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 (IP
) 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.
A disturbance observer-based control (DOBC) approach is proposed in this paper for control design and qualitative robustness analysis of PWM-based DC-DC buck power converters. A disturbance ...compensation gain is constructed for the composite control algorithm to cancel the unmatched uncertainties in the output voltage channel. Rigorous criterion is provided to show the quantitative robustness between controller parameters and circuit uncertainties. The DOBC approach delivers not only a promising disturbance rejection performance but also a superior property of tracking performance recovery. The feasibility and efficiency of the proposed approach is validated by experimental results based on LabVIEW real-time control test setup.
Under the noncascade structure, a permanent-magnet synchronous motor (PMSM) regulates the speed and current in one loop. On the one hand, fast dynamic performance requires large transient current to ...provide a high torque. On the other hand, unlike a cascade control, the q-axis current is no longer governed by a reference current signal. In such a system, the nominal controllers cannot guarantee that the q-axis current is within the required range. But an excessively large transient current may threaten the circuit safety. To solve the overcurrent protection problem, the ordinary solution is to choose conservative control parameters, but the dynamic performance inevitably suffers a certain degree of loss. In order to improve this drawback, a simple and effective control scheme is introduced with a current-constrained technique. By constructing a special nonlinear gain, the punishment mechanism for the q-axis current is established in the control action directly. The proposed control approach does not impose limitations on the initial state. Moreover, it has good robustness to load torque uncertainty and undergoes rigorous theoretical analysis. Besides, the proposed current-constrained controller has a very concise structure. It yields a higher reliability of the PMSM control system. Comparative simulation and experimental results between the classic PID and the current-constrained controller on the PMSM servo system verify the feasibility of the presented control scheme.
Finite-time boundedness and finite-time weighted L2-gain for a class of switched delay systems with time-varying exogenous disturbances are studied. Based on the average dwell-time technique, ...sufficient conditions which guarantee the switched linear system with time-delay is finite-time bounded and has finite-time weighted L2-gain are given. These conditions are delay-dependent and are given in terms of linear matrix inequalities. Detail proofs are given by using multiple Lyapunov-like functions. An example is employed to verify the efficiency of the proposed method.
Huntington disease (HD) represents a family of neurodegenerative diseases that are caused by misfolded proteins. The misfolded proteins accumulate in the affected brain regions in an age-dependent ...manner to cause late-onset neurodegeneration. Transgenic mouse models expressing the HD protein, huntingtin, have been widely used to identify therapeutics that may retard disease progression. Here we report that Berberine (BBR), an organic small molecule isolated from plants, has protective effects on transgenic HD (N171-82Q) mice. We found that BBR can reduce the accumulation of mutant huntingtin in cultured cells. More importantly, when given orally, BBR could effectively alleviate motor dysfunction and prolong the survival of transgenic N171-82Q HD mice. We found that BBR could promote the degradation of mutant huntingtin by enhancing autophagic function. Since BBR is an orally-taken drug that has been safely used to treat a number of diseases, our findings suggest that BBR can be tested on different HD animal models and HD patients to further evaluate its therapeutic effects.
The work presented here considers the attitude synchronization problem for a group of spacecraft in the presence of communication delays. Based on the backstepping control and finite-time control ...techniques, a novel nonsmooth distributed cooperative attitude control algorithm is proposed for multiple spacecraft with attitude described by quaternion. Rigorous proof shows that attitude synchronization can be achieved asymptotically under the proposed control law if the communication topology graph among the spacecraft is strongly connected. Finally, a simulation example is given to demonstrate the efficiency of the proposed method.
The elimination of periodic torque disturbance in permanent magnet synchronous machine (PMSM) drives is a multifrequency control task, and adding resonant parts to the controller has an impact on the ...robustness of the system. This article aims to address the torque-ripple reduction in PMSM drives for smooth speed control, where an extended harmonic state observer (EHSO) is designed for estimation and attenuation of the selective periodic disturbance. The defects of applying the conventional bandwidth-parameterization method to the harmonic disturbance observer are explored. To improve the disturbance-rejection capability and the relative stability, a pole-placement strategy is proposed and analyzed through sensitivity function, which can preserve the comparable dynamic performance as the conventional extended state observer at the low-frequency range. The proposed EHSO also features easy parameter tuning and a modular structure for multiple harmonic disturbance rejection. Finally, the proposed method is evaluated on a laboratory PMSM platform.
The Huntington’s disease (HD) protein, huntingtin (HTT), is essential for early development. Because suppressing the expression of mutant HTT is an important approach to treat the disease, we must ...first understand the normal function of Htt in adults versus younger animals. Using inducible Htt knockout mice, we found that Htt depletion does not lead to adult neurodegeneration or animal death at >4 mo of age, which was also verified by selectively depleting Htt in neurons. On the other hand, young Htt KO mice die at 2 mo of age of acute pancreatitis due to the degeneration of pancreatic acinar cells. Importantly, Htt interacts with the trypsin inhibitor, serine protease inhibitor Kazal-type 3 (Spink3), to inhibit activation of digestive enzymes in acinar cells in young mice, and transgenic HTT can rescue the early death of Htt KO mice. These findings point out age- and cell type-dependent vital functions of Htt and the safety of knocking down neuronal Htt expression in adult brains as a treatment.
African swine fever virus (ASFV) is a large double-stranded DNA virus with an icosahedral multilayered structure. ASFV causes a lethal swine hemorrhagic disease and is currently responsible for ...widespread damage to the pork industry in Asia. Neither vaccines nor antivirals are available and the molecular characterization of the ASFV particle is outstanding. Here, we describe the cryogenic electron microscopy (cryo-EM) structure of the icosahedral capsid of ASFV at 4.6-Å. The ASFV particle consists of 8,280 copies of the major capsid protein p72, 60 copies of the penton protein, and at least 8,340 minor capsid proteins, of which there might be 3 different types. Like other nucleocytoplasmic large DNA viruses, the minor capsid proteins form a hexagonal network below the outer capsid shell, functioning as stabilizers by “gluing” neighboring capsomers together. Our findings provide a comprehensive molecular model of the ASFV capsid architecture that will contribute to the future development of countermeasures, including vaccines.
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•Cryo-EM structure of the icosahedrally averaged ASFV capsid described at 4.6-Å•ASFV capsid comprises 8,280 major capsid protein p72 and 60 penton protein copies•At least three different minor proteins stabilize capsid by gluing neighboring capsomers•ASFV differs from other NCLDVs in multilayered structure and icosahedral morphology
African swine fever virus (ASFV) is a large DNA virus that causes a lethal swine hemorrhagic disease and is currently responsible for widespread outbreaks in domestic pigs. Liu et al. describe the cryo-EM structure of ASFV capsid at 4.6-Å, which reveals several critical proteins and structural elements.
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