Parkinson's Disease (PD) is currently considered a systemic neurodegenerative disease manifested with not only motor but also non-motor symptoms. In particular, weight loss and malnutrition, a set of frequently neglected non-motor symptoms, are indeed negatively associated with the life quality of PD patients. Moreover, comorbidity of weight loss and malnutrition may impact disease progression, giving rise to dyskinesia, cognitive decline and orthostatic hypotension, and even resulting in disability and mortality. Nevertheless, the underlying mechanism of weight loss and malnutrition in PD remains obscure and possibly involving multitudinous, exogenous or endogenous, factors. What is more, there still does not exist any weight loss and malnutrition appraision standards and management strategies. Given this, here in this review, we elaborate the weight loss and malnutrition study status in PD and summarize potential determinants and mechanisms as well. In conclusion, we present current knowledge and future prospects of weight loss and malnutrition in the context of PD, aiming to appeal clinicians and researchers to pay a closer attention to this phenomena and enable better management and therapeutic strategies in future clinical practice.
MicroRNAs (miRNAs) are regulatory RNA molecules that are deregulated in many disease types, including cancer. Recently, miRNAs have shown promise as markers for cancer diagnosis. The aim of this study was to investigate whether serum miRNAs can be used as biomarkers for the detection of diffuse large B cell lymphoma (DLBCL). We measured the levels of miRNAs (miR-15a, miR-16-1, miR-21, miR-29c, miR-34a, miR-155, and miR-223) in serum samples from patients with DLBCL and healthy controls using real-time quantitative reverse-transcription polymerase chain reaction (qRT-PCR). We show here that miRNAs are present in human serum in a remarkably stable form. Four of miRNAs (miR-15a, miR-16-1, miR-29c, and miR-155) were significantly elevated in DLBCL serum when compared with normal controls (P < 0.05), while miR-34a was downregulated in DLBCL serum when compared with controls (P < 0.05). Receiver operating characteristic analyses reflects strong discriminating DLBCL from controls, with area under the curves of 0.7722, 0.7002, 0.6672, 0.8538, and 0.7157 for miR-15a, miR-16-1, miR-29c, miR-34a, and miR-155, respectively. At the cut-off value of 0.0006 for miR-15a, the sensitivity was 80% and the specificity was 76%; at the cut-off value of 0.0886 for miR-16-1, the sensitivity was 94% and the specificity was 51%; at the cut-off value of 1.395 for miR-34a, the sensitivity was 100% and the specificity was 70%; at the cut-off value of 0.0022 for miR-155, the sensitivity was 83% and the specificity was 65%. In conclusion, these data suggest that serum miRNAs are potentially useful tools as novel noninvasive biomarker for the diagnosis of DLBCL.
BackgroundRepetitive transcranial magnetic stimulation (rTMS) can modulate cortical excitability, and may be beneficial for motor recovery after stroke. However, the neuroplasticity effects of rTMS have not been thoroughly investigated in the early stage after stroke.ObjectiveTo comprehensively assess the effects of high- and low-frequency repetitive transcranial magnetic stimulations on motor recovery in early stroke patients, using a randomized controlled trial based on clinical, neurophysiological and functional imaging assessments.MethodsSixty hospitalized, first-ever ischemic stroke patients (within 2 weeks after stroke) with motor deficits were randomly allocated to receive, in addition to standard physical therapy, five consecutive sessions of either: (1) High-frequency (HF) rTMS at 10 Hz over the ipsilesional primary motor cortex (M1); (2) Low-frequency (LF) rTMS at 1 Hz over the contralesional M1; (3) sham rTMS. The primary outcome measure was a motor impairment score (Upper Extremity Fugl-Meyer) evaluated at baseline, after rTMS intervention, and at 3-month follow-up. Cortical excitability and functional magnetic resonance imaging (fMRI) data were obtained within 24 h before and after rTMS intervention. Analyses of variance were conducted to compare the recovery effects among the three rTMS groups, assessed using clinical, neurophysiological and fMRI tests.ResultsMotor improvement was significantly larger in the two rTMS groups than in the control group. The HF-rTMS group showed significantly increased cortical excitability and motor-evoked fMRI activation in ipsilesional motor areas, whereas the LF-rTMS group had significantly decreased cortical excitability and motor-evoked fMRI activation in contralesional motor areas. Activity in ipsilesional motor cortex significantly correlated with motor function, after intervention as well as at 3-month follow-up.ConclusionHF- and LF-rTMS can both improve motor function by modulating motor cortical activation in the early phase of stroke.
The transforming growth factor beta (TGFβ) related signaling is one of the most important signaling pathways regulating early developmental events. Smad2 and Smad3 are structurally similar and it is mostly considered that they are equally important in mediating TGFβ signals. Here, we show that Smad3 is an insensitive TGFβ transducer as compared with Smad2. Smad3 preferentially localizes within the nucleus and is thus sequestered from membrane signaling. The ability of Smad3 in oligomerization with Smad4 upon agonist stimulation is also impaired given its unique linker region. Smad2 mediated TGFβ signaling plays a crucial role in epiblast development and patterning of three germ layers. However, signaling unrelated nuclear localized Smad3 is dispensable for TGFβ signaling-mediated epiblast specification, but important for early neural development, an event blocked by TGFβ/Smad2 signaling. Both Smad2 and Smad3 bind to the conserved Smads binding element (SBE), but they show nonoverlapped target gene binding specificity and differential transcriptional activity. We conclude that Smad2 and Smad3 possess differential sensitivities in relaying TGFβ signaling and have distinct roles in regulating early developmental events.
Central to the recognition, signaling, and repair of DNA double-strand breaks (DSBs) are the MRE11-RAD50-NBS1 (MRN) complex and mediator of DNA damage checkpoint protein 1 (MDC1), the interplay of which is essential for initiation and amplification of the DNA damage response (DDR). The intrinsic rule governing the regulation of the function of this molecular machinery remains to be investigated. We report here that the ubiquitin-specific protease USP7 was physically associated with the MRN-MDC1 complex and that the MRN-MDC1 complex acted as a platform for USP7 to efficiently deubiquitinate and stabilize MDC1, thereby sustaining the DDR. Accordingly, depletion of USP7 impaired the engagement of the MRN-MDC1 complex and the consequent recruitment of the downstream factors p53-binding protein 1 (53BP1) and breast cancer protein 1 (BRCA1) at DNA lesions. Significantly, USP7 was overexpressed in cervical cancer, and the level of its expression positively correlated with that of MDC1 and worse survival rates for patients with cervical cancer. We demonstrate that USP7-mediated MDC1 stabilization promoted cervical cancer cell survival and conferred cellular resistance to genotoxic insults. Together, our study reveals a role for USP7 in regulating the function of the MRN-MDC1 complex and activity of the DDR, supporting the pursuit of USP7 as a potential therapeutic target for MDC1-proficient cancers.
Parkinson’s disease (PD) is one of the synucleinopathies spectrum of disorders typified by the presence of intraneuronal protein inclusions. It is primarily composed of misfolded and aggregated forms of alpha-synuclein (α-syn), the toxicity of which has been attributed to the transition from an α-helical conformation to a β-sheetrich structure that polymerizes to form toxic oligomers. This could spread and initiate the formation of “LB-like aggregates,” by transcellular mechanisms with seeding and subsequent permissive templating. This hypothesis postulates that α-syn is a prion-like pathological agent and responsible for the progression of Parkinson’s pathology. Moreover, the involvement of the inflammatory response in PD pathogenesis has been reported on the excessive microglial activation and production of pro-inflammatory cytokines. At last, we describe several treatment approaches that target the pathogenic α-syn protein, especially the oligomers, which are currently being tested in advanced animal experiments or are already in clinical trials. However, there are current challenges with therapies that target α-syn, for example, difficulties in identifying varying α-syn conformations within different individuals as well as both the cost and need of long-duration large trials.
Simple sequence repeats (SSRs) have been widely used in maize genetics and breeding, because they are co-dominant, easy to score, and highly abundant. In this study, we used whole-genome sequences from 16 maize inbreds and 1 wild relative to determine SSR abundance and to develop a set of high-density polymorphic SSR markers. A total of 264 658 SSRs were identified across the 17 genomes, with an average of 135 693 SSRs per genome. Marker density was one SSR every of 15.48 kb. (C/G)n, (AT)n, (CAG/CTG)n, and (AAAT/ATTT)n were the most frequent motifs for mono, di-, tri-, and tetra-nucleotide SSRs, respectively. SSRs were most abundant in intergenic region and least frequent in untranslated regions, as revealed by comparing SSR distributions of three representative resequenced genomes. Comparing SSR sequences and e-polymerase chain reaction analysis among the 17 tested genomes created a new database, including 111 887 SSRs, that could be develop as polymorphic markers in silico. Among these markers, 58.00, 26.09, 7.20, 3.00, 3.93, and 1.78% of them had mono, di-, tri-, tetra-, penta-, and hexa-nucleotide motifs, respectively. Polymorphic information content for 35 573 polymorphic SSRs out of 111 887 loci varied from 0.05 to 0.83, with an average of 0.31 in the 17 tested genomes. Experimental validation of polymorphic SSR markers showed that over 70% of the primer pairs could generate the target bands with length polymorphism, and these markers would be very powerful when they are used for genetic populations derived from various types of maize germplasms that were sampled for this study.
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