression during the initial visit is pivotal in the disease management of patients with adolescent idiopathic scoliosis (AIS)-identifying patients at high risk of progression is essential for timely and proactive interventions. Both radiological and clinical factors have been investigated as predictors of curve progression. With the evolution of machine learning technologies, the integration of multidimensional information now enables precise predictions of curve progression. This review focuses on the application of machine learning methods to predict AIS curve progression, analyzing 15 selected studies that utilize various machine learning models and the risk factors employed for predictions. Key findings indicate that machine learning models can provide higher precision in predictions compared to traditional methods, and their implementation could lead to more personalized patient management. However, due to the model interpretability and data complexity, more comprehensive and multi-center studies are needed to transition from research to clinical practice.

Cornea-SELEX for aptamers targeting the surface of eyes and liposomal drug delivery.

Cornea is the major barrier to drug delivery to the eye, which results in low bioavailability and poor efficacy of topical eye treatment. In this work, we first select cornea-binding aptamers using tissue-SELEX on pig cornea. The top two abundant aptamers, Cornea-S1 and Cornea-S2, could bind to pig cornea, and their K d values to human corneal epithelial cells (HCECs) were 361 and 174 nм, respectively. Aptamer-functionalized liposomes loaded with cyclosporine A (CsA) were developed as a treatment for dry eye diseases. The K d of Cornea-S1- or Cornea-S2-functionalized liposomes reduces to 1.2 and 15.1 nм, respectively, due to polyvalent binding. In HCECs, Cornea-S1 or Cornea-S2 enhanced liposome uptake within 15 min and extended retention to 24 h. Aptamer CsA liposomes achieved similar anti-inflammatory and tight junction modulation effects with ten times less CsA than a free drug. In a rabbit dry eye disease model, Cornea-S1 CsA liposomes demonstrated equivalence in sustaining corneal integrity and tear break-up time when compared to commercial CsA eye drops while utilizing a lower dosage of CsA. The aptamers obtained from cornea-SELEX can serve as a general ligand for ocular drug delivery, suggesting a promising avenue for the treatment of various eye diseases and even other diseases.

Raynaud's phenomenon on initiation of Lithium therapy: a case report.

Lithium Carbonate is an effective treatment for affective disorders, but has a range of side effects. This case report highlights a rare side effect of Raynaud's phenomenon following initiation of Lithium therapy in a patient with recurrent depressive disorder. He was commenced on Lithium therapy to treat severe treatment resistant depression with psychotic symptoms when alternative treatments trialled were ineffective. He had no other risk factors or known aetiological causes for development of Raynaud's phenomenon. Symptoms resolved on discontinuation of Lithium and re-emerged on recommencement. Previous case series have shown Lithium effectively treating vasospastic disorders such as cluster headache and Raynaud's phenomenon. However, a paradoxical reaction to those previously described was induced in this case.

Integrating both restoration and regeneration potentials into real-world forest restoration planning: A case study of Hong Kong.

Forest restoration is a vital nature-based solution for mitigating climate change and land degradation. To ensure restoration effectiveness, the costs and benefits of alternative restoration strategies (i.e., active restoration vs. natural regeneration) need to be evaluated. Existing studies generally focus on maximum restoration potential, neglecting the recovery potential achievable through natural regeneration processes, leading to incomplete understanding of the true benefits and doubts about the necessity of active restoration. In this study, we introduce a multi-stage framework incorporating both restoration and regeneration potential into prioritized planning for ecosystem restoration. We used the vegetated landscape of Hong Kong (covering 728 km2) as our study system due to its comprehensive fine-resolution data and unique history of vegetation recovery, making it an ideal candidate to demonstrate the importance of this concept and inspire further research. We analyzed vegetation recovery status (i.e., recovering, degrading, and stable) over the past decade based on the canopy height data derived from multi-temporal airborne LiDAR. We assessed natural regeneration potential and maximum restoration potential separately, producing spatially-explicit predictions. Our results show that 44.9% of Hong Kong's vegetated area has showed evidence of recovery, but remaining gains through natural regeneration are limited, constituting around 4% of what could be attained through active restoration. We further estimated restoration priority by maximizing the restoration gain. When prioritizing 5% of degraded areas, the increment in canopy height could be up to 10.9%. Collectively, our findings highlight the importance of integrating both restoration and regeneration potential into restoration planning. The proposed framework can aid policymakers and land managers in optimizing forest restoration options and promoting the protection and recovery of fragile ecosystems.

Icariin promotes cell adhesion for osteogenesis in bone marrow stromal cells via binding to integrin α5ß1.

BACKGROUND AND PURPOSE: Icariin, an 8-prenylated flavonoid glycoside, is an anabolic agent that could exert rapid estrogenic actions via ligand-independent activation of estrogen receptor alpha (ERα) in osteoblastic cells to promote osteogenesis. However, relatively little is known about its direct cellular target, its protective effects, and cell adhesion activities in bone marrow stromal cells (BMSCs) against microgravity. In the present study, the effects of icariin on osteogenesis and cell adhesion under microgravity were examined with the involvement of integrin receptor α5ß1, connexin 43, and CAMs. STUDY DESIGN AND METHODS: Icariin was orally administered to 6-month-old ovariectomized (OVX) Sprague-Dawley (SD) rats for 3 months through daily intake of phytoestrogen-free rodent diets containing icariin at 2 different dosages (50 and 500 ppm). BMSCs were harvested for experiments and RNA-sequencing analysis to examine the mechanism of action of icariin and its direct cellular target in stimulating osteogenesis. RESULTS: The results revealed that icariin induced the expression of cell adhesion molecules (CAMs) and protected against microgravity-induced disruption of actin cytoskeleton and the loss of osteogenic activities in BMSCs through the activation of connexin-43 (Cx43) and Ras homolog family member A (RhoA) and Rac family small GTPase 1 (Rac1)-mediated signaling pathways. Computerized molecular docking techniques and the competitive solid-phase binding ELISA assay confirmed that icariin could be a direct ligand of integrin alpha 5 beta 1 (α5ß1), and it could also increase the protein expression of integrin α5ß1 for mechanosensing. CONCLUSION: Our findings suggest that icariin could directly activate cell adhesion signaling by binding to integrin α5ß1, which opens up new avenues for the development of integrin α5ß1 ligand as an agent to protect against unloading-induced bone loss.

Molecular engineering of a theranostic molecule that detects Aß plaques, inhibits Iowa and Dutch mutation Aß self-aggregation and promotes lysosomal biogenesis for Alzheimer's disease.

Extracellular clustering of amyloid-ß (Aß) and an impaired autophagy lysosomal pathway (ALP) are the hallmark features in the early stages of incurable Alzheimer's disease (AD). There is a pressing need to find or develop new small molecules for diagnostics and therapeutics for the early stages of AD. Herein, we report a small molecule, namely F-SLCOOH, which can bind and detect Aß1-42, Iowa mutation Aß, Dutch mutation Aß fibrils and oligomers exhibiting enhanced emission with high affinity. Importantly, F-SLCOOH can readily pass through the blood-brain barrier and shows highly selective binding toward the extracellular Aß aggregates in real-time in live animal imaging of a 5XFAD mice model. In addition, a high concentration of F-SLCOOH in both brain and plasma of wildtype mice after intraperitoneal administration was found. The ex vivo confocal imaging of hippocampal brain slices indicated excellent colocalization of F-SLCOOH with Aß positive NU1, 4G8, 6E10 A11 antibodies and THS staining dye, affirming its excellent Aß specificity and targetability. The molecular docking studies have provided insight into the unique and specific binding of F-SLCOOH with various Aß species. Importantly, F-SLCOOH exhibits remarkable anti-fibrillation properties against toxic Aß aggregate formation of Aß1-42, Iowa mutation Aß, and Dutch mutation Aß. F-SLCOOH treatment also exerts high neuroprotective functions and promotes autophagy lysosomal biogenesis in neuronal AD cell models. In summary, the present results suggest that F-SLCOOH is a highly promising theranostic agent for diagnosis and therapeutics of AD.

Exploring the phylogeny and depth evolution of cusk eels and their relatives (Ophidiiformes: Ophidioidei).

With 289 known species in 51 genera, the ophidiiform family Ophidiidae together with their relatives from the Carapidae (36 species in eight genera) of the same suborder Ophidioidei dominate the deep sea, but some occur also in shallow water habitats. Despite their high species diversity in the deep sea and wide bathymetric distributions, their phylogenetic relationships and evolution remain unexplored due in part to sampling difficulties. Thanks to the biodiversity exploratory program entitled "Tropical Deep-Sea Benthos" and joint efforts between Taiwan and French teams for sampling from different localities across the Indo-West Pacific over the last two decades, we are able to compile comprehensive datasets for investigations. In this study, 59 samples representing 36 of 59 known ophidioid genera are selected and used to construct a multi-gene dataset to infer the phylogenetic relationships of ophidioid fishes and their relatives. Our results reveal that the Ophidiidae forms a paraphyletic group with respect to the Carapidae. The four main clades of Ophidioidei resolved are the (1) clade comprising species from the subfamily Brotulinae; (2) clade that includes species in the genera Acanthonus and Xyelacyba; (3) clade grouping Hypopleuron caninum with species from the family Carapidae; and (4) clade containing the species in the subfamily Brotulotaenilinae, Neobythitinae (in part), and Ophidiinae. Accordingly, we suggest the following new revisions based on our results and proposed morphological diagnoses. The subfamily Brotulinae should be elevated to the family level. The genera Xyelacyba and probably Tauredophidium (unsampled in this study) should be included in the newly established family Acanthonidae with Acanthonus. The families Carapidae and Ophidiidae are re-defined. Our time-calibrated phylogenetic and ancestral depth reconstructions enable us to clarify the evolutionary history of ophidiiform fishes and infer past patterns of species distributions at different depths. While Ophidiiformes is inferred to have originated in shallow waters around 96.25 million years ago (Mya), the common ancestor to the Ophidioidei is inferred to have invaded the deep sea around 90.22 Mya, the dates coinciding with the global anoxic event of the OAE2. The observed bathymetric distribution patterns in Ophidioidei most likely point to the mesopelagic zone as the center of origin and diversification. This was followed by multiple events of depth transitions or range expansions towards either shallower waters or greater depth zones, which were likely triggered by past climate changes during the Paleogene-Neogene.

The effect of stretching exercises before orthotic treatment on the immediate in-orthosis correction of the patients with adolescent idiopathic scoliosis: A pilot study.

BACKGROUND: Stretching exercise is generally used for improving flexibility. However, its application to promote orthotic treatment for patients with adolescent idiopathic scoliosis (AIS) remains unknown. OBJECTIVE: This study was to explore the effect of pre-orthosis stretching exercises on spinal flexibility and initial in-orthosis correction for the patients with AIS. STUDY DESIGN: A pilot-controlled study. METHODS: An experimental group (EG) of 13 subjects (10 girls and 3 boys) with AIS allocating to self-stretching exercises and a control group (CG) of 19 AIS subjects (14 girls and 5 boys) with no stretching before orthosis fitting were recruited. The spinal flexibility of the EG was evaluated with an ultrasound imaging system and physical measurements. The initial in-orthosis correction rates between the 2 groups were compared with the independent t test, and the correlation analysis between the spinal flexibility measured from ultrasound images and physical measurement was performed with the Pearson correlation test. RESULTS: The initial Cobb angle of EG and CG were 25.70° ± 7.30° and 28.09° ± 5.58°, respectively. No significant difference was observed between the initial in-orthosis Cobb angle of EG (11.13° ± 6.80°) and CG (15.65° ± 9.10°) (p = 0.06). However, the spinal flexibility after stretching exercises was improved (p < 0.001), and the spinal flexibility changes measured with ultrasound and physical forward-bending method were significantly correlated (r = 0.57, p < 0.05). CONCLUSION: Stretching exercises before orthotic treatment could improve the spinal flexibility but did not cause a better in-orthosis correction. A study with a larger sample size and longer follow-up period should be conducted to investigate the long-term effect of stretching exercises.

Modular synthesis of pentacyclic-fused pyranoquinoliziniums as organelle-selective fluorescent probes.

On basis of their unique chemical and photophysical properties, and excellent biological activities, quinoliziniums have been widely used in various research fields. Herein, modular synthetic strategies for efficient synthesis of novel fluorescent quinoliziniums by using one-pot and stepwise rhodium(III)-catalyzed C-H annulations were developed. In the one-pot synthesis, the reaction between 2-aryl-4-quinolones (1) and 1,2-diarylalkynes (2) proceeded in a chemo- and regioselective manner to give quinolinone-fused isoquinolines (3) and pentacyclic-fused pyranoquinoliziniums (4). The structural diversity of pentacyclic-fused pyranoquinoliziniums (4) was expanded by the stepwise synthesis from 3 and 2, allowing the strategic incorporation of electron-donating (OMe and OH) and electron-withdrawing (Cl) substituents on the top and bottom parts of the pyranoquinoliziniums (4). These newly synthesized pyranoquinoliziniums (4) exhibited tunable absorptions (455-532 nm), emissions (520-610 nm), fluorescence lifetime (0.3-5.6 ns), large Stokes shifts (up to 120 nm), and excellent fluorescence quantum yields (up to 0.73) upon adjusting the different substituents. The the unique arrangement of N and O atoms and extended π-conjugation of 4 could cause the relocation of HOMO comparing with our previous quinoliziniums. Importantly, pyranoquinoliziniums (4a-4g and 4i) targeted the mitochondria, while 4h was localized in lysosome. Due to the remarkable photophysical properties and the potential for organelle targeting of the novel class of quinoliziniums, they could be further applied for biological, chemical and material applications.

Anti-acetylated-tau immunotherapy is neuroprotective in tauopathy and brain injury.

BACKGROUND: Tau is aberrantly acetylated in various neurodegenerative conditions, including Alzheimer's disease, frontotemporal lobar degeneration (FTLD), and traumatic brain injury (TBI). Previously, we reported that reducing acetylated tau by pharmacologically inhibiting p300-mediated tau acetylation at lysine 174 reduces tau pathology and improves cognitive function in animal models. METHODS: We investigated the therapeutic efficacy of two different antibodies that specifically target acetylated lysine 174 on tau (ac-tauK174). We treated PS19 mice, which harbor the P301S tauopathy mutation that causes FTLD, with anti-ac-tauK174 and measured effects on tau pathology, neurodegeneration, and neurobehavioral outcomes. Furthermore, PS19 mice received treatment post-TBI to evaluate the ability of the immunotherapy to prevent TBI-induced exacerbation of tauopathy phenotypes. Ac-tauK174 measurements in human plasma following TBI were also collected to establish a link between trauma and acetylated tau levels, and single nuclei RNA-sequencing of post-TBI brain tissues from treated mice provided insights into the molecular mechanisms underlying the observed treatment effects. RESULTS: Anti-ac-tauK174 treatment mitigates neurobehavioral impairment and reduces tau pathology in PS19 mice. Ac-tauK174 increases significantly in human plasma 24 h after TBI, and anti-ac-tauK174 treatment of PS19 mice blocked TBI-induced neurodegeneration and preserved memory functions. Anti-ac-tauK174 treatment rescues alterations of microglial and oligodendrocyte transcriptomic states following TBI in PS19 mice. CONCLUSIONS: The ability of anti-ac-tauK174 treatment to rescue neurobehavioral impairment, reduce tau pathology, and rescue glial responses demonstrates that targeting tau acetylation at K174 is a promising neuroprotective therapeutic approach to human tauopathies resulting from TBI or genetic disease.

Deep Learning-Based Prediction Model for the Cobb Angle in Adolescent Idiopathic Scoliosis Patients.

Scoliosis, characterized by spine deformity, is most common in adolescent idiopathic scoliosis (AIS). Manual Cobb angle measurement limitations underscore the need for automated tools. This study employed a vertebral landmark extraction method and Feedforward Neural Network (FNN) to predict scoliosis progression in 79 AIS patients. The novel intervertebral angles matrix format showcased results. The mean absolute error for the intervertebral angle progression was 1.5 degrees, while the Pearson correlation of the predicted Cobb angles was 0.86. The accuracy in classifying Cobb angles (<15°, 15-25°, 25-35°, 35-45°, >45°) was 0.85, with 0.65 sensitivity and 0.91 specificity. The FNN demonstrated superior accuracy, sensitivity, and specificity, aiding in tailored treatments for potential scoliosis progression. Addressing FNNs' over-fitting issue through strategies like "dropout" or regularization could further enhance their performance. This study presents a promising step towards automated scoliosis diagnosis and prognosis.

Prevalence and factors associated with diabetes-related distress in type 2 diabetes patients: a study in Hong Kong primary care setting.

Diabetes-related distress (DRD) refers to the psychological distress specific to living with diabetes. DRD can lead to negative clinical consequences such as poor self-management. By knowing the local prevalence and severity of DRD, primary care teams can improve the DRD evaluation in our daily practice. This was a cross-sectional study conducted in 3 General Out-patient Clinics (GOPCs) from 1 December 2021 to 31 May 2022. A random sample of adult Chinese subjects with T2DM, who regularly followed up in the selected clinic in the past 12 months, were included. DRD was measured by the validated 15-item Chinese version of the Diabetes Distress Scale (CDDS-15). An overall mean score ≥ 2.0 was considered clinically significant. The association of DRD with selected clinical and personal factors was investigated. The study recruited 362 subjects (mean age 64.2 years old, S.D. 9.5) with a variable duration of living with T2DM (median duration 7.0 years, IQR 10.0). The response rate was 90.6%. The median HbA1c was 6.9% (IQR 0.9). More than half (59.4%) of the subjects reported a clinically significant DRD. Younger subjects were more likely to have DRD (odds ratio of 0.965, 95% CI 0.937-0.994, p = 0.017). Patients with T2DM in GOPCs commonly experience clinically significant DRD, particularly in the younger age group. The primary care clinicians could consider integrating the evaluation of DRD as a part of comprehensive diabetes care.

APOE3-R136S mutation confers resilience against tau pathology via cGAS-STING-IFN inhibition.

The Christchurch mutation (R136S) on the APOE3 (E3S/S) gene is associated with low tau pathology and slowdown of cognitive decline despite the causal PSEN1 mutation and high levels of amyloid beta pathology in the carrier1. However, the molecular effects enabling E3S/S mutation to confer protection remain unclear. Here, we replaced mouse Apoe with wild-type human E3 or E3S/S on a tauopathy background. The R136S mutation markedly mitigated tau load and protected against tau-induced synaptic loss, myelin loss, and spatial learning. Additionally, the R136S mutation reduced microglial interferon response to tau pathology both in vivo and in vitro, suppressing cGAS-STING activation. Treating tauopathy mice carrying wild-type E3 with cGAS inhibitor protected against tau-induced synaptic loss and induced similar transcriptomic alterations to those induced by the R136S mutation across brain cell types. Thus, cGAS-STING-IFN inhibition recapitulates the protective effects of R136S against tauopathy.