Adaptive functions of structural variants in human brain development.

Quantifying the structural variants (SVs) in nonhuman primates could provide a niche to clarify the genetic backgrounds underlying human-specific traits, but such resource is largely lacking. Here, we report an accurate SV map in a population of 562 rhesus macaques, verified by in-house benchmarks of eight macaque genomes with long-read sequencing and another one with genome assembly. This map indicates stronger selective constrains on inversions at regulatory regions, suggesting a strategy for prioritizing them with the most important functions. Accordingly, we identified 75 human-specific inversions and prioritized them. The top-ranked inversions have substantially shaped the human transcriptome, through their dual effects of reconfiguring the ancestral genomic architecture and introducing regional mutation hotspots at the inverted regions. As a proof of concept, we linked APCDD1, located on one of these inversions and down-regulated specifically in humans, to neuronal maturation and cognitive ability. We thus highlight inversions in shaping the human uniqueness in brain development.

A Novel Acoustic Evaluation Method for the Diagnosis of Adductor Spasmodic Dysphonia.

INTRODUCTION: Adductor spasmodic dysphonia (ADSD) is characterized by involuntary laryngeal muscle spasms. Due to the lack of a quantitative evaluation method, most measurements have demonstrated difficulty in validity and reliability for diagnosing ADSD. This study aimed to establish a novel indicator for ADSD and determine its diagnostic effects. METHODS: We investigated 98 voice samples from 49 patients with ADSD and 49 healthy subjects. A sustained vowel was recorded by a high-definition audio recorder. Voice samples underwent regular acoustic evaluation and a novel global dimension method. Global dimension (GD), Jitter, Shimmer, HNR, Frequency shift, and CPPS were measured for both groups. RESULTS: Statistical analysis revealed that the global dimension method effectively differentiated ADSD patients from healthy subjects (P<0.001, D'>0.8). Subsequent multiclass receiver operating characteristic analysis demonstrated that GD possessed the most significant classification accuracy (AUC = 0.988) compared with other acoustic parameters. CONCLUSION: GD was an effective metric for objective differentiation between ADSD patients and healthy subjects. This metric could assist clinicians in the diagnosis of ADSD patients.

Introduction of Voice Type Component (VTC) as an Effective Acoustic Voice Analysis Method in Tele-evaluation.

OBJECTIVE: Telepractice in voice health care and evaluation services has attracted much attention in recent years. Multiple studies have proven the effectiveness of voice therapy with telepractice. However, voice evaluations are still mostly conducted in person due to the lack of sensitive acoustic analysis methods. METHODS: This study examined various acoustic analysis methods for voice evaluation in telepractice. Eighteen female elementary school teachers with self-reported voice disorders volunteered to participate in the study. Speech samples were collected before and after the interventions using two voice sampling methods concurrently. One set of data was collected using the traditional voice sample collection method by the therapist in person. The second set of data was collected on the same speech samples using the clients' own smartphones, and the collected voice samples were later sent to the researcher for further acoustic analysis. The voice type component (VTC) measurement represented the proportion of different VTCs in a voice by measuring the chaos and intrinsic dimension. RESULTS: Voice analyses were conducted on both sets of data, and the correlation between the two sampling procedures was analyzed. It appears that the VTC could be a more reliable method for producing acoustic analysis results with voice samples collected from smartphones compared to other objective voice assessment procedures. This reliability has been demonstrated via statistical analysis, including correlation coefficient, pairwise t test, d-prime, and area under the curve. The results of this study highlighted the VTC as an effective and accurate acoustic analysis method in tele-evaluation. CONCLUSIONS: This feasible voice sampling method, which utilizes participants' own smartphones, will reduce barriers to accessing limited voice specialists due to distance and will decrease the cost of care by minimizing expenses associated with travel and additional equipment for voice sampling. Ultimately, this approach will enhance the effectiveness of voice care delivered through telepractice to patients in remote and underserved areas.

De novo genes with an lncRNA origin encode unique human brain developmental functionality.

Human de novo genes can originate from neutral long non-coding RNA (lncRNA) loci and are evolutionarily significant in general, yet how and why this all-or-nothing transition to functionality happens remains unclear. Here, in 74 human/hominoid-specific de novo genes, we identified distinctive U1 elements and RNA splice-related sequences accounting for RNA nuclear export, differentiating mRNAs from lncRNAs, and driving the origin of de novo genes from lncRNA loci. The polymorphic sites facilitating the lncRNA-mRNA conversion through regulating nuclear export are selectively constrained, maintaining a boundary that differentiates mRNAs from lncRNAs. The functional new genes actively passing through it thus showed a mode of pre-adaptive origin, in that they acquire functions along with the achievement of their coding potential. As a proof of concept, we verified the regulations of splicing and U1 recognition on the nuclear export efficiency of one of these genes, the ENSG00000205704, in human neural progenitor cells. Notably, knock-out or over-expression of this gene in human embryonic stem cells accelerates or delays the neuronal maturation of cortical organoids, respectively. The transgenic mice with ectopically expressed ENSG00000205704 showed enlarged brains with cortical expansion. We thus demonstrate the key roles of nuclear export in de novo gene origin. These newly originated genes should reflect the novel uniqueness of human brain development.

Resveratrol attenuates autophagy and inflammation after traumatic brain injury by activation of PI3K/Akt/mTOR pathway in rats.

AIM OF THE STUDY: Accumulating studies have demonstrated that neuronal autophagy and inflammation are crucial for hippocampus development in rats subjected to traumatic brain injury (TBI). Therefore, we have investigated whether resveratrol is protective against brain damage through the attenuation of neuronal autophagy and inflammation, and explored underlying mechanisms. MATERIAL AND METHODS: Rats were injected with resveratrol (50 mg/kg, i.p.), following controlled cortical impact (CCI) injury. Brain water content, behavioral studies, and mNSS score were measured to assess the effects of resveratrol treatment. Autophagy-related proteins and inflammatory cytokines in the hippocampus were detected by Western blotting at 12, 24, and 48 hours after TBI. In addition, spatial distribution of LC3 was evaluated with immunofluorescence analysis 24 hours after injury. Finally, factors related to PI3K/Akt/mTOR signaling pathway were assessed at the same time in the hippocampus. RESULTS: Our results depicted that resveratrol could reduce the cerebral edema caused by TBI and improve the recovery of functional deficits in rats. Resveratrol was also able to remarkably reduce the expression of LC3 II and Beclin-1, while increased the expression levels of P62 in the hippocampus. Moreover, we found that interleukin b (IL-1b) and tumor necrosis factor a (TNF-a) were significantly decreased in resveratrol-treated rats. Indeed, we observed an activation of the PI3K/Akt/mTOR pathway after TBI, which may be related to the neuro-protective effect of resveratrol. CONCLUSIONS: Data presented herein support that resveratrol is a potential treatment against TBI through the inhibition of neuronal autophagy and inflammation by activation of PI3K/Akt/mTOR pathway.

Repeated intracerebral hemorrhage after craniotomy for a distal middle cerebral artery aneurysm: A case report.

RATIONALE: Distal middle cerebral artery aneurysms are very rare in the clinic, and craniotomy clipping is the better treatment after diagnosis. However, patients can also have repeated acute intracerebral hemorrhage after craniotomy for aneurysm, which has not been previously reported. PATIENT CONCERNS: A 24-year-old male patient was admitted to our hospital with headache, nausea, and vomiting. He was well before, had no family history of cerebrovascular disease or hypertension, and had no history of trauma. DIAGNOSES: Computer tomography and digital subtraction angiography of the brain revealed intracranial hematoma and an aneurysm located at the M4 segment of the left middle cerebral artery. INTERVENTIONS: The patient underwent 2 surgeries to treat the aneurysm, followed by 2 operations for acute cerebral hemorrhage. OUTCOMES: Despite repeated surgical treatments, the patient had a poor prognosis and eventually died of respiratory and circulatory failure after repeated brain bleeding. LESSONS: Briefly, it is of great importance to consider the risk factors of cerebral hemorrhage, and provide individualized treatment and psychological counseling for patients with intracerebral hemorrhage.

Protective role of wogonin following traumatic brain injury by reducing oxidative stress and apoptosis via the PI3K/Nrf2/HO­1 pathway.

Traumatic brain injury (TBI) is usually caused by accidental injuries and traffic accidents, with a very high mortality rate. Treatment and management following TBI are essential to reduce patient injury and help improve long­term prognosis. Wogonin is a flavonoid compound with an antioxidant effect extracted from Scutellaria baicalensis Georgi. However, the function and mechanism of wogonin in protecting brain injury remain to be elucidated. The present study established a TBI model of Sprague­Dawley rats and treated them with wogonin following trauma. The results showed that wogonin treatment significantly reduced neurobehavioral disorders, brain edema and hippocampal neuron damage caused by TBI. It was found that in TBI rats, administration of wogonin increased the levels of antioxidant factors glutathione, superoxide dismutase and catalase in the CA1 region of the hippocampus and significantly inhibited the production of malondialdehyde and reactive oxygen species. western blotting data showed that wogonin exerted antioxidant activity by downregulating the level of NOX2 protein. In inhibiting cell apoptosis, wogonin upregulated the expression of Bcl­2 protein in the hippocampal CA1 region of TBI rats and inhibited caspase­3 and Bax proteins. Additionally, wogonin inhibited the progression of injury following TBI through the PI3K/Akt/nuclear factor­erythroid factor 2­related factor 2 (Nrf2)/heme oxygenase­1 (HO­1) signaling pathway. Wogonin increased the expression of phosphorylated Akt, Nrf2 and HO­1 in the hippocampus of TBI rats. Following the administration of PI3K inhibitor LY294002, the upregulation of these proteins by wogonin was partly reversed. In addition, LY294002 partially reversed the regulation of wogonin on NOX2, caspase­3, Bax and Bcl­2 proteins. Therefore, wogonin exerts antioxidant and anti­apoptotic properties to prevent hippocampal damage following TBI, which is accomplished through the PI3K/Akt/Nrf2/HO­1 pathway.

Polyadenylation-related isoform switching in human evolution revealed by full-length transcript structure.

Rhesus macaque is a unique nonhuman primate model for human evolutionary and translational study, but the error-prone gene models critically limit its applications. Here, we de novo defined full-length macaque gene models based on single molecule, long-read transcriptome sequencing in four macaque tissues (frontal cortex, cerebellum, heart and testis). Overall, 8 588 227 poly(A)-bearing complementary DNA reads with a mean length of 14 106 nt were generated to compile the backbone of macaque transcripts, with the fine-scale structures further refined by RNA sequencing and cap analysis gene expression sequencing data. In total, 51 605 macaque gene models were accurately defined, covering 89.7% of macaque or 75.7% of human orthologous genes. Based on the full-length gene models, we performed a human-macaque comparative analysis on polyadenylation (PA) regulation. Using macaque and mouse as outgroup species, we identified 79 distal PA events newly originated in humans and found that the strengthening of the distal PA sites, rather than the weakening of the proximal sites, predominantly contributes to the origination of these human-specific isoforms. Notably, these isoforms are selectively constrained in general and contribute to the temporospatially specific reduction of gene expression, through the tinkering of previously existed mechanisms of nuclear retention and microRNA (miRNA) regulation. Overall, the protocol and resource highlight the application of bioinformatics in integrating multilayer genomics data to provide an intact reference for model animal studies, and the isoform switching detected may constitute a hitherto underestimated regulatory layer in shaping the human-specific transcriptome and phenotypic changes.

Host RAB11FIP5 protein inhibits the release of Kaposi's sarcoma-associated herpesvirus particles by promoting lysosomal degradation of ORF45.

Open reading frame (ORF) 45 is an outer tegument protein of Kaposi's sarcoma-associated herpesvirus (KSHV). Genetic analysis of an ORF45-null mutant revealed that ORF45 plays a key role in the events leading to the release of KSHV particles. ORF45 associates with lipid rafts (LRs), which is responsible for the colocalization of viral particles with the trans-Golgi network and facilitates their release. In this study, we identified a host protein, RAB11 family interacting protein 5 (RAB11FIP5), that interacts with ORF45 in vitro and in vivo. RAB11FIP5 encodes a RAB11 effector protein that regulates endosomal trafficking. Overexpression of RAB11FIP5 in KSHV-infected cells decreased the expression level of ORF45 and inhibited the release of KSHV particles, as reflected by the significant reduction in the number of extracellular virions. In contrast, silencing endogenous RAB11FIP5 increased ORF45 expression and promoted the release of KSHV particles. We further showed that RAB11FIP5 mediates lysosomal degradation of ORF45, which impairs its ability to target LRs in the Golgi apparatus and inhibits ORF45-mediated colocalization of viral particles with the trans-Golgi network. Collectively, our results suggest that RAB11FIP5 enhances lysosome-dependent degradation of ORF45, which inhibits the release of KSHV particles, and have potential implications for virology and antiviral design.

Studies of the mechanism of selectivity of protein tyrosine phosphatase 1B (PTP1B) bidentate inhibitors using molecular dynamics simulations and free energy calculations.

Bidentate inhibitors of protein tyrosine phosphatase 1B (PTP1B) are considered as a group of ideal inhibitors with high binding potential and high selectivity in treating type II diabetes. In this paper, the binding models of five bidentate inhibitors to PTP1B, TCPTP, and SHP-2 were investigated and compared by using molecular dynamics (MD) simulations and free energy calculations. The binding free energies were computed using the Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) methodology. The calculation results show that the predicted free energies of the complexes are well consistent with the experimental data. The Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) free energy decomposition analysis indicates that the residues ARG24, ARG254, and GLN262 in the second binding site of PTP1B are essential for the high selectivity of inhibitors. Furthermore, the residue PHE182 close to the active site is also important for the selectivity and the binding affinity of the inhibitors. According to our analysis, it can be concluded that in most cases the polarity of the portion of the inhibitor that binds to the second binding site of the protein is positive to the affinity of the inhibitors while negative to the selectivity of the inhibitors. We expect that the information we obtained here can help to develop potential PTP1B inhibitors with more promising specificity.