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This study aimed to investigate the efficacy and safety of fire needle plus cupping (FC) combined with oral famciclovir and gabapentin for the treatment of acute-phase herpes zoster (AHZ). This study was conducted as a superiority, randomized controlled trial in which 84 patients with AHZ who met the diagnostic criteria were selected and randomly assigned to three groups on a 1:1 basis. Group A: received oral famciclovir with gabapentin treatment (FG); Group B: received fire needle plus cupping (FC) with FG. The primary outcome was the difference in patients' pain levels as assessed by the VAS scale. Secondary outcomes were changes in sign-symptom scores, incidence of adverse effects, and incidence of PHN. After one week of treatment, both groups showed decreased VAS scores and symptom-sign scores compared to baseline. However, the decrease in VAS scores was significantly higher in Group B compared to Group A (p < 0.0001). Similarly, the improvement in symptom-sign scores was significantly better in Group B (p < 0.0001). Group A experienced a higher rate of adverse reactions (21.95%) compared to Group B (4.76%), with a significant difference between the groups (p = 0.021). Furthermore, the incidence of PHN was significantly lower in Group B (4.76%) compared to Group A (29.27%) (p = 0.003). Fire needle therapy combined with medication demonstrated superior analgesic effects, improved symptom relief, and reduced adverse reactions and the incidence of PHN compared to medication alone in the treatment of AHZ. Importantly, the fire needle and cupping therapy should be considered an add-on therapy to standard drug treatment, rather than a standalone treatment. Additionally, due to the lack of a sham-treated control group, the placebo effect associated with invasive therapies such as fire needling and cupping. Future studies should include a sham control group to better isolate the true effects of the treatment. Clinical trial registration: This study was registered with the Chinese Clinical Trial Registry under the code ChiCTR1800015372 (). Registered on 28 March 2018. All experiments on the participants were following the Declaration of Helsinki. [ABSTRACT FROM AUTHOR]

In some practical applications, the performance requirements of mechanisms differ significantly in various directions. However, this factor is not considered during the configuration design phase of parallel mechanisms (PMs), resulting in performance mismatches with actual needs in different directions. This mismatch leads to increased energy consumption, higher costs, and greater space occupation. To achieve a high degree of match between mechanism performance and practical needs, a type synthesis method for three translational (3T) PMs while considering velocity/force anisotropy is proposed in this paper. Furthermore, within the context of contact lens packaging, configuration synthesis for anisotropic 3T PMs is performed using the proposed method. By analyzing the speed transmission indices and experimental results of the 2URU/PPaPa PM in different directions, it is found that the anisotropic speed characteristics of this mechanism are consistent with the requirements of the actual application, thereby validating the proposed configuration synthesis method. [ABSTRACT FROM AUTHOR]

Pointing mechanism is widely used in aerospace field, and its pointing accuracy and stability have high requirements. The pointing mechanism will be affected by external interference when it works. In order to eliminate the impact of interference forces on the output accuracy of the mechanism, firstly, this paper proposes a design method for high-precision pointing mechanisms based on interference separation, aiming at the high-precision pointing requirements of pointing mechanisms. Based on the screw theory, a synthesis method for inner compensation mechanisms has been proposed. And a new type of double-layer parallel mechanism has been designed to compensate for interference forces. Then, the kinematics and dynamics of the mechanism are carried out. An evaluation index for compensating external interference forces is proposed. The interference compensation analysis is conducted for the pointing mechanism. The correctness of the proposed interference force compensation coefficient is verified. Finally, in order to find the optimal solution for the workspace and interference force compensation coefficient of the pointing mechanism, multi-objective optimization design of the structural parameters of the mechanism was carried out based on the particle swarm optimization algorithm. This provides a theoretical basis for the prototype design of the subsequent double-layer parallel mechanism. This double-layer parallel mechanism combines the advantages of large load-bearing capacity, large workspace, and high output accuracy. It can be better applied in the aerospace field where high-precision pointing and force interference compensation are integrated. [ABSTRACT FROM AUTHOR]

This paper investigates the finite-time position trajectory tracking control problem of quadrotor unmanned aerial vehicles (UAVs). Different from the standard inner–outer-loop control scheme, the proposed finite-time controller is constructed with an order-supplementary mechanism. Concretely, some virtual extended states with second-order dynamics are utilized in the controller design of the UAV's position-loop subsystem, to replace the original feedback part of tracking errors. Then, the adding a power integrator technique is used in the establishment of the virtual state dynamics, such that the position loop of quadrotor UAVs achieves the trajectory tracking tasks in finite time. Meanwhile, the attitude command references are directly formulated from the virtual extended states. Moreover, to deal with disturbances or unknown velocities, some finite-time observers are further combined in the proposed approach to obtain the corresponding estimates of disturbances and velocities. Compared with the existing results, the proposed order-supplementary finite-time trajectory tracking approach can remove the use of filters in the attitude command resolution and realize strict finite-time convergence. The thrust control input for the position-loop subsystem can be adjusted more flexibly by setting the initial values of the introduced virtual states. In addition, the finite-time velocity observer provided in this paper takes aerodynamic damping into account and has more accurate estimation in practice. Some simulations are given to validate the effectiveness of the proposed approach. [ABSTRACT FROM AUTHOR]

The nuclear loss and cytoplasmic accumulation of TDP-43 (TAR DNA/RNA binding protein 43) are pathological hallmarks of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Previously, we reported that the primate-specific cleavage of TDP-43 accounts for its cytoplasmic mislocalization in patients’ brains. This prompted us to investigate further whether and how the loss of nuclear TDP-43 mediates neuropathology in primate brain. In this study, we report that TDP-43 knockdown at the similar effectiveness, induces more damage to neuronal cells in the monkey brain than rodent mouse. Importantly, the loss of TDP-43 suppresses the E3 ubiquitin ligase PJA1 expression in the monkey brain at transcriptional level, but yields an opposite upregulation of PJA1 in the mouse brain. This distinct effect is due to the species-dependent binding of nuclear TDP-43 to the unique promoter sequences of the PJA1 genes. Further analyses reveal that the reduction of PJA1 accelerates neurotoxicity, whereas overexpressing PJA1 diminishes neuronal cell death by the TDP-43 knockdown in vivo. Our findings not only uncover a novel primate-specific neurotoxic contribution to the loss of function theory of TDP-43 proteinopathy, but also underscore a potential therapeutic approach of PJA1 to the loss of nuclear TDP-43. [ABSTRACT FROM AUTHOR]

This paper concludes a robust optimal tracking control law for a class of nonlinear systems. A characteristic of this paper is that the designed controller can guarantee both robustness and optimality under nonlinearity and mismatched disturbances. Optimal controllers for nonlinear systems are difficult to obtain, hence a reinforcement learning method is adopted with two neural networks (NNs) approximating the cost function and optimal controller, respectively. We designed weight update laws for critic NN and actor NN based on gradient descent and stability, respectively. In addition, matched and mismatched disturbances are estimated by fixed-time disturbance observers and an artful transformation based on backstepping method is employed to convert the system into a filtered error nonlinear system. Through a rigorous analysis using the Lyapunov method, we demonstrate states and estimation errors remain uniformly ultimately bounded. Finally, the effectiveness of the proposed method is verified through two illustrative examples. [ABSTRACT FROM AUTHOR]

In order to solve the problem of weak stiffness of the existing fully decoupled parallel mechanism, a new synthesis method of fully decoupled three translational (3T) parallel mechanisms (PMs) with closed-loop units and high stiffness is proposed based on screw theory. Firstly, a new criterion for the full decoupled of PMs is presented that the reciprocal product of the transmission wrench screw matrix and the output twist screw matrix of PMs is a diagonal matrix, and all elements on the main diagonal are nonzero constants. The forms of the transmission wrench screws are determined by the criterion. Secondly, the forms of the actuated and unactuated screws can be obtained according to their relationships with the transmission wrench screws. The basic decoupled limbs are generated by combination of the above actuated and unactuated screws. Finally, a closed-loop units construction method is investigated to apply the decoupled mechanisms in a better way on the high stiffness occasion. The closed-loop units are constructed in the basic decoupled limbs to generate a high-stiffness fully decoupled 3T PM. Kinematic and stiffness analyses show that the Jacobian matrix is a diagonal matrix, and the stiffness is obviously higher than that of the coupling mechanisms, which verifies the correctness of the proposed synthesis method. The mechanism synthesized by this method has a good application prospect in vehicle durability test platform. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the therapeutic efficacy, feasibility, and safety of total parathyroidectomy (tPTX) in the treatment of secondary hyperparathyroidism (SHPT). Methods: The clinical data of 34 SHPT patients admitted to the Department of Nephrology, Yuxi People's Hospital, from January 2018 to January 2021 who had received tPTX, were retrospectively analyzed. The indications for tPTX were severe SHPT that did not respond to medical treatment and was ineligible for kidney transplantation. tPTX without autotransplantation was adopted to compare the level of symptom relief and changes in serum intact parathyroid hormone (iPTH), blood calcium, and blood phosphorus pre- and postoperatively. Results: In 34 patients, 142 parathyroid glands were removed, including 21 ectopic parathyroid glands (14.78%). Six patients (17.64%, 6/34) had supernumerary parathyroid glands. At 6 h postoperatively, arthralgia and bone pain were significantly reduced to almost zero in 94.12% (32/34) of patients. At 24 h postoperatively, relief of bone pain and improvement of limb movement were observed in 100% (34/34) of patients, and pruritus almost disappeared in 86.36% (19/22) of patients. There were significant differences in iPTH (χ2 = 134.93, P < 0.05), calcium (χ2 = 23.02, P < 0.05), and phosphorus (χ2 = 102.11, P < 0.05) levels preoperatively and 40 min, 24 h, 1 week, half a year, and last available (> 1 year) postoperatively. The patients were followed up for 15–47 months (median 33 months). Hypoparathyroidism was observed in three patients, who underwent neck dissection or partial thymotomy concurrently for different reasons. No intractable hypocalcemia or adynamic bone disease occurred during the follow-up period. Conclusion: In SHPT patients who were ineligible for renal transplantation, tPTX was effective, safe, and reliable, with a low recurrence rate. However, when tPTX was performed alone without autologous transplantation, bilateral neck exploration was sufficient, and central neck dissection and thymic resection were inadvisable. [ABSTRACT FROM AUTHOR]

In a very short time, higher education transitioned to online and blended learning, in response to the global COVID-19 pandemic. Although research literature is replete with rationale for instructors to develop digital competence during the Great Online Transition, research on the correlates of digital competence and effort expectancy in relation to their work engagement has remained insufficient. Thus, the objective of this study is to investigate the effects of digital competence and effort expectancy and how they predict teachers' work engagement. A sample of 321 in-service teachers selected from universities in China took part in this study. The results of structural equation modeling indicated that teachers' digital competence positively and significantly correlated with their work engagement and their effort expectancy. In addition, effort expectancy significantly influenced teachers' work engagement. Lastly, effort expectancy, as the mediator variable, was found to mediate the relationship between teachers' digital competence and their work engagement. Implications were suggested for improving teachers' work engagement to support digital shifts. [ABSTRACT FROM AUTHOR]

With the rapid development of diesel engines, reducing the pressure fluctuation of the common rail has become a key factor to improve the performance of the high pressure common rail (HPCR) system. Among traditional rail pressure control approaches, the influence of time-varying disturbances on the HPCR system is not fully considered and is not well dealt with. To this end, a nonlinear model of the HPCR system is firstly established based on fluid dynamics and mechanics laws. And a composite controller based on the nonlinear model is proposed. It consists of two parts: 1) A sliding mode feedback part; 2) A disturbance feedforward compensation part based on a generalized proportional integral observer. Finally, a group of test is simulated in the AMESim simulation environment and the results are shown to demonstrate the effectiveness of the proposed method. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) is an autosomal dominantly-inherited neurodegenerative disease, which is caused by CAG trinucleotide expansion in exon 1 of the Huntingtin (HTT) gene. Although HD is a rare disease, its monogenic nature makes it an ideal model in which to understand pathogenic mechanisms and to develop therapeutic strategies for neurodegenerative diseases. Clustered regularly-interspaced short palindromic repeats (CRISPR) is the latest technology for genome editing. Being simple to use and highly efficient, CRISPR-based genome-editing tools are rapidly gaining popularity in biomedical research and opening up new avenues for disease treatment. Here, we review the development of CRISPR-based genome-editing tools and their applications in HD research to offer a translational perspective on advancing the genome-editing technology to HD treatment. [ABSTRACT FROM AUTHOR]

Huntingtin-associated protein 1 (HAP1) is the first identified protein whose function is affected by its abnormal interaction with mutant huntingtin (mHTT), which causes Huntington disease. However, the expression patterns of Hap1 and Htt in the rodent brain are not correlated. Here we found that the primate HAP1, unlike the rodent Hap1, is correlatively expressed with HTT in the primate brains. CRISPR/Cas9 targeting revealed that HAP1 deficiency in the developing human neurons did not affect neuronal differentiation and gene expression as seen in the mouse neurons. However, deletion of HAP1 exacerbated neurotoxicity of mutant HTT in the organotypic brain slices of adult monkeys. These findings demonstrate differential HAP1 expression and function in the mouse and primate brains, and suggest that interaction of HAP1 with mutant HTT may be involved in mutant HTT-mediated neurotoxicity in adult primate neurons. [ABSTRACT FROM AUTHOR]

New evidence suggests that abnormal expression of circular RNA (circRNA) is associated with the development of human cancers. This study aims to reveal circMYOF roles in the malignant phenotype of laryngeal squamous cell carcinoma (LSCC). The expression of circMYOF, microRNA (miR)-145-5p, and orthodenticle homeobox 1 (OTX1) was detected by quantitative real-time PCR. Cell proliferation, migration, invasion, and apoptosis were determined using colony formation assay and EdU assay, wound healing assay, transwell assay, and flow cytometry, respectively. Protein expression was examined by western blot analysis. Cell glycolysis was assessed by detecting glucose consumption and lactate production. Mice xenograft models were constructed to evaluate the regulation of circMYOF on LSCC tumorigenesis. The regulatory relationships among circMYOF, miR-145-5p, and OTX1 were identified using dual-luciferase reporter assay and RIP assay. Serum exosomes were isolated to confirm the existence of circMYOF in LSCC patients. CircMYOF was upregulated in LSCC tissues and cells, and its knockdown suppressed LSCC cell growth, metastasis, and glycolysis, as well as inhibited LSCC tumor growth. MiR-145-5p had decreased expression in LSCC, and it could be sponged by circMYOF. The inhibition effect of circMYOF lentivirus short hairpin RNA (sh-circMYOF) on LSCC progression was restored by the inhibitor of miR-145-5p (in-miR-145-5p). Also, OTX1 was targeted by miR-145-5p and was positively regulated by circMYOF. MiR-145-5p could repress LSCC progression, and OTX1 overexpression also eliminated this effect. In addition, we found that circMYOF was significantly overexpressed in the serum exosomes of LSCC patients. Our data revealed that circMYOF contributed to LSCC progression by promoting cell growth, metastasis, and glycolysis through miR-145-5p/OTX1 axis. [ABSTRACT FROM AUTHOR]

The electroplated super-hard abrasive wheel is prone to cause the blockage of wheel and the burnout of workpiece in high efficiency grinding due to insufficient of chip storage space. Ordered arrangement of abrasives technology is an effective method to improve sharpness and chip storage space of wheel. Moreover, it also can reduce grinding heat generation. Therefore, an ordered electroplated CBN wheel with dislocation arrangement of abrasives is developed by a new imprint dispensing method in this paper. Grinding force model of a dislocation arrangement of abrasives is established and discussed. Grinding forces, grinding temperatures and surface morphology of workpiece and wheel are compared with the traditional electroplated CBN wheel in dry grinding experiments. The results show that grinding force decreases by 15–20% and grinding temperature decreases by 6–20% in high-speed shallow grinding. However, grinding force increases by 5–15% and grinding temperature increases about 5% in high-efficiency deep grinding. Grinding forces are not only affected by abrasive arrangement but also by grinding amount. Surface quality of workpiece is worse when using the ordered wheel due to a considerable reduction in abrasive number, but the ordered wheel is no blockage. [ABSTRACT FROM AUTHOR]

Compared with the strongly-coupled parallel mechanism, the weakly-coupled mechanism can realize two kinds of mutually independent motions. In this paper, a new method for type synthesis of weakly-coupled compliant parallel mechanisms is proposed. The synthesis conditions, that is, the synthesis conditions of the shared flexure hinges and synthesis condition of the weakly-coupled, are given. The synthesis process is formulated. From the perspective of mechanism innovation, a new synthesis idea of weakly-coupled CPMs is introduced. New weakly-coupled CPMs without intermediate platform are obtained by sharing the flexure hinges of two compliant parallel mechanisms. To obtain five degree of freedom (5-DOFs) weakly-coupled compliant parallel mechanisms, two kinds of sub-sets of compliant mechanism blocks, a two-rotation and one-translation compliant mechanism and a two-translation compliant mechanism are proposed. With the proposed synthesis method, two blocks are indirectly connected by sharing flexure hinges to obtain an integral mechanism. Then, new 5-DOF weakly-coupled compliant parallel mechanisms are proposed by the synthesis conditions. Additionally, finite element simulation is carried out to verify the correctness of the proposed synthesis method. Thirteen new 5-DOF weakly-coupled compliant parallel mechansims have been synthesized, which enriches the compliant parallel mechanism configurations. And, they have simple structure, compact structure, ease of control and light weight. The synthesized 5-DOF weakly-coupled compliant parallel mechanisms have potential application to pointing, vibration isolation and mirror adjustment platform. [ABSTRACT FROM AUTHOR]

The performance of attitude stabilization control algorithms for rigid spacecraft can be limited by disturbances. In this paper, the global finite-time attitude stabilization problem with disturbances is investigated and handled by constructing a second-order sliding mode controller. Firstly, a virtual controller based on set stabilization idea is constructed to globally finite-time stabilize the system. Then, a relay polynomial second-order sliding mode controller is constructed to guarantee that the tracking error toward the virtual controller will converge to zero in finite-time. Finite-time Lyapunov theory is applied to support the proof and stability analysis. The global finite-time stability holds even with bounded disturbances. The effectiveness and feasibility of the controller are illustrated by the numerical simulations. [ABSTRACT FROM AUTHOR]

This paper proposes a new synthesis method of three translational and two rotational (3T2R) decoupled hybrid mechanism with large bearing capacity, based on the screw theory and the atlas method. According to the degree of freedom and decoupled characteristics of the 3T and 2R mechanisms, the decoupled conditions for the 3T and 2R parallel mechanisms are proposed. The optimal conditions for the motion/force transmission performance of the 3T decoupled parallel mechanisms with redundant actuation is presented. A redundant actuated limb construction method is proposed to improve the load capacity of the hybrid mechanism. Following the design steps of the fully decoupled hybrid mechanism, 3T2R hybrid mechanisms with large load capacity are obtained. Kinematics and statics analysis verify the correctness of the proposed synthesis method. The mechanism synthesized by this method has a good application prospect in large load occasion. [ABSTRACT FROM AUTHOR]

Laser directed energy deposition (LDED) is a promising additive manufacturing technology based on the fused deposition of metal powder, but the low utilization rate of powder limits its commercial application. The deposition process is very complex, and the correlation between physical properties of powder and performance of specimens manufactured has not been fully revealed. So the objective of this paper is to investigate the recyclability of 316L stainless steel powder used by LDED. The morphology, particle size distribution and surface phase composition of the standard and recycled powder were compared. The micro-hardness and mechanical property of different components were also tested. The results show that under the multiple effects from laser, powder was gradually coarsened, the proportion of irregularly shaped particles increased and the elements content of surface were slightly changed. But the surface phase composition did not transform. Microstructure of specimens fabricated by recycled powder was coarser, some internal metallurgical defects appeared and a decrease in plasticity occurred. However, little difference in the micro-hardness and tensile strength was found for samples fabricated by virgin and recycled powder. [ABSTRACT FROM AUTHOR]

Selective neuronal accumulation of misfolded proteins is a key step toward neurodegeneration in a wide range of neurodegenerative diseases, including Huntington's (HD) diseases. Our recent studies suggest that Hsp70-binding protein 1 (HspBP1), an Hsp70/CHIP inhibitor that reduces protein folding, is highly expressed in neuronal cells and accounts for the accumulation of the HD protein huntingtin (HTT) in neuronal cells. To further determine the role of HspBP1 in regulation of mutant protein accumulation, we investigated whether increasing expression of HspBP1 in glial cells can also induce the accumulation of endogenous mutant HTT in glial cells and yield non-cell-autonomous toxic effects. We performed stereotaxic injection of AAV to selectively express HspBP1 in astrocytes in the brains of HD140Q knock-in (KI) mice that express mutant HTT ubiquitously but do not display obvious neurodegeneration. However, HspBP1 expression in HD140Q astrocytes led to the increased accumulation of endogenous mutant HTT and robust neuronal loss in the striatum of HD140Q KI mice. In transgenic HD mice that selectively express mutant HTT in astrocytes, increased accumulation of mutant HTT in astrocytes via HspBP1 expression did not elicit neurodegeneration but could exacerbate neurological symptoms. Consistently, suppressing the expression of endogenous HspBp1 in the striatum of HD140Q KI mice via CRISPR/Cas9 led to a significant reduction of mutant HTT accumulation. Our findings suggest that although endogenous mutant HTT in astrocytes can exacerbate neurological symptoms, it mediates neurodegeneration only when mutant HTT is also accumulated in neuronal cells. [ABSTRACT FROM AUTHOR]

The lower-mobility parallel mechanism has been widely used in the engineering field due to its numerous excellent characteristics. However, little work has been devoted to the actuator selection and placement that best satisfy the system's functional requirements during concept design. In this study, a unified approach for synthesizing the actuation spaces of both rigid and flexure parallel mechanisms has been presented, and all possible combinations of inputs could be obtained, laying a theoretical foundation for the subsequent optimization of inputs. According to the linear independence of actuation space and constraint space of the lower-mobility parallel mechanism, a general expression of actuation spaces in the format of screw systems is deduced, a unified synthesis process for the lower-mobility parallel mechanism is derived, and the efficiency of the method is validated with two selective examples based on screw theory. This study presents a theoretical framework for the input selection problems of parallel mechanisms, aiming to help designers select and place actuators in a correct and even optimal way after the configuration design. [ABSTRACT FROM AUTHOR]

In this paper, the autonomous landing control issue on moving shipboard is investigated for unmanned helicopters subject to disturbances. The issue is studied by stabilizing the error system of the helicopter and the shipboard. The landing process is divided into two phases, i.e., homing phase, where a hierarchical double-loop control scheme is developed such that the helicopter is forced to hover synchronously at a certain altitude over the shipboard, and landing phase, where a composite landing control scheme is proposed such that the helicopter lands vertically on the shipboard in synchronization with its attitudes. The velocity and acceleration information of the shipboard as well as lump disturbances is estimated through joint state and disturbance observers. The estimates are then incorporated into the baseline feedback controller, formulating composite active anti-disturbance landing control schemes. A continuous terminal sliding mode control method is proposed for the feedback controller design, which not only effectively mitigates the chattering of the control action, but also simplifies the design process of the controller. Numerical simulations demonstrate the effectiveness and superiorities of the proposed control schemes. [ABSTRACT FROM AUTHOR]

In recent years, inspired by the structure of natural lotus leaves and fish scales, the oil/water separation membrane with special wettability has made remarkable progress. A cost-effective, eco-friendly and facile approach of membranes with special wettability performance is highly desired. Herein, magnesium hydroxide (Mg(OH)2) is synthesized in situ on cotton fabrics through a surface micro-dissolution method to prepare superhydrophilic and underwater superoleophobic functionalized fabrics. Driven by gravity, the Mg(OH)2@fabric can successfully separate the oil/water mixture with high flux of 3027–4137 L/m2 h and high separation efficiency of 99.5%. In addition, after soaking in harsh environment for 72 h, such as alkali and salt solution, it still has high stability and can be used as a membrane to separate a series of oil/water mixtures. Driven by a constant current pump (200 mL/min), the developed fabric can separate oil-in-water emulsions with a high separation efficiency of 99.5%. After 50 cycles, the separation efficiency of the treated fabric for oil–water mixture is more than 99.3%, and the underwater contact angle is more than 156.6°. This method can simply and effectively produce fabrics that can be used to treat water purification and oily wastewater, and has a broad application prospect. [ABSTRACT FROM AUTHOR]

Demyelination is a common pathological feature of a large number of neurodegenerative diseases including multiple sclerosis and Huntington's disease (HD). Laquinimod (LAQ) has been found to have therapeutic effects on multiple sclerosis and HD. However, the mechanism underlying LAQ's therapeutic effects remains unknown. Using HD mice that selectively express mutant huntingtin in oligodendrocytes and show demyelination, we found that LAQ reduces the Ser259 phosphorylation on myelin regulatory factor (MYRF), an oligodendrocyte‐specific transcription factor promoting the expression of myelin‐associated genes. The reduced MYRF phosphorylation inhibits MYRF's binding to mutant huntingtin and increases the expression of myelin‐associated genes. We also found that PRKG2, a cGMP‐activated protein kinase subunit II, promotes the Ser259‐MYRF phosphorylation and that knocking down PRKG2 increased myelin‐associated protein's expression in HD mice. Our findings suggest that PRKG2‐regulated phosphorylation of MYRF is involved in demyelination and can serve as a potential therapeutic target for reducing demyelination. Synopsis: Laquinimod reduces Ser259 phosphorylation of myelin regulatory factor and its binding to mutant huntingtin, alleviating expression of myelin‐associated genes and demyelination caused by mutant huntingtin in oligodendrocytes. Laquinimod alleviates the phenotypes and pathology of HD mice expressing mutant HTT in oligodendrocytes.Laquinimod inhibits the interaction of mutant HTT with MYRF by reducing the phosphorylation of MYRF and restores the expression of myelin genes.Reducing the phosphorylation of MYRF by knocking down PRKG2 increases the expression of myelin genes in HD mice. [ABSTRACT FROM AUTHOR]

Polyglutamine expansion in proteins can cause selective neurodegeneration, although the mechanisms are not fully understood. In Huntington's disease (HD), proteolytic processing generates toxic N-terminal huntingtin (HTT) fragments that preferentially kill striatal neurons. Here, using CRISPR/Cas9 to truncate full-length mutant HTT in HD140Q knock-in (KI) mice, we show that exon 1 HTT is stably present in the brain, regardless of truncation sites in full-length HTT. This N-terminal HTT leads to similar HD-like phenotypes and age-dependent HTT accumulation in the striatum in different KI mice. We find that exon 1 HTT is constantly generated but its selective accumulation in the striatum is associated with the age-dependent expression of striatum-enriched HspBP1, a chaperone inhibitory protein. Our findings suggest that tissue-specific chaperone function contributes to the selective neuropathology in HD, and highlight the therapeutic potential in blocking generation of exon 1 HTT. The mechanisms by which mutant Huntington protein Htt leads to selective neurodegeneration are not fully understood. Here, using gene editing in HD140Q knock-in mice, the authors show that exon1 Htt is a critical pathological form of the protein. [ABSTRACT FROM AUTHOR]

Spinocerebellar ataxias 17 (SCA17) is caused by polyglutamine (polyQ) expansion in the TATA box-binding protein (TBP). The selective neurodegeneration in the cerebellum in SCA17 raises the question of why ubiquitously expressed polyQ proteins can cause neurodegeneration in distinct brain regions in different polyQ diseases. By expressing mutant TBP in different brain regions in adult wild-type mice via stereotaxic injection of adeno-associated virus, we found that adult cerebellar neurons are particularly vulnerable to mutant TBP. In SCA17 knock-in mice, mutant TBP inhibits SP1-mediated gene transcription to down-regulate INPP5A, a protein that is highly abundant in the cerebellum. CRISPR/Cas9-mediated deletion of Inpp5a in the cerebellum of wild-type mice leads to Purkinje cell degeneration, and Inpp5a overexpression decreases inositol 1,4,5-trisphosphate (IP3) levels and ameliorates Purkinje cell degeneration in SCA17 knock-in mice. Our findings demonstrate the important contribution of a tissue-specific protein to the polyQ protein-mediated selective neuropathology. It is not yet clear how ubiquitously-expressed proteins can cause the selective degeneration of particular populations of neurons, such as in spinocerebellar ataxia type 17, SCA17, which results from a CAG trinucleotide repeat expansion in the ubiquitously expressed transcription factor TBP. Here, the authors show that mutant TBP suppresses the cerebellum-enriched transcription of Inpp5a and link altered levels of INPP5A to the selective degeneration of cerebellar neurons. [ABSTRACT FROM AUTHOR]

A hallmark of Alzheimer's disease (AD) pathogenesis is the accumulation of extracellular plaques mainly composed of amyloid-β (Aβ) derived from amyloid precursor protein (APP) cleavage. Recent reports suggest that transport of APP in vesicles with huntingtin-associated protein-1 (HAP1) negatively regulates Aβ production. In neurons, HAP1 forms a stable complex with Abelson helper integration site-1 (AHI1), in which mutations cause neurodevelopmental and psychiatric disorders. HAP1 and AHI1 interact with tropomyosin receptor kinases (Trks), which are also associated with APP and mediate neurotrophic signaling. In this study, we hypothesize that AHI1 participates in APP trafficking and processing to rescue AD pathology. Indeed, AHI1 was significantly reduced in mouse neuroblastoma N2a cells expressing human Swedish and Indiana APP (designed as AD model cells) and in 3xTg-AD mouse brain. The AD model cells as well as Ahi1-knockdown cells expressing wild-type APP-695 exhibited a significant reduction in viability. In addition, the AD model cells were reduced in neurite outgrowth. APP C-terminal fragment-β (CTFβ) and Aβ42 were increased in the AD cell lysates and the culture media, respectively. To investigate the mechanism how AHI1 alters APP activities, we overexpressed human AHI1 in the AD model cells. The results showed that AHI1 interacted with APP physically in mouse brain and transfected N2a cells despite APP genotypes. AHI1 expression facilitated intracellular translocation of APP and inhibited APP amyloidogenic process to reduce the level of APP-CTFβ in the total lysates of AD model cells as well as Aβ in the culture media. Consequently, AHI1–APP interactions enhanced neurotrophic signaling through Erk activation and led to restored cell survival and differentiation. [ABSTRACT FROM AUTHOR]

Because the mechanisms that cause hydraulic fracturing to increase coal seam permeability are not clear, the effective application of hydraulic fracturing has limitations. This paper presents hydraulic fracturing and gas seepage experiments using raw coal under different stress states. The results showed that fracture propagation in coal was influenced by the properties of natural cleats and their ability to induce complex fractures. Using complex fracture abstraction and a connectivity coefficient β, a permeability model of coal subject to hydraulic fracturing with a stimulated reservoir volume (SRV) was established. The SRV effect was optimal when the pressure coefficient (Rn) was 1.46. The value of the Biot coefficient α remained unchanged at approximately 0.854 as the net pressure coefficient was changed. As Rn was increased, the stress sensitive coefficient Cf decreased and the increase in permeability caused by SRV was higher. The permeability of coal subjected to SRV was about two to three orders of magnitude higher than before fracturing. Conventional fracturing only increased the permeability to twice that before fracturing. Therefore, the influence and benefits of SRV should be considered when predicting coal-bed methane production from the permeability of coal beds. [ABSTRACT FROM AUTHOR]

Background: Huntingtin-associated protein 1 (HAP1) is a neuronal protein that is predominantly expressed in neurons in the brain. HAP1 is critical for maintenance of neuronal survival as well as regulation of food intake and body weight in animals. In addition to the critical
role of HAP1 in the central nervous system, HAP1 is also found in endocrine cells, raising an interesting issue of whether HAP1 is expressed in the digestive system.Aims: To examine the expression and localization of HAP1 in the human gastrointestinal tract and to compare the differences of the HAP1 expression between benign and malignant tissues in the digestive system.Methods: We used Western blot and immunohistochemistry to examine the expression and distribution of HAP1 in the human gastrointestinal tract tissues.Results: We observed that the presence of HAP1-positive cells in the gastrointestinal tract was not uniform with immunohistochemistry staining. Western blot revealed that only one isoform (75KD) HAP1 was present in the human gastrointestinal system. Interestingly, the expression of HAP1 was higher in the stomach than other regions of the gastrointestinal tract and was at the lowest level in the intestine. We also found that HAP1 was unlikely altered in benign gastric polyps, but was downregulated in pancreatic cancer.Conclusions: This is the first study showing the differential expression and location of HAP1 in the human digestive system. These findings suggested that HAP1 may have cell-type-dependent function in the gastrointestinal tract and may serve as a diagnostic marker for pancreatic cancer. [ABSTRACT FROM AUTHOR]

Land-use information provides a direct representation of the effect of human activities on the environment, and an accurate and efficient land-use classification of remote sensing images is an important element of land-use and land-cover change research. To solve the problems associated with traditional land-use classification methods (e.g., rapid increase in dimensionality of data, inadequate feature extraction, and low running efficiency), a method that combines object-oriented approach with deep convolutional neural network (COCNN) is presented. First, a multi-scale segmentation algorithm is used to segment images to generate image segmentation regions with high homogeneity. Second, a typical rule set of feature objects is constructed on the basis of the object-oriented segmentation results, and the segmentation objects are classified and extracted to form a training sample set. Third, a convolutional neural network (CNN) model structure is modified to improve classification performance, and the training algorithm is optimized to avoid the overfitting phenomenon that occurs during training using small datasets. Ten land-use types are classified by using the remote sensing images covering the area around Fuxian Lake as an example. By comparing the COCNN method with the method based solely on CNN, precision and kappa index were selected to evaluate the classification accuracy of the two methods. For the COCNN method, on the basis of the classification statistics, precision and kappa index coefficients are 96.2% and 0.96, respectively, which are 8.98% and 0.1 higher than those of the method based solely on CNN. Experimental results show that the COCNN method reasonably and efficiently combines object-oriented and deep learning approaches, thereby effectively solving the problem of the inaccurate classification of typical features with better classification accuracy than the simple use of CNN. [ABSTRACT FROM AUTHOR]

The cytoplasmic accumulation of the nuclear TAR DNA-binding protein 43 (TDP-43) is a pathologic hallmark in amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and other neurological disorders. However, most transgenic TDP-43 rodent models show predominant nuclear distribution of TDP-43 in the brain. By expressing mutant TDP-43 (M337V) in the brains of rhesus monkeys and mice, we verified that mutant TDP-43 is distributed in the cytoplasm of the monkey brain and that the majority of mutant TDP-43 remains in the nuclei of the mouse brain. The primate-specific caspase-4, but not mouse homologue caspase-11, could remove the NLS-containing N-terminal domain and generate fragmented TDP-43 that accumulates in the cytoplasm. Moreover, increased expression of caspase-4 in the monkey brain promotes the cytoplasmic accumulation of endogenous TDP-43, and suppressing caspase-4 reduces the cytoplasmic distribution of endogenous TDP-43 in cultured human neural cells. Our findings suggest that primate-specific caspase-4-mediated cleavage of TDP-43 accounts for its cytoplasmic mislocalization in the primate brains and may serve as a potential therapeutic target. [ABSTRACT FROM AUTHOR]

This paper investigates a generalized active disturbance rejection control framework for a class of uncertain nonlinear systems subject to additive disturbance. First, a new extended state observer with less dependence of the system information is developed which will enable an easy-transplantable characteristic for nonlinear systems with variable nonlinearity restrictions. Then integrating with an output feedback domination technique, an effective disturbance attenuation law is designed to handle a wider class of systems whose nonlinear items may go beyond the strict-feedback structure and Lipschitz continuity requirement. A rigorous stability analysis is also carried out with a semi-global output feedback control objective. Numerical simulation results and an application into a DC-DC buck power converters demonstrate the feasibility and improved control performance of the proposed method. [ABSTRACT FROM AUTHOR]

Although it is common to eliminate the singularity of parallel mechanism by adding the branched chain with actuation redundancy, there is no theory and method for the configuration synthesis of the branched chain with actuation redundancy in parallel mechanism. Branched chains with actuation redundancy are synthesized for eliminating interior singularity of 3-translational and 1- rotational(3T1R) parallel mechanisms. Guided by the discriminance method of hybrid screw group according to Grassmann line geometry, all the possibilities are listed for the occurrence of interior singularities in 3T1R parallel mechanism. Based on the linear relevance of screw system and the principles of eliminating parallel mechanism singularity with actuation redundancy, different types of branched chains with actuation redundancy are synthesized systematically to indicate the layout and the number of the branched chainsinterior with actuation redundancy. A general method is proposed for the configuration synthesis of the branched chains with actuation redundancy of the redundant parallel mechanism, and it builds a solid foundation for the subsequent performance optimization of the redundant actuation parallel mechanism. [ABSTRACT FROM AUTHOR]

Berberine (BBR) is an organic small molecule isolated from various plants that have been used in traditional Chinese medicine. Isolation of this compound was its induction into modern medicine, and its usefulness became quickly apparent as seen in its ability to combat bacterial diarrhea, type 2 diabetes, hypercholesterolemia, inflammation, heart diseases, and more. However, BBR's effects on neurodegenerative diseases remained relatively unexplored until its ability to stunt Alzheimer's disease (AD) progression was characterized. In this review, we will delve into the multi-faceted defensive capabilities and bio-molecular pathways of BBR against AD, Parkinson's disease (PD), and trauma-induced neurodegeneration. The multiple effects of BBR, some of which enhance neuro-protective factors/pathways and others counteract targets that induce neurodegeneration, suggest that there are many more branches to the diverse capabilities of BBR that have yet to be uncovered. The promising results seen provide a convincing and substantial basis to support further scientific exploration and development of the therapeutic potential of BBR against neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

This paper concerns the problem of constructing $$C^1$$ (continuously differentiable) controllers to stabilize a class of uncertain non-linear systems whose linearization around the origin may contain uncontrollable modes. Based on a new definition of homogeneity with monotone degrees, a polynomial Lyapunov function and a $$C^1$$ global stabilizer are constructed recursively. Moreover, several special cases are investigated to show the advantages of the proposed approaches using the generalized homogeneity compared to the existing approaches using the traditional homogeneity. [ABSTRACT FROM AUTHOR]