Spastic paraplegia type 4 (SPG4) is the most common type of autosomally inherited spastic paraplegia. Its main clinical features include typical simple hereditary spastic paraplegia, with neurological impairments limited to lower limb spasticity, hypertonic bladder dysfunction, and mild weakening of lower limb vibration sensation, without accompanying features such as nerve atrophy, ataxia, cognitive impairment, seizures, and muscle tone disorders. SPAST is the main pathogenic gene underlying SPG4, and various pathogenic SPAST variants have been discovered. This disease has featured a high degree of clinical heterogeneity, and the same pathogenic variant can have different age of onset and severity among different patients and even within the same family. There is a lack of systematic research on the correlation between the genotype and phenotype of SPG4, and the pathogenic mechanism has remained controversial. This article has provided a review for the clinical characteristics, pathogenic gene characteristics, correlation between the genotype and phenotype, and pathogenic mechanism of this disease, with an aim to provide reference for its clinical diagnosis and treatment.
Patients with Alzheimer's disease (AD) commonly show anxiety behaviors, but the molecular mechanisms are not clear and no efficient intervention exists. Here, we found that overexpression of human wild-type, full-length tau (termed htau) in hippocampus significantly decreased the extracellular γ-aminobutyric acid (GABA) level with inhibition of γ oscillation and the evoked inhibitory postsynaptic potential (eIPSP). With tau accumulation, the mice show age-dependent anxiety behaviors. Among the factors responsible for GABA synthesis, release, uptake, and transport, we found that accumulation of htau selectively suppressed expression of the intracellular vesicular GABA transporter (vGAT). Tau accumulation increased miR92a, which targeted vGAT mRNA 3' UTR and inhibited vGAT translation. Importantly, we found that upregulating GABA tones by intraperitoneal injection of midazolam (a GABA agonist), ChR2-mediated photostimulating and overexpressing vGAT, or blocking miR92a by using specific antagomir or inhibitor efficiently rescued the htau-induced GABAergic dysfunctions with attenuation of anxiety. Finally, we also demonstrated that vGAT level decreased while the miR92a increased in the AD brains. These findings demonstrate that the AD-like tau accumulation induces anxiety through disrupting miR92a-vGAT-GABA signaling, which reveals molecular mechanisms underlying the anxiety behavior in AD patients and potentially leads to the development of new therapeutics for tauopathies.
Transcription factors with a large number of target genes--transcription hub(s), or THub(s)--are usually crucial components of the regulatory system of a cell, and the different patterns through which they transfer the transcriptional signal to downstream cascades are of great interest. By profiling normalized abundances (A(N)) of basic regulatory patterns of individual THubs in the yeast Saccharomyces cerevisiae transcriptional regulation network under five different cellular states and environmental conditions, we have investigated their preferences for different basic regulatory patterns. Subgraph-normalized abundances downstream of individual THubs often differ significantly from that of the network as a whole, and conversely, certain over-represented subgraphs are not preferred by any THub. The THub preferences changed substantially when the cellular or environmental conditions changed. This switching of regulatory pattern preferences suggests that a change in conditions does not only elicit a change in response by the regulatory network, but also a change in the mechanisms by which the response is mediated. The THub subgraph preference profile thus provides a novel tool for description of the structure and organization between the large-scale exponents and local regulatory patterns.
Abstract A strong animal survival instinct is to approach objects and situations that are of benefit and to avoid risk. In humans, a large proportion of mental disorders are accompanied by impairments in risk avoidance. One of the most important genes involved in mental disorders is disrupted-in-schizophrenia-1 ( DISC1 ), and animal models in which this gene has some level of dysfunction show emotion-related impairments. However, it is not known whether DISC1 mouse models have an impairment in avoiding potential risks. In the present study, we used DISC1-N terminal truncation ( DISC1-N TM ) mice to investigate risk avoidance and found that these mice were impaired in risk avoidance on the elevated plus maze (EPM) and showed reduced social preference in a three-chamber social interaction test. Following EPM tests, c-Fos expression levels indicated that the nucleus accumbens (NAc) was associated with risk-avoidance behavior in DISC1-N TM mice. In addition, in vivo electrophysiological recordings following tamoxifen administration showed that the firing rates of fast-spiking neurons (FS) in the NAc were significantly lower in DISC1-N TM mice than in wild-type (WT) mice. In addition, in vitro patch clamp recording revealed that the frequency of action potentials stimulated by current injection was lower in parvalbumin (PV) neurons in the NAc of DISC1-N TM mice than in WT controls. The impairment of risk avoidance in DISC1-N TM mice was rescued using optogenetic tools that activated NAc PV neurons. Finally, inhibition of the activity of NAc PV neurons in PV-Cre mice mimicked the risk-avoidance impairment found in DISC1-N TM mice during tests on the elevated zero maze. Taken together, our findings confirm an impairment in risk avoidance in DISC1-N TM mice and suggest that reduced excitability of NAc PV neurons is responsible.
AbstractBackground In recent years, headache diseases have spread throughout the world, causing great suffering and even severe disability to patients, and increasing the burden on health care systems. However, studies of specific regions are rare. The purpose of our study is to comprehensively analyze the current situation and trends of headache diseases in Asia between 1990 and 2021, to provide details of headache diseases in Asia, and to provide scientific data to support health development strategies. Methods Data from the Global Burden of Disease (GBD) 2021 database were used to calculate the incidence, prevalence and disability-adjusted life years (DALYs) of headache disorders in Asia from 1990 to 2021. Differences between years, ages, sexes and countries were also assessed, and we evaluated the correlation between epidemiological and sociodemographic indices (SDIs). Result In 2021, there were approximately 11,584,32824 cases of migraine in Asia. Meanwhile, there are now 2011612877 cases associated with tension-type headache (TTH) in Asia. Specifically, the age-standardized DALYs (ASDR) [607 cases per 100,000 people (95% UI: 70-1363)] for migraine were highest in East Asia, and the ASDR [422 cases per 100,000 people (95% UI: 86-938)] was lowest in high-income countries of the Asia-Pacific region. ASDR [67 cases per 100,000 people (95% UI: 18-236)] was highest for TTH in Central Asia and lowest for ASDR [43 cases per 100,000 people (95% UI: 13-141)] in East Asia. In addition, women are the key population for migraine and TTH prevalence. In Asia, there were negative and positive correlations between migraine and TTH and SDI, respectively. Conclusions Headache disorders pose a serious threat to the quality of life and safety of patients in Asia, increasing the burden on society, and this impact will continue to grow. Our findings suggest that active public awareness, improved guidelines, and better disease management are necessary to expand the public and healthcare system's attention to headache disorders, and thereby gain a greater advantage in combating the burden of headache disorders in the future.
Neuronal Intranuclear Inclusion Disease (NIID) is a degenerative disease with heterogeneous clinical manifestations. We aim to analysis the relationship between clinical manifestations, neuroimaging and skin pathology in a Chinese NIID cohort.Patients were recruited from a Chinese cohort. Detail clinical information were collected. Visual rating scale was used for evaluation of neuroimaging. The relationship between clinical presentations and neuroimaging, as well as skin pathology was statistically analyzed.Thirty-two patients were recruited. The average onset age was 54.3 y/o. 28.1% had positive family history. Dementia, autonomic nervous system dysfunction, episodic attacks were three main presentations. CSF analysis including Aβ42 and tau level was almost normal. The most frequently involved on MRI was periventricular white matter (100%), frontal subcortical and deep white matter (96.6%), corpus callosum (93.1%) and external capsule (72.4%). Corticomedullary junction DWI high intensity was found in 87.1% patients. Frontal and external capsule DWI high intensity connected to form a "kite-like" specific image. Severity of dementia was significantly related to leukoencephalopathy (r = 0.465, p = 0.0254), but not cortical atrophy and ventricular enlargement. Grey matter lesions were significantly associated with encephalopathy like attacks (p = 0.00077) but not stroke like attacks. The density of intranuclear inclusions in skin biopsy was not associated with disease duration, severity of leukoencephalopathy and dementia.Specific distribution of leukoencephalopathy and DWI high intensity were indicative. Leukoencephalopathy and subcortical mechanism were critical in pathogenesis of NIID. Irrelevant of inclusion density and clinical map suggested the direct pathogenic factor need further investigation.
Rational crop community structure plays an important role in maximizing the intercropping yield advantage. Effects of increasing maize densities in maize (Zea mays L.)/peanut (Arachis hypogaea L.) intercropping on yields and other agronomic traits, and the community stability of productivity were conducted across three different experimental sites. There were significant and positive correlations between maize densities and both maize grain/biomass yields and corresponding partial land equivalent ratios (LERs) across all three locations; but grain/biomass yields and partial LERs of peanut were all negatively correlated with maize densities in each or across all locations. LERs of grain yields averaged over three locations ranged from 0.89 to 0.98, while LERs of biomass yields ranged from 0.94 to 1.09 (>1.0 except for the maize inter-plant distance of 27 cm), indicating the intercropping advantage on biomass yields but not grain yields. Peanut had significantly lower kernel harvest indexes than those in monoculture. Excessive narrowing maize inter-plant distances reduced the community stability of productivity severely (especially for maize and total LERs) and are more likely to lead to abnormal maize and peanut plants. Therefore, a rational increase of maize densities in intercropping is suggested to keep the balance between maize and peanut and the comprehensive yield advantage.
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