Structural Insights into the Stability and Recognition Mechanism of the Antiquinalphos Nanobody for the Detection of Quinalphos in Foods.

Nanobodies (Nbs) have great potential in immunoassays due to their exceptional physicochemical properties. With the immortal nature of Nbs and the ability to manipulate their structures using protein engineering, it will become increasingly valuable to understand what structural features of Nbs drive high stability, affinity, and selectivity. Here, we employed an anti-quinalphos Nb as a model to illustrate the structural basis of Nbs' distinctive physicochemical properties and the recognition mechanism. The results indicated that the Nb-11A-ligand complexes exhibit a "tunnel" binding mode formed by CDR1, CDR2, and FR3. The orientation and hydrophobicity of small ligands are the primary determinants of their diverse affinities to Nb-11A. In addition, the primary factors contributing to Nb-11A's limited stability at high temperatures and in organic solvents are the rearrangement of the hydrogen bonding network and the enlargement of the binding cavity. Importantly, Ala 97 and Ala 34 at the active cavity's bottom and Arg 29 and Leu 73 at its entrance play vital roles in hapten recognition, which were further confirmed by mutant Nb-F3. Thus, our findings contribute to a deeper understanding of the recognition and stability mechanisms of anti-hapten Nbs and shed new light on the rational design of novel haptens and directed evolution to produce high-performance antibodies.

Large-scale omics data reveal the cooperation of mutation-circRNA-miRNA-target gene network in liver cancer oncogenesis.

Aims: Clarifying the initial trigger of the differentially expressed genes in cancers helps researchers understand the cellular system as a whole network. Materials & methods: We retrieve the transcriptome and translatome of tumor and normal tissues from ten liver cancer patients and define differentially expressed genes and tumor-specific mutations. We associate the oncogenesis with the mutations by target prediction and experimental verification. Results: Upregulated genes have tumor-specific mutations in 3'UTRs that abolish the binding of miRNAs. For downregulated genes, their corresponding miRNAs are mutually targeted by two circRNAs, with mutations in base-pairing regions. Transfection experiments support the oncogenic role of these mutations. Conclusions: The tumor-specific mutations serve as the initial trigger of liver cancer. The mutation-circRNA-miRNA-target gene chain is completed.

Retrieving the deleterious mutations before extinction: genome-wide comparison of shared derived mutations in liver cancer and normal population.

STUDY PURPOSE: Deleterious mutations would be rapidly purged from natural populations along with the extinction of their carriers. The currently observed mutations in existing species are mostly neutral. The inaccessibility of deleterious mutations impedes the functional studies on how these mutations affect the fitness at individual level. STUDY DESIGN: The connection between the deleterious genotype and the non-adaptive phenotype could be bridged by sequencing the genome before extinction. Although this approach is no longer feasible for evolutionary biologists, it is feasible for cancer biologists by profiling the mutations in tumour samples which are so deleterious that the carriers hardly live. RESULTS: By comparing the derived mutation profile between normal populations and patients with liver cancer, we found that the shared mutations, which are highly deleterious, are suppressed to low allele frequencies in normal populations and tissues, but show remarkably high frequency in tumours. The density of shared mutations is negatively correlated with gene conservation and expression levels. CONCLUSIONS: Deleterious mutations are suppressed in functionally important genes as well as in normal populations. This work deepened our understanding on how natural selection act on deleterious mutations by analogising the cancer evolution to species evolution, which are essentially the same molecular process but at different time scales.

Synonymous mutations that regulate translation speed might play a non-negligible role in liver cancer development.

BACKGROUND: Synonymous mutations do not change the protein sequences. Automatically, they have been regarded as neutral events and are ignored in the mutation-based cancer studies. However, synonymous mutations will change the codon optimality, resulting in altered translational velocity. METHODS: We fully utilized the transcriptome and translatome of liver cancer and normal tissue from ten patients. We profiled the mutation spectrum and examined the effect of synonymous mutations on translational velocity. RESULTS: Synonymous mutations that increase the codon optimality significantly enhanced the translational velocity, and were enriched in oncogenes. Meanwhile, synonymous mutations decreasing codon optimality slowed down translation, and were enriched in tumor suppressor genes. These synonymous mutations significantly contributed to the translational changes in tumor samples compared to normal samples. CONCLUSIONS: Synonymous mutations might play a role in liver cancer development by altering codon optimality and translational velocity. Synonymous mutations should no longer be ignored in the genome-wide studies.

Alterations of Hippocampal Myelin Sheath and Axon Sprouting by Status Convulsion and Regulating Lingo-1 Expression with RNA Interference in Immature and Adult Rats.

Seizure-induced brain damage is age-dependent, as evidenced by the different alterations of neural physiopathology in developing and mature brains. However, little is known about the age-dependent characteristics of myelinated fiber injury induced by seizures. Considering the critical functions of oligodendrocyte progenitor cells (OPCs) in myelination and Lingo-1 signaling in regulating OPCs' differentiation, the present study aimed to explore the effects of Lingo-1 on myelin and axon in immature and adult rats after status convulsion (SC) induced by lithium-pilocarpine, and the differences between immature and adult brains. Dynamic variations in electrophysiological activity and spontaneous recurrent seizures were recorded by electroencephalogram monitoring after SC. The impaired microstructures of myelin sheaths and decrease in myelin basic protein caused by SC were observed through transmission electron microscopy and western blot analysis respectively, which became more severe in adult rats, but improved gradually in immature rats. Aberrant axon sprouting occurred in adult rats, which was more prominent than in immature rats, as shown by a Timm stain. This damage was improved or negatively affected after down or upregulating Lingo-1 expression. These results demonstrated that in both immature and adult brains, Lingo-1 signaling plays important roles in seizure-induced damage to myelin sheaths and axon growth. The plasticity of the developing brain may provide a potential window of opportunity to prevent the brain from damage.

Can radical parametrectomy be omitted in occult cervical cancer after extrafascial hysterectomy?

BACKGROUND: Occult invasive cervical cancer discovered after simple hysterectomy is not common, radical parametrectomy (RP) is a preferred option for young women. However, the morbidity of RP was high. The aim of our study is to assess the incidence of parametrial involvement in patients who underwent radical parametrectomy for occult cervical cancer or radical hysterectomy for early-stage cervical cancer and to suggest an algorithm for the triage of patients with occult cervical cancer to avoid RP. METHODS: A total of 13 patients with occult cervical cancer who had undergone RP with an upper vaginectomy and pelvic lymphadenectomy were included in this retrospective study. Data on the clinicopathologic characteristics of the cases were collected. The published literature was also reviewed, and low risk factors for parametrial involvement in early-stage cervical cancer were analyzed. RESULTS: Of the 13 patients, 9 had a stage IB1 lesion, and 4 had a stage IA2 lesion. There were four patients with grade 1 disease, seven with grade 2 disease, and two with grade 3 disease. The median age of the entire patients was 41 years. The most common indication for extrafascial hysterectomy was cervical intraepithelial neoplasia 3. Three patients had visible lesions measuring 10-30 mm, in diameter and ten patients had cervical stromal invasions with depths ranging from 4 to 9 mm; only one patient had more than 50% stromal invasion, and four patients had lymph-vascular space invasion (LVSI). Perioperative complications included intraoperative bowel injury, blood transfusion, vesico-vaginal fistula, and ileus (1 case for each). Postoperative pathologic examination results did not show residual disease or parametrial involvement. One patient with positive lymph nodes received concurrent radiation therapy. Only one patient experienced recurrence. CONCLUSIONS: Perioperative complications following RP were common, whereas the incidence of parametrial involvement was very low among selected early-stage cervical cancer patients. Based on these results, we thought that patients with very low-risk parametrial involvement(tumor size ≤ 2 cm, no LVSI, less than 50% stromal invasion, negative lymph nodes) may benefit from omitting RP. Further prospective data are warranted.

Explainable machine learning for early predicting treatment failure risk among patients with TB-diabetes comorbidity.

The present study aims to assess the treatment outcome of patients with diabetes and tuberculosis (TB-DM) at an early stage using machine learning (ML) based on electronic medical records (EMRs). A total of 429 patients were included at Chongqing Public Health Medical Center. The random-forest-based Boruta algorithm was employed to select the essential variables, and four models with a fivefold cross-validation scheme were used for modeling and model evaluation. Furthermore, we adopted SHapley additive explanations to interpret results from the tree-based model. 9 features out of 69 candidate features were chosen as predictors. Among these predictors, the type of resistance was the most important feature, followed by activated partial throm-boplastic time (APTT), thrombin time (TT), platelet distribution width (PDW), and prothrombin time (PT). All the models we established performed above an AUC 0.7 with good predictive performance. XGBoost, the optimal performing model, predicts the risk of treatment failure in the test set with an AUC 0.9281. This study suggests that machine learning approach (XGBoost) presented in this study identifies patients with TB-DM at higher risk of treatment failure at an early stage based on EMRs. The application of a convenient and economy EMRs based on machine learning provides new insight into TB-DM treatment strategies in low and middle-income countries.

[Effects of ant nesting on seasonal dynamics of soil CH4 emissions in a tropical rubber-plantation forest]. / 蚂蚁筑巢对热带橡胶人工林土壤甲烷排放季节动态的影响.

Ant nests can affect the process and seasonal dynamics of forest soil methane emissions through mediating methane oxidation/reduction microorganisms and physicochemical environments. To explore the process and mechanism by which ant nests affect soil methane emissions from Hevea brasiliensis plantation in Xishuangbanna, we measured the seasonal dynamics of methane emissions from ant nest and non-nest soils by using static chamber-gas chromatography method, and analyzed the effect of ant nesting on the changes in functional microbial diversity, microhabitats, and soil nutrients in the plantations. The results showed that: 1) Ant nests significantly affected the mean annual soil methane emissions in tropical plantation. Methane emissions in ant nest were decreased by 59.9% than the non-nest soil. In the dry season, ant nest soil was a methane sink (-1.770 µg·m-2·h-1), which decreased by 87.2% compared with the non-nest soil, while it was a methane source (0.703 µg·m-2·h-1) that increased by 152.7% in the wet season. 2) Ant nesting affected methane emissions via changing soil temperature, humidity, carbon and nitrogen concentrations. In contrast to the control, the mean annual temperature, humidity, and carbon and nitrogen content increased by 4.9%-138.5% in ant nest soils, which explained 90.1%, 97.3%, 27.3%-90.0% of the variation in methane emissions, respectively. 3) Ant nesting affected the emission dynamics through changing the diversity and community structure of methane functional microbe. Compared with the control, the average annual methanogen diversity (Ace, Chao1, Shannon, and Simpson indices) in the ant nest ranged from -9.9% to 61.2%, which were higher than those (-8.7%-31.2%) of the methane-oxidising bacterial communities. The relative abundance fluctuations of methanogens and methanotrophic bacteria were 46.76% and -6.33%, respectively. The explaining rate of methanogen diversity to methane emissions (78.4%) was higher than that of oxidizing bacterial diversity (54.5%), the relative abundance explained by the dominant genus of methanogens was 68.9%. 4) The structural equation model showed that methanogen diversity, methanotroph diversity, and soil moisture were the main factors controlling methane emissions, contributing 95.6%, 95.0%, and 91.2% to the variations of emissions, respectively. The contribution (73.1%-87.7%) of soil temperature and carbon and nitrogen components to the emission dynamics was ranked the second. Our results suggest that ant nesting mediates the seasonal dynamics of soil methane emissions, primarily through changing the diversity of methane-function microorganisms and soil water conditions. The research results deepen the understanding of the mechanism of biological regulation of methane emission in tropical forest soil.

Effects of ant nests on soil CH4 emissions from Syzygium oblatum communities of a secondary tropical forest.

Exploring the effects of ant nests on soil CH4 emissions in the secondary tropical forests is of great scientific significance to understand the contribution of soil faunal activities to greenhouse gas emissions. With static chamber-gas chromatography method, we measured the dry-wet seasonal dynamics of CH4 emissions from ant nests and control soils in the secondary forest of Syzygium oblatum communities in Xishuangbanna. We also examined the linkages of ant-mediated changes in functional microbial diversity and soil physicochemical properties with CH4 emissions. The results showed that: 1) Ant nests significantly accelerated soil CH4 emissions, with average CH4 emissions in the ant nests being 2.6-fold of that in the control soils. 2) The CH4 emissions had significant dry-wet seasonal variations, which was a carbon sink in the dry seasons (from -0.29±0.03 to -0.53±0.02 µg·m-2·h-1) and a carbon source in the wet seasons (from 0.098±0.02 to 0.041±0.009 µg·m-2·h-1). The CH4 emissions were significantly higher in ant nests than in control soils. The CH4 emissions from the ant nests had smaller dry-wet seasonal variation (from -0.38±0.01 to 0.12±0.02 µg·m-2·h-1) than those in the control soils (from -0.65±0.04 to 0.058±0.006 µg·m-2·h-1). 3) Ant nests significantly increased the values (6.2%-37.8%) of soil methanogen diversity (i.e., Ace and Shannon indices), temperature and humidity, carbon pools (i.e., total, easily oxidizable, and microbial carbon), and nitrogen pools (i.e., total, hydrolyzed, ammonium, and microbial biomass nitrogen), but decreased the diversity (i.e., Ace and Chao1 indices) of methane-oxidizing bacteria by 21.9%-23.8%. 4) Results of the structural equation modeling showed that CH4 emissions were promoted by soil methanogen diversity, temperature and humidity, and C and N pools, but inhibited by soil methane-oxidizing bacterial diversity. The explained extents of soil temperature, humidity, carbon pool, nitrogen pool, methanogen diversity, and methane-oxidizing bacterial diversity for the CH4 emission changes were 6.9%, 21.6%, 18.4%, 15.2%, 14.0%, and 10.8%, respectively. Therefore, ant nests regulated soil CH4 emission dynamics through altering soil functional bacterial diversities, micro-habitat, and carbon and nitrogen pools in the secondary tropical forests.

The treatment of patients with non-small cell lung cancer carrying uncommon EGFR mutations, HER2 mutations, or brain metastases: a systematic review of pre-clinical and clinical findings for dacomitinib.

Background: Accumulating evidence has shown that dacomitinib has potential activities for patients with non-small cell lung cancer (NSCLC) harboring uncommon epidermal growth factor receptor (EGFR) mutations, human epidermal growth factor receptor 2 (HER2) mutations, or central nervous system (CNS) metastases. Methods: This study aimed to give a systematic review on its potential applications in the above settings by searching MEDLINE/PubMed, Embase, Cochrane Library, American Society of Clinical Oncology.org, European Society for Medical Oncology.org, and ClinicalTrials.gov. Results: The literature search yielded 649 publications in total. According to our findings, dacomitinib exhibited promising efficacy in patients with major uncommon EGFR mutations (including G719X, S768I, and L861Q). Both EGFR exon 20 insertional mutation (Ex20ins) and HER2 Ex20ins demonstrated significant internal heterogeneity in response to dacomitinib, among which specific subtypes (including EGFR D770delinsGY, A763_Y764insFQEA, and HER2 M774delinsWLV) were highly sensitive. Other uncommon EGFR mutations including 18del and L747P have also been shown responsive to dacomitinib. Interestingly, limited studies suggested dacomitinib application on certain first or third generation tyrosine kinase inhibitors (TKIs)' resistant secondary mutations. Last but not least, both pre-clinical and clinical data indicated that dacomitinib has an encouraging intracranial tumor control ability, regardless of uncommon mutations. Conclusions: Dacomitinib demonstrated good disease control on patients with NSCLC harboring major uncommon EGFR mutations and specific EGFR or HER2 mutation subtypes, and selective clinical application of dacomitinib is considerable in this setting, especially for those with intracranial metastases.

Effects of ant nesting on seasonal dynamics of soil N2O emission in a secondary tropical forest.

We assessed the seasonal dynamics of N2O emission in ant nests soils in secondary tropical Millettia leptobotrya forest of Xishuangbanna by using the static chamber-gas chromatography method, and determined the lin-kages between ant-mediated changes in soil properties (e.g., carbon pool, nitrogen pool, and temperature and humidity) and N2O emission. The results showed that ant nesting significantly affected soil N2O emission. The ave-rage soil N2O emission (0.67 mg·m-2·h-1) in ant nests was 40.2% higher than that in the control (0.48 mg·m-2·h-1). N2O emission in ant nests and the control showed substantial seasonal variation, with higher rate in June (0.90 and 0.83 mg·m-2·h-1, respectively) than that in March (0.38 and 0.19 mg·m-2·h-1, respectively). Ant nesting significantly increased the values (7.1%-74.1%) of moisture, temperature, organic carbon, total nitrogen, hydrolytic nitrogen, ammonium nitrogen, nitrate nitrogen, and microbial biomass carbon, but decreased pH (9.9%) compared with the control. Results of structural equation model showed that soil N2O emission was promoted by soil C and N pool, temperature, and humidity, but was inhibited by soil pH. The explained extents of soil nitrogen pool, carbon pool, temperature and humidity, and pH for N2O emission changes were 37.2%, 27.7%, 22.9% and 9.4%, respectively. Therefore, ant nesting regulated N2O emission dynamics by changing nitrification and denitrification substrates (e.g., nitrate and ammoniacal nitrogen), carbon pool, and micro-habitat (temperature and moisture) of soil in the secondary tropical forest.

Melatonin alleviates traumatic brain injury-induced anxiety-like behaviors in rats: Roles of the protein kinase A/cAMP-response element binding signaling pathway.

Melatonin is a hormone produced by the pineal gland. Given its capabilities of neuroprotection and low neurotoxicity, melatonin could be a therapeutic strategy for traumatic brain injury (TBI). The present study was conducted to determine the neuroprotective effects of melatonin on TBI-induced anxiety and the possible molecular mechanism. Rats were randomly divided into seven groups. The rodent model of TBI was established using the weight-drop method. Melatonin was administered by intraperitoneal injection at a dose of 10 mg/kg after TBI. H89 (0.02 mg/kg), a special protein kinase A (PKA) inhibitor, or dibutyryl-cyclic adenosine monophosphate (cAMP; 0.1 mg/kg), an activator of PKA, were administered by stereotactic injection of the brain to evaluate the roles of PKA and cAMP-response element-binding protein (CREB) in melatonin-related mood regulation, respectively. At 30 days post-TBI, the changes in anxiety-like behaviors in rats were measured using the open field and elevated plus maze tests. At 24 h post-TBI, the number of activated astrocytes and neuronal apoptosis were evaluated using immunofluorescence assay. The expression levels of inflammatory cytokines (TNF-α and IL-6) in the amygdala were measured using an enzyme-linked immunosorbent assay. The expression levels of PKA, phosphorylated (p)-PKA, CREB, p-CREB, NF-κB and p-NF-κB in the amygdala were detected using western blotting. It was revealed that melatonin partially reversed TBI-induced anxiety-like behavior in rats, and decreased the number of activated astrocytes and neuronal apoptosis in the amygdala induced by TBI. H89 partially blocked the neuroprotective effects of melatonin; while dibutyryl-cAMP not only reduced the H89-induced emotional disturbance but also enhanced the protective effects of melatonin against TBI. Overall, melatonin can alleviate TBI-induced anxiety-like behaviors in rats. Moreover, the underlying mechanism may be associated with the activation of the PKA/CREB signaling pathway.

Lens nucleus dislocation in hypermature cataract: Case report and literature review.

INTRODUCTION: Hypermature cataract is a form of late-stage cataract progression that can lead to a variety of complications. Spontaneous capsular rupture with lens nucleus displacement in hypermature cataracts has rarely been reported. We describe 2 cases of spontaneous dislocation of the lens nucleus in a hypermature cataract and perform a review of the literature on this complication. PATIENT CONCERNS: We report 2 rural men aged 50 and 76 years with deteriorating vision. DIAGNOSIS: The final diagnosis was senile hypermature cataract with dislocation of the lens nucleus in both patients and secondary glaucoma for the second patient. INTERVENTIONS AND OUTCOMES: During admission, both patients complained of deteriorating vision. Slit-lamp examination showed lens nucleus dislocation into the anterior chamber. The 50-year-old patient exhibited a residual lens capsule and a turbid cortex, with a normal anterior chamber and intraocular pressure. The 76-year-old patient presented a shrunken and ruptured capsule and no cortex in the pupillary area, mild inflammation in the anterior chamber, and high intraocular pressure. Both patients underwent intracapsular cataract extraction combined with anterior vitrectomy and achieved good postoperative recovery. CONCLUSION: Lens nucleus dislocation in hypermature cataracts can be seen in clinical practice, particularly in underdeveloped areas. Early recognition and surgery can improve vision.

Melatonin mitigates traumatic brain injury-induced depression-like behaviors through HO-1/CREB signal in rats.

In addition to significant antioxidant properties, melatonin exhibits neuroprotective effects against various neurological diseases including traumatic brain injury (TBI) and ischemic stroke. Several potential mechanisms have been reported in the neuroprotection of melatonin among patients with TBI. Notably, the heme oxygenase-1 (HO-1)/cAMP response element-binding protein (CREB) signaling pathway is implicated in the development of a depressive state. Moreover, the activity of CREB in the nucleus accumbens (NAc) participates in reward and motivation, further contributing to depression induced by TBI. This study aims to explore whether melatonin could mitigate TBI-induced depression by activating of HO-1/CREB signal in a rodent model of weight-drop. As a consequence, melatonin (10 mg/kg) attenuated TBI-induced elevated immobility time in the force swim test, decreased time spent sniffing the novel rat in 3-chambered social test, and downregulated phosphorylated CERB in the NAc. However, a special inhibitor of HO-1 (SnPP) via intracerebroventricular injection partially reversed the neuroprotective effects of melatonin. Furthermore, melatonin decreased the number of summarized intersects in the astrocyte, A1-type astrocytes, IL-6-positive astrocytes in the NAc after TBI exposure, nevertheless, these changes could partially be restored by SnPP. Therefore, our findings demonstrate a novel neuroprotective mechanism for melatonin against TBI which can be a potential neuroprotective agent for the treatment of TBI-induced depression.

Genome-wide expression changes mediated by A-to-I RNA editing correlate with hepatic oncogenesis.

BACKGROUND: Adenosine-to-inosine (A-to-I) RNA editing is one of the most prevalent RNA modifications in the animal kingdom. Since inosine is recognized as guanosines, the A-to-I process mimics A-to-G DNA mutations but can be controlled in a more flexible manner compared to DNA alterations. METHODS: We parsed the transcriptomes and translatomes of liver cancer and normal tissues from ten patients. We profiled the landscape of the A-to-I RNA editome in these samples and interrogated whether the A-to-I processes participated in the gene expression regulation in oncogenesis. RESULTS: Globally, editing activity was enhanced in all tumor samples compared to that in normal samples. Accordingly, expression of the gene encoding the RNA editing enzyme ADAR (adenosine deaminase acting on RNA) was elevated. Two intronic self-editing sites in ADAR mRNAs controlled its splicing pattern and may regulate its translation efficiency (TE). Moreover, the expression of oncogenes was generally upregulated in tumors, whereas tumor suppressor genes (TSG) were downregulated, possibly due to alterations to microRNA binding sites or RNA splicing defects caused by A-to-I editing. CONCLUSIONS: A-to-I RNA editing plays a crucial role in the oncogenesis of liver cancer. ADAR regulates its own expression via self-editing, and it also affects global transcriptomes and translatomes involving cancer-related genes by RNA editing and changing their expression patterns.

Androgen is responsible for enhanced susceptibility of melatonin against traumatic brain injury in females.

BACKGROUND: Numerous publications have demonstrated that melatonin administration is associated with mortality reduction and improvement in neurological outcomes after traumatic brain injury (TBI). However, there are significant sex differences in several diseases associated with melatonin. We aimed to determine whether androgen was responsible for enhanced susceptibility of melatonin against TBI in females, as well as potential molecular mechanisms. METHODS: Weight-drop was used to establish a rodent model of TBI. Melatonin (10 mg/kg) and testosterone (1 mg/kg) were administered three times every day for three days after TBI using subcutaneous injection, respectively. Seven days after TBI, an open field assay was used to evaluate locomotor and exploratory activities. Neuronal amount, neuronal apoptosis, and expression of phosphorylated extracellularly regulated protein kinases 1/2 (ERK1/2), c-jun N-terminal kinase 1/2 (JNK1/2), and p38 mitogen-activated protein kinase (p38MAPK) in neurons were assessed using immunofluorescence assay seven days after TBI. The expression of caspase-3, Bax, and Bcl-2 in the frontal cortex was detected using western blot. RESULTS: Compared with female rats, melatonin administration exhibited more neuroprotective effects (including improved locomotor and exploratory activities, elevated neuronal amount, and reduced neuronal apoptosis) in male rats exposed to TBI. Moreover, testosterone significantly improved locomotor and exploratory activities, elevated neuronal amount, decreased neuronal apoptosis, downregulated phosphorylation of JNK1/2- and p38MAPK-positive neurons, but upregulated phosphorylation of ERK1/2-positive neurons in the frontal cortex, and reduced the expressions of cleaved caspase-3, Bax, but increased Bcl-2 expressions in female rats exposed to TBI. CONCLUSIONS: Androgen was responsible for the enhanced susceptibility to TBI under melatonin supplementation in females through a mechanism that may be associated with MAPK pathway regulation.

Clinical characteristics of children with Guillain-Barré syndrome and factors associated with disease severity.

Guillain-Barré syndrome (GBS) is the leading cause of pediatric acute flaccid paralysis. This study aimed to summarize the clinical features of children with GBS and to explore factors associated with the severity of weakness. One hundred and twenty-two children with GBS (73 males and 49 females) were retrospectively analysed. The median age (IQR) at diagnosis was 4.0 years (2.9-7.2 years), and 26.2% of patients were at the age of 2-3 years. Of the 122 cases, 71 (58.2%) had an antecedent infection, 58 (47.5%) had cranial nerve involvement, 36 (29.1%) had dysautonomia, 77 (63.1%) had sensory symptoms, 28 (23.0%) had difficulty in breathing of which 15 (12.3%) patients required mechanical ventilation, and 8 (6.6%) had normal tendon reflex or hyperreflexia. Cytoalbuminologic dissociation of the cerebrospinal fluid was observed in 97 cases (82.9%). Further, 120 patients underwent nerve conduction studies: 76 (63.3%) exhibited demyelinating features whereas 36 (30.0%) had axonal type of CBS. 70.2% of patients could walk independently at 12 weeks. Fourteen (11.5%) patients were classified into the mild group [GBS disability score (GBS-DS) < 3] and 108 (88.5%) were classified into the severe group (GBS-DS ≥ 3). The incidence of cranial involvement (P = 0.038) and decreased tendon reflexes (P = 0.048) were significantly different between the two groups. These findings suggested that cranial nerve involvement is associated with severe muscle weakness in children with GBS.

The Genotype and Phenotype of Proline-Rich Transmembrane Protein 2 Associated Disorders in Chinese Children.

Objectives: To study the genetic and clinical characteristics of Chinese children with pathogenic proline-rich transmembrane protein 2 (PRRT2) gene-associated disorders. Methods: Targeted next generation sequencing (NGS) was used to identify pathogenic PRRT2 variations in Chinese children with epilepsy and/or kinesigenic dyskinesia. Patients with confirmed PRRT2-associated disorders were monitored and their clinical data were analyzed. Results: Forty-four patients with pathogenic PRRT2 variants were recruited. Thirty-five of them (79.5%) had heterozygous mutations, including 30 frameshifts, three missenses, one nonsense, and one splice site variant. The c.649dupC was the most common variant (56.8%). Eight patients (18.2%) showed whole gene deletions, and one patient (2.3%) had 16p11.2 microdeletion. Thirty-four cases (97.1%) were inherited and one case (2.9%) was de novo. Forty patients were diagnosed with benign familial infantile epilepsy (BFIE), two patients had paroxysmal kinesigenic dyskinesia (PKD) and two had infantile convulsions and choreoathetosis (ICCA). Patients with whole gene deletions had a later remission than patients with heterozygous mutations (13.9 vs. 7.1 months, P = 0.001). Forty-two patients were treated with antiseizure medications (ASMs). At last follow-up, 35 patients, including one who did not receive therapy, were asymptomatic, and one patient without ASMs died of status epilepticus at 12 months of age. One patient developed autism, and one patient showed mild developmental delay/intellectual disability. Conclusion: Our data suggested that patients with whole gene deletions could have more severe manifestations in PRRT2-associated disorders. Conventional ASMs, especially Oxcarbazepine, showed a good treatment response.

Clinical and genetic characteristics of epilepsy of infancy with migrating focal seizures in Chinese children.

OBJECTIVE: Epilepsy of infancy with migrating focal seizures (EIMFS) is a rare and severe developmental epileptic encephalopathy. The aim of this study was to improve our understanding of EIMFS by using phenotype-genotype correlation. METHODS: We recruited, performed clinical genetic testing, and summarized the clinical features and genetic characteristics in five patients with EIMFS in China. RESULTS: The five recruited patients included 2 males and 3 females. The median age of seizure onset was 2 months (range, day 3 to 3 months). All patients exhibited the characteristics of clinically migrating focal motor (tonic or clonic) seizures. Typical migrating ictal electrical patterns were found in 1 patient; the remaining four patients presented with overlapping seizures with different areas of ictal onset in differing hemispheres. All the patients had the associated variants, including KCNT1, SCN1A, SCN2A, TBC1D24 and ALG1. All patients received two or more antiseizure medications, and 1 patient became seizure-free, 1 reported >75 % seizure reduction, 2 reported >50 % seizure reduction, and 1 patient showed no improvement. Varying degrees of psychomotor developmental delays were observed in all patients. CONCLUSIONS: The course of EIMFS could be related to the type of gene variant present, and different genes may have specific clinical features. Larger cohorts are required to elucidate such potential phenotype-genotype correlations.

Efficacy of the ketogenic diet in patients with Dravet syndrome: A meta-analysis.

PURPOSE: Dravet syndrome is an infantile epilepsy syndrome with drug resistant seizures and cognitive impairment. The aim of this meta-analysis was to summarize the findings of relevant published studies to identify the efficacy of a ketogenic diet in patients with Dravet syndrome and their compliance thereof, and to provide useful information for clinical practice. METHODS: The PubMed, Embase, Wanfang, and CNKI databases were searched for relevant studies published up to September 25, 2019; the included studies were reviewed. Meta-analyses were performed using R software to determine the combined efficacy rates and retention rate for the ketogenic diet in patients with Dravet syndrome. RESULTS: Seven studies involving 167 patients met the inclusion criteria: four were retrospective studies, and three were prospective studies. The meta-analysis revealed that 63 %, 60 %, and 47 % of responder patients achieved ≥50 % seizure reduction at month 3, 6, and 12, respectively. The pooled retention rate of the ketogenic diet at month 6 and month 12 was 78 % and 49 %, respectively. CONCLUSIONS: Our meta-analysis indicates that the ketogenic diet is a treatment option for patients with Dravet syndrome. The ketogenic diet is safe and its adverse effects are mostly acceptable. However, further investigations, especially high-quality controlled trials with large samples, are required.