A Huntingtin Knockin Pig Model Recapitulates Features of Selective Neurodegeneration in Huntington's Disease.

Huntington's disease (HD) is characterized by preferential loss of the medium spiny neurons in the striatum. Using CRISPR/Cas9 and somatic nuclear transfer technology, we established a knockin (KI) pig model of HD that endogenously expresses full-length mutant huntingtin (HTT). By breeding this HD pig model, we have successfully obtained F1 and F2 generation KI pigs. Characterization of founder and F1 KI pigs shows consistent movement, behavioral abnormalities, and early death, which are germline transmittable. More importantly, brains of HD KI pig display striking and selective degeneration of striatal medium spiny neurons. Thus, using a large animal model of HD, we demonstrate for the first time that overt and selective neurodegeneration seen in HD patients can be recapitulated by endogenously expressed mutant proteins in large mammals, a finding that also underscores the importance of using large mammals to investigate the pathogenesis of neurodegenerative diseases and their therapeutics.

Cortical activation and brain network efficiency during dual tasks: An fNIRS study.

OBJECTIVE: Dual task (DT) is a commonly used paradigm indicative of executive functions. Brain activities during DT walking is usually measured by portable functional near infrared spectroscopy (fNIRS). Previous studies focused on cortical activation in prefrontal cortex and overlooked other brain regions such as sensorimotor cortices. This study is aimed at investigating the modulations of cortical activation and brain network efficiency in multiple brain regions from single to dual tasks with different complexities and their relationships with DT performance. METHODS: Forty-two healthy adults [12 males; mean age: 27.7 (SD=6.5) years] participated in this study. Participants performed behavioral tasks with portable fNIRS simultaneous recording. There were three parts of behavioral tasks: cognitive tasks while standing (serial subtraction of 3's and 7's), walking alone and DT (walk while subtraction, including serial subtraction of 3's and 7's). Cognitive cost, walking cost and cost sum (i.e., sum of cognitive and walking costs) were calculated for DT. Cortical activation, local and global network efficiency were calculated for each task. RESULTS: The cognitive cost was greater and the walking cost was less during DT with subtraction 3's compared with 7's (P's = 0.032 and 0.019, respectively). Cortical activation and network efficiency were differentially modulated among single and dual tasks (P's < 0.05). Prefrontal activation during DT was positively correlated with DT costs, while network efficiency was negatively correlated with DT costs (P's < 0.05). CONCLUSIONS: Our results revealed prefrontal over-activation and reduced network efficiency in individuals with poor DT performance. Our findings suggest that reduced network efficiency could be a possible mechanism contributing to poor DT performance, which is accompanied by compensatory prefrontal over-activation.

Functional near-infrared spectroscopy evidence of cognitive-motor interference in different dual tasks.

Dual tasks (DTs) combining walking with a cognitive task can cause various levels of cognitive-motor interference, depending on which brain resources are recruited in each case. However, the brain activation and functional connectivity underlying cognitive-motor interferences remain to be elucidated. Therefore, this study investigated the neural correlation during different DT conditions in 40 healthy young adults (mean age: 27.53 years, 28 women). The DTs included walking during subtraction or N-Back tasks. Cognitive-motor interference was calculated, and brain activation and functional connectivity were analysed. Portable functional near-infrared spectroscopy was utilized to monitor haemodynamics in the prefrontal cortex (PFC), motor cortex and parietal cortex during each task. Walking interference (decrease in walking speed during DT) was greater than cognitive interference (decrease in cognitive performance during DT), regardless of the type of task. Brain activation in the bilateral PFC and parietal cortex was greater for walking during subtraction than for standing subtraction. Furthermore, brain activation was higher in the bilateral motor and parietal and PFCs for walking during subtraction than for walking alone, but only increased in the PFC for walking during N-Back. Coherence between the bilateral lateral PFC and between the left lateral PFC and left motor cortex was significantly greater for walking during 2-Back than for walking. The PFC, a critical brain region for organizing cognitive and motor functions, played a crucial role in integrating information coming from multiple brain networks required for completing DTs. Therefore, the PFC could be a potential target for the modulation and improvement of cognitive-motor functions during neurorehabilitation.

Prediction of specific structural damage to the knee joint using qualitative isokinetic analysis.

BACKGROUND: An isokinetic moment curve (IMC) pattern-damaged structure prediction model may be of considerable value in assisting the diagnosis of knee injuries in clinical scenarios. This study aimed to explore the association between irregular IMC patterns and specific structural damages in the knee, including anterior cruciate ligament (ACL) rupture, meniscus (MS) injury, and patellofemoral joint (PFJ) lesions, and to develop an IMC pattern-damaged structure prediction model. METHODS: A total of 94 subjects were enrolled in this study and underwent isokinetic testing of the knee joint (5 consecutive flexion-extension movements within the range of motion of 90°-10°, 60°/s). Qualitative analysis of the IMCs for all subjects was completed by two blinded examiners. A multinomial logistic regression analysis was used to investigate whether a specific abnormal curve pattern was associated with specific knee structural injuries and to test the predictive effectiveness of IMC patterns for specific structural damage in the knee. RESULTS: The results of the multinomial logistic regression revealed a significant association between the irregular IMC patterns of the knee extensors and specific structural damages ("Valley" - ACL, PFJ, and ACL + MS, "Drop" - ACL, and ACL + MS, "Shaking" - ACL, MS, PFJ, and ACL + MS). The accuracy and Macro-averaged F1 score of the predicting model were 56.1% and 0.426, respectively. CONCLUSION: The associations between irregular IMC patterns and specific knee structural injuries were identified. However, the accuracy and Macro-averaged F1 score of the established predictive model indicated its relatively low predictive efficacy. For the development of a more accurate predictive model, it may be essential to incorporate angle-specific and/or speed-specific analyses of qualitative and quantitative data in isokinetic testing. Furthermore, the utilization of artificial intelligence image recognition technology may prove beneficial for analyzing large datasets in the future.

GABA promotes interstitial fluid clearance in an AQP4-dependent manner by activating the GABAA R.

The glymphatic system is a newly discovered perivascular network where cerebrospinal fluid mixes with interstitial fluid, facilitating clearance of protein solutes and metabolic waste from the parenchyma. The process is strictly dependent on water channel aquaporin-4 (AQP4) expressed on the perivascular astrocytic end-feet. Various factors, such as noradrenaline levels related to the arousal state, influence clearance efficiency, highlighting the possibility that other neurotransmitters additionally modulate this process. To date, the specific role of γ-aminobutyric acid (GABA) in the glymphatic system remains unknown. We used C57BL/6J mice to observe the regulatory effect of GABA on glymphatic pathway by administering a cerebrospinal fluid tracer containing GABA or its GABAA receptor (GABAA R) antagonist through cisterna magna injection. Then, we employed an AQP4 knockout mouse model to explore the regulatory effects of GABA on glymphatic drainage and further study whether transcranial magnetic stimulation-continuous theta burst stimulation (cTBS) could regulate the glymphatic pathway through the GABA system. Our data showed that GABA promotes glymphatic clearance in an AQP4-dependent manner by activating the GABAA R. Furthermore, cTBS was found to modulate the glymphatic pathway by activating the GABA system. Accordingly, we propose that regulating the GABA system by cTBS could modulate glymphatic clearance and provide new insight for clinical prevention and treatment of abnormal protein deposition-related diseases.

Asymmetric Synthesis of Vicinal Tetrasubstituted Diamines via Reductive Coupling of Ketimines Templated by Chiral Diborons.

We herein describe the chiral diboron-templated asymmetric homocoupling of aryl alkyl ketimines, providing for the first time a series of chiral vicinal tetrasubstituted diamines with excellent ee values and good to high yields. The powerful and efficient diboron-participated [3,3]-sigmatropic rearrangement is successfully demonstrated by the homocoupling of a variety of ketimines thanks to the rational design and engineering of chiral diborons. Systematic DFT studies suggest that two chiral diborons adopt different conformational assembling strategies to couple the diboron template with ketimine substrates in their tight concerted transition states to ensure the excellent enantioselectivities. The synthetic value of chiral vicinal tetrasubstituted diamines is demonstrated by the asymmetric α-bromination of aliphatic aldehydes by employing a chiral vicinal tetrasubstituted diamine-based organocatalyst.

Continuous Theta-Burst Stimulation Promotes Paravascular CSF-Interstitial Fluid Exchange through Regulation of Aquaporin-4 Polarization in APP/PS1 Mice.

Amyloid-ß (Aß) deposition plays a crucial role in the occurrence and development of Alzheimer's disease (AD), and impaired Aß clearance is the leading cause of Aß deposition. Recently, studies have found that the glymphatic system performs similar functions to the peripheral lymphatic system. Glymphatic fluid transport mainly consists of cerebrospinal fluid (CSF) entering the brain from the paravascular space (PVS) by penetrating arteries and CSF and interstitial fluid exchanging mediated by aquaporin-4 (AQP4). This system promotes the drainage of interstitial fluid (ISF) in the parenchyma and removes metabolic waste, including Aß, in the brain. Glymphatic system dysfunction plays an essential role in the occurrence and progression of AD. Regulation of glymphatic fluid transport may be a critical target for AD therapy. This study explored the regulatory effects of continuous theta-burst stimulation (CTBS) on the glymphatic system in APPswe/PS1dE9 (APP/PS1) mice with two-photon imaging. The results demonstrated that CTBS could increase glymphatic fluid transport, especially CSF and ISF exchange, mediated by improved AQP4 polarization. In addition, the accelerated glymphatic pathway reduced Aß deposition and enhanced spatial memory cognition. It provided new insight into the clinical prevention and treatment of Aß deposition-related diseases.

Metal-free reduction of unsaturated carbonyls, quinones, and pyridinium salts with tetrahydroxydiboron/water.

A series of unsaturated carbonyls, quinones, and pyridinium salts have been effectively reduced to the corresponding saturated carbonyls, dihydroxybenzenes, and hydropyridines in moderate to high yields with tetrahydroxydiboron/water as a mild, convenient, and metal-free reduction system. Deuterium-labeling experiments have revealed this protocol to be an exclusive transfer hydrogenation process from water.

Effect of Cognitive Function on Balance and Posture Control after Stroke.

Hemiplegic gait is the most common sequela of stroke. Patients with hemiplegic gait are at a risk of falling because of poor balance. The theory of cognitive-motor networks paved the way for a new field of research. However, the mechanism of the relationship of cognition with gait or posture control networks is unclear because of the dynamic characteristics of walking and changing postures. To explore differences in the balance function and fall risk between patients with and without cognitive impairment after stroke, we utilized the Berg balance scale, Timed "Up and Go" test, and 10 m walking test. Patients were divided into two groups: the observation group (16 patients, female 6 and male 10), comprising patients with cognitive impairment after stroke, and the control group (16 patients, female 7 and male 9), comprising patients without cognitive impairment after stroke. We found that patients with cognitive impairment had worse balance function and a higher risk of falls. They needed a longer time to turn around or sit down. Our findings indicated that posture control in turning around and sitting down required more cognitive resources in daily life.

Enantioselective Reductive Coupling of Imines Templated by Chiral Diboron.

We herein report a general, practical, and highly efficient method for asymmetric synthesis of a wide range of chiral vicinal diamines via reductive coupling of imines templated by chiral diboron. The protocol features high enantioselectivity and stereospecificity, mild reaction conditions, simple operating procedures, use of readily available starting materials, and a broad substrate scope. The method signifies the generality of diboron-enabled [3,3]-sigmatropic rearrangement.

P-Chiral Phosphorus Ligands Based on a 2,3-Dihydrobenzo[ d][1,3]oxaphosphole Motif for Asymmetric Catalysis.

Despite the rapid progress in the field of asymmetric catalysis, the search for new, efficient, and practical asymmetric catalytic transformations to facilitate the green synthesis of chiral natural products and drugs will continue to be a major ongoing effort in organic chemistry. Chiral phosphorus ligands have played a significant role in recent advances in transition-metal-catalyzed asymmetric transformations. However, there remain numerous challenging issues of reactivity and selectivity in catalysis. The development of new and efficient chiral phosphorus ligands with new structural motifs remains highly desirable. P-Chiral phosphorus ligands have been overlooked and are underdeveloped, except for the early success of DIPAMP, introduced first by Knowles in the early 1970s. It was not until the late 1990s that the development of P-chiral phosphorus ligands regained attention with the advent of bisP*, TangPhos, etc. Nonetheless, most P-chiral phosphorus ligands were either difficult to prepare or operationally inconvenient. The development of efficient, practical, and operationally convenient P-chiral phosphorus ligands with new structural motifs remains an important subject of research. This Account introduces the design and development of a series of practical and efficient P-chiral bis- and monophosphorus ligands based on a 2,3-dihydrobenzo[ d][1,3]oxaphosphole motif. Their unique structural and physical properties include conformational unambiguousness, high tunability of electronic and steric properties, and operational simplicity as air-stable solids, which make them practical and exceptional ligands for asymmetric catalysis. Chiral bisphosphorus ligands such as MeO-BIBOP (L3), WingPhos (L4), and iPr-BABIBOP (L7) have demonstrated excellent enantioselectivities and unprecedented turnover numbers (TONs) in various asymmetric hydrogenations and other transformations, providing practical and efficient solutions leading to chiral amines, alcohols, carboxylic acids, and α- and ß-amino acids. Chiral biaryl monophosphorus ligands, including BI-DIME (L9), AntPhos (L15), iPr-BI-DIME (L11), etc., have proven to be a class of versatile and powerful ligands for a number of catalytic asymmetric transformations, including asymmetric Suzuki-Miyaura coupling, asymmetric palladium-catalyzed dearomative cyclization, asymmetric hydroboration/diboration, asymmetric nickel-catalyzed reductive coupling, asymmetric palladium-catalyzed intramolecular arylation, asymmetric alkene aryloxyarylation, asymmetric α-arylation, asymmetric Heck reaction, and asymmetric nucleophilic addition, providing efficient solutions leading to various synthetically challenging chiral structures such as chiral biaryls, chiral tertiary alcohols, chiral α-amino tertiary boronic esters, and chiral all-carbon quaternary stereocenters. The high enantioselectivities and TONs obtained with these ligands have resulted in the syntheses of several chiral natural products and therapeutic agents in concise and highly efficient manners. While our efforts on the development of P-chiral phosphorus ligands are ongoing, it should be emphasized that the development of ligands and catalysts with new structural motifs should continue in the search for new reactivity and selectivity to tackle current synthetic challenges. Such effort is destined to promote the advances of asymmetric catalysis as well as synthetic organic chemistry.

Effectiveness of Telemedicine Intervention for Chronic Obstructive Pulmonary Disease in China: A Systematic Review and Meta-Analysis.

Background: Telemedicine market in China has been rapidly developing. However, no systematic review has been published in China. Details of the implementation of telemedicine interventions in the chronic obstructive pulmonary disease (COPD) in China have not been described, and the effectiveness of telemedicine interventions is still unclear. Therefore, in this review, we describe the implementation details of telemedicine intervention in China and access the efficacy of telemedicine. Materials and Methods: A literature search was conducted in Embase, Cochrane Library, PubMed, China National Knowledge Infrastructure (CNKI), Wan Fang Data, and China Science and Technology Journal Database by July 9, 2018. Results: A total number of 24 studies were meta-analyzed. There are many differences during the implementation of telemedicine in China. Quality of life in the group of the telemedicine intervention was better than that in the control group (mean difference = -4.93 [95% confidence interval; CI -6.86 to -3.01], p < 0.00001), but the heterogeneity is high (I2 = 86%, p = 0.0001). The rates of hospitalization were lower than those in the control group (odds ratio = 0.24 [95% CI 0.20-0.29], p < 0.00001), and the heterogeneity was low (I2 = 25%, p = 0.14). Conclusion: The implementation of telemedicine in China has not yet been standardized. Nonetheless, results of our review indicated that telemedicine in China can improve the quality of life and reduce the rates of hospitalization in COPD patients.

In situ electrochemical oxidation of electrodeposited Ni-based nanostructure promotes alkaline hydrogen production.

Highly active and stable electrocatalysts based on non-precious metals for hydrogen evolution reaction (HER) in alkaline solution are urgently required for enabling mass production of clean hydrogen in industry. Herein, core-shell NiOOH/Ni nanoarchitectures supported on the conductive carbon cloth have been successfully prepared by a facile electrodeposition process of Ni, and a subsequent in situ electrochemical oxidation. When explored as an alkaline HER electrocatalyst, the as-synthesized NiOOH/Ni nanoarchitecture requires only a low overpotential of ∼111 mV to attain a current density of -10 mA cm-2, demonstrating its strong catalytic capability of hydrogeneration. The excellent HER activity could well be attributed to the decreasing charge transfer resistance and competitive electrochemical active area of the amorphous NiOOH, compared with inactive Ni substrate. The feasible methodology established in this study can be easily expanded to obtain a series of nano-sized metal oxyhydroxide materials for various energy conversion and storage applications, where Ni-based nanomaterials are among the highly active ones.

Efficient Enantioselective Syntheses of (+)-Dalesconol A and B.

We herein report the first enantioselective syntheses of immunosuppressants (+)-dalesconol A and B in a highly efficient and concise manner, which features an efficient palladium-catalyzed enantioselective dearomative cyclization-kinetic resolution cascade to install the chiral all-carbon quaternary center, an effective sterically hindered Stille coupling, a powerful 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) oxidation to furnish all requisite unsaturation, and a tandem hydrolysis-ring closure sequence.

Practical and Asymmetric Reductive Coupling of Isoquinolines Templated by Chiral Diborons.

We herein describe a chiral diboron-templated highly diastereoselective and enantioselective reductive coupling of isoquinolines that provided expedited access to a series of chiral substituted bisisoquinolines in good yields and excellent ee's under mild conditions. The method enjoys a broad substrate scope and good functional group compatibility. Mechanistic investigation suggests the reaction proceeds through a concerted [3,3]-sigmatropic rearrangement.

Synthesis of α-Bi2Mo3O12/TiO2 Nanotube Arrays for Photoelectrochemical COD Detection Application.

One-dimensional anodic TiO2 nanotube arrays hold great potential as a photoelectrochemical sensor for the determination of chemical oxygen demand (COD). In this work, we report a warm synthesis of modified TiO2 nanotube arrays with enhanced photoelectrochemical determination performance. Herein, a bismuth-based semiconductor (α-Bi2Mo3O12) was introduced into TiO2 nanotube arrays by sequential chemical bath deposition (CBD) at room temperature. Field-emission scanning electron microscopy, X-ray diffraction, Raman, and X-ray photoelectron spectroscopy were used to investigate the morphologies, structures, and elemental analysis of the products. The photoelectrochemical properties of TiO2 and α-Bi2Mo3O12/TiO2 NTAs were measured by amperometry and cyclic votammetry methods. The α-Bi2Mo3O12/TiO2 nanotube arrays decrease the background photocurrent and increase the current response to organics at the same time, both of which are beneficial to enhancing the photoelectrochemical detection performance. The optimized α-Bi2Mo3O12/TiO2 NTAs with enhanced photoelectrochemical detection performance can achieve a detection sensitivity of 2.05 µA·cm-2/(mg·L-1) and a COD detection range of 0.366-208.9 mg/L respectively. With the α-Bi2Mo3O12 modification, the surface electrochemical reactions of TiO2 NTAs were regulated, the mechanisms of which were also further studied.

Deferoxamine inhibits microglial activation, attenuates blood-brain barrier disruption, rescues dendritic damage, and improves spatial memory in a mouse model of microhemorrhages.

Cerebral microbleeds are strongly linked to cognitive dysfunction in the elderly. Iron accumulation plays an important role in the pathogenesis of intracranial hemorrhage. Deferoxamine (DFX), a metal chelator, removes iron overload and protects against brain damage in intracranial hemorrhage. In this study, the protective effects of DFX against microhemorrhage were examined in mice. C57BL6 and Thy-1 green fluorescent protein transgenic mice were subjected to perforating artery microhemorrhages on the right posterior parietal cortex using two-photon laser irradiation. DFX (100 mg/kg) was administered 6 h after microhemorrhage induction, followed by every 12 h for three consecutive days. The water maze task was conducted 7 days after induction of microhemorrhages, followed by measurement of blood-brain barrier permeability, iron deposition, microglial activation, and dendritic damage. Laser-induced multiple microbleeds in the right parietal cortex clearly led to spatial memory disruption, iron deposits, microglial activation, and dendritic damage, which were significantly attenuated by DFX, supporting the targeting of iron overload as a therapeutic option and the significant potential of DFX in microhemorrhage treatment. Irons accumulation after intracranial hemorrhage induced a serious secondary damage to the brain. We proposed that irons accumulation after parietal microhemorrhages impaired spatial cognition. After parietal multiple microhemorrhages, increased irons and ferritin contents induced blood-brain barrier disruption, microglial activation, and further induced dendrites loss, eventually impaired the water maze, deferoxamine treatment protected from these damages.

The correlation between manometric and videofluoroscopic measurements of the swallowing function in brainstem stroke patients with Dysphagia.

GOALS: The objective of the current study was to examine the correlation between high-resolution manometric and videofluoroscopic measurements of the swallowing function. BACKGROUND: In such cases in which manometric analysis is not feasible, it would be ideal if information regarding pressure during swallowing could be inferred from a videofluoroscopic swallowing study (VFSS) evaluation alone. STUDY: The swallowing function was examined using simultaneous VFSS and high-resolution manometry (HRM) in 24 brainstem stroke survivors with dysphagia. The pharyngeal constriction ratio (PCR) and upper esophageal sphincter (UES) maximum opening diameter were measured using VFSS digital analysis. The pharyngeal maximum pressure and UES residual pressure were measured using HRM. The correlation coefficients between the PCR and pharyngeal maximum pressure and between the UES maximum opening diameter and UES residual pressure were calculated. The Spearman analyses were used to calculate the correlation coefficients between manometric and fluoroscopic parameters. RESULTS: The increase in the pharyngeal maximum pressure wave amplitude was significantly correlated with a decrease in the PCR (r=-0.849, P<0.001). The increase in the UES opening diameter was significantly correlated with a decrease in the UES residual pressure (r=-0.705, P<0.001). High space-time correlations between the pressure and kinematics of swallowing-related structures were obtained using simultaneous manometric and videofluoroscopic measurements. CONCLUSIONS: Certain VFSS measures are significantly correlated with measures of pressure assessed using HRM. The measures may be used as indicators of possible pressure deficits of swallowing.

Controllable fabrication of immobilized ternary CdS/Pt-TiO2 heteronanostructures toward high-performance visible-light driven photocatalysis.

Immobilized TiO2 nanotube arrays (NTAs) co-modified with Pt and CdS nanoparticles were fabricated by using the combination of photoreduction and chemical bath deposition methods. XRD, SEM, TEM, XPS, UV-Vis and EDX methods were employed to characterize the microstructure and composition of samples, and the results showed that CdS and Pt NPs were uniformly deposited on the surface of TiO2 nanotubes. The CdS/Pt/TiO2 NTAs exhibited a much higher photocatalytic activity compared to pure TiO2 NTAs and binary CdS (or Pt)/TiO2 NTAs under visible light irradiation. A kinetic study showed that the rate constants of Pt/TiO2, CdS/TiO2 and CdS/Pt/TiO2 NTAs are 0.00736, 0.01717 and 0.02077 min(-1), respectively, revealing a remarkable kinetic enhancement in the ternary heteronanostructures due to the synergistic effect of the three components. Besides, the CdS/Pt/TiO2 NTAs exhibit high stability after being used 22 times. Thus we proposed that such ternary heteronanostructures show great promise as immobilized catalysts for high efficient visible-light-driven photocatalysis.

Efficient syntheses of korupensamines A, B and michellamine B by asymmetric Suzuki-Miyaura coupling reactions.

Efficient asymmetric Suzuki-Miyaura coupling reactions are employed for the first time in total syntheses of chiral biaryl natural products korupensamine A and B in combination with an effective diastereoselective hydrogenation, allowing ultimately a concise and stereoselective synthesis of michellamine B. Chiral monophosphorus ligands L1-3 are effective for the syntheses of a series of functionalized chiral biaryls by asymmetric Suzuki-Miyaura coupling reactions in excellent yields and enantioselectivities (up to 99% ee). The presence of a polar-π interaction between the highly polarized BOP group and the extended π system of arylboronic acid coupling partner is believed to be important for the high enantioselectivity.