Discovery of Potent and Selective Blockers Targeting the Epilepsy-Associated KNa1.1 Channel.

Gain-of-function (GOF) mutations of the sodium-activated potassium channel KNa1.1 (Slack, Slo2.2, or KCa4.1) induce severe, drug-resistant forms of epilepsy in infants and children. Although quinidine has shown promise in treating KCNT1-related epilepsies compared to other drugs, its limited efficacy and substantial side effects necessitate the development of new KNa1.1 channel inhibitors. In this study, we developed a novel class of KNa1.1 inhibitors using combined silico approaches and structural optimization. Among these inhibitors, compound Z05 was identified as a selective potential KNa1.1 inhibitor, especially against the hERG channel. Moreover, its binding site and potential counteraction to a GOF mutant Y796H were identified by the mutation studies. Our data also showed that Z05 had significant pharmacological profiles, including high brain penetration and moderate oral bioavailability, offering a valuable in vitro tool compound for further drug development in treating KCNT1-related epilepsies.

Carvedilol inhibits neuronal hyperexcitability caused by epilepsy-associated KCNT1 mutations.

BACKGROUND AND PURPOSE: KCNT1 encodes a sodium-activated potassium channel (Slack channel), and its mutation can cause several forms of epilepsy. Traditional antiepileptic medications have limited efficacy in treating patients with KCNT1 mutations. Here, we describe one heterozygous KCNT1 mutation, M267T, in a patient with EIMFS. The pathological channel properties of this mutation and its effect on neuronal excitability were investigated. Additionally, this study aimed to develop a medication for effective prevention of KCNT1 mutation-induced seizures. EXPERIMENTAL APPROACH: Wild-type or mutant KCNT1 plasmids were expressed heterologously in Xenopus laevis oocytes, and channel property assessment and drug screening were performed based on two-electrode voltage-clamp recordings. The single-channel properties were investigated using the excised inside-out patches from HEK293T cells. Through in utero electroporation, WT and M267T Slack channels were expressed in the hippocampal CA1 pyramidal neurons in male mice, followed by the examination of the electrical properties using the whole-cell current-clamp technique. The kainic acid-induced epilepsy model in male mice was used to evalute the antiseizure effects of carvedilol. KEY RESULTS: The KCNT1 M267T mutation enhanced Slack channel function by increasing single-channel open probability. Through screening 16 FDA-approved ion channel blockers, we found that carvedilol effectively reversed the mutation-induced gain-of-function channel properties. Notably, the KCNT1 M267T mutation in the mouse hippocampal CA1 pyramidal neurons affected afterhyperpolarization properties and induced neuronal hyperexcitability, which was inhibited by carvedilol. Additionally, carvedilol exhibited antiseizure effects in the kainic acid-induced epilepsy model. CONCLUSION AND IMPLICATION: Our findings suggest carvedilol as a new potential candidate for treatment of epilepsies.

Enhancing the performance of molecule-based piezoelectric sensors by optimizing their microstructures.

By combining the rigidity of inorganic components with the flexibility of organic components, molecule-based ferroelectrics emerge as promising candidates for flexible, self-powered piezoelectric sensors. While it is well known that the performance of piezoelectric sensor devices depends not only on the materials' piezoelectric properties but also on the device architecture, research into enhancing molecule-based piezoelectric sensor performance through microstructure optimization has never been investigated. Here, we report the synthesis of a molecule-based ferroelectric, [(2-bromoethyl) trimethylammonium][GaBr4] ([(CH3)3NCH2CH2Br][GaBr4]) (1), which exhibits a piezoelectric coefficient (d 33) of up to 331 pC N-1. Our investigation reveals that the power density of a composite piezoelectric sensor device made from 1@S-PDMS(800#) (with microstructures) is twelve times that of 1-Flat-PDMS (without microstructures), due to a synergistic combination of piezoelectric and triboelectric effects. Interestingly, this flexible piezoelectric sensor can effectively detect human physiological signals, such as finger bending, breathing, and speech recognition, without the need for an external power supply.

Smart photonic crystal hydrogels for visual glucose monitoring in diabetic wound healing.

Diabetes is a global chronic disease that seriously endangers human health and characterized by abnormally high blood glucose levels in the body. Diabetic wounds are common complications which associate with impaired healing process. Biomarkers monitoring of diabetic wounds is of great importance in the diabetes management. However, actual monitoring of biomarkers still largely relies on the complex process and additional sophisticated analytical instruments. In this work, we prepared hydrogels composed of different modules, which were designed to monitor different physiological indicators in diabetic wounds, including glucose levels, pH, and temperature. Glucose monitoring was achieved based on the combination of photonic crystal (PC) structure and glucose-responsive hydrogels. The obtained photonic crystal hydrogels (PCHs) allowed visual monitoring of glucose levels in physiological ranges by readout of intuitive structural color changes of PCHs during glucose-induced swelling and shrinkage. Interestingly, the glucose response of double network PCHs was completed in 15 min, which was twice as fast as single network PCHs, due to the higher volume fraction of glucose-responsive motifs. Moreover, pH sensing was achieved by incorporation of acid-base indicator dyes into hydrogels; and temperature monitoring was obtained by integration of thermochromic powders in hydrogels. These hydrogel modules effectively monitored the physiological levels and dynamic changes of three physiological biomarkers, both in vitro and in vivo during diabetic wound healing process. The multifunctional hydrogels with visual monitoring of biomarkers have great potential in wound-related monitoring and treatment.

Enhancing Variant Calling in Whole-Exome Sequencing Data Using Population-Matched Reference Genomes.

Whole-exome sequencing (WES) data are frequently used for cancer diagnosis and genome-wide association studies (GWAS), based on high-coverage read mapping, informative variant calling, and high-quality reference genomes. The center position of the currently used genome assembly, GRCh38, is now challenged by two newly published telomere-to-telomere (T2T) genomes, T2T-CHM13 and T2T-YAO, and it becomes urgent to have a comparative study to test population specificity using the three reference genomes based on real case WES data. Here we report our analysis along this line for 19 tumor samples collected from Chinese patients. The primary comparison of the exon regions among the three references reveals that the sequences in up to ∼ 1% target regions in T2T-YAO are widely diversified from GRCh38 and may lead to off-target in sequence capture. However, T2T-YAO still outperforms GRCh38 genomes by obtaining 7.41% more mapped reads. Due to more reliable read-mapping and closer phylogenetic relationship with the samples than GRCh38, T2T-YAO reduces half of variant calls of clinical significance which are mostly benign, while maintaining sensitivity in identifying pathogenic variants. T2T-YAO also outperforms T2T-CHM13 in reducing calls of Chinese-specific variants. Our findings highlight the critical need for employing population-specific reference genomes in genomic analysis to ensure accurate variant analysis and the significant benefits of tailoring these approaches to the unique genetic backgrounds of each ethnic group.

Research Progress on NMDA Receptor Enhancement Drugs for the Treatment of Depressive Disorder.

Major depressive disorder (MDD) is a severe mental illness with a complex etiology. Currently, many medications employed in clinical treatment exhibit limitations such as delayed onset of action and a high incidence of adverse reactions. Therefore, there is a pressing need to develop antidepressants that exhibit enhanced efficacy and safety. The N-methyl-D-aspartate receptor (NMDAR), a distinctive glutamate-gated ion channel receptor, has been implicated in the onset and progression of depressive disorder, as evidenced by both preclinical and clinical research. The NMDAR antagonist, ketamine, exhibits rapid and sustained antidepressant effects, holding promise as a novel therapeutic approach for depressive disorder. However, its psychotomimetic impact and potential for addiction have restricted its widespread clinical application. Notably, over the past decade, studies have suggested that enhancing NMDAR functionality can produce antidepressant effects with improved safety, especially with the emergence of NMDAR-positive allosteric modulators (PAMs). We view this as a potential novel strategy for treating depression, forming the basis for the narrative review that follows.

The transcription factor MfbHLH104 from Myrothamnus flabellifolia promotes drought tolerance of Arabidopsis thaliana by enhancing stability of the photosynthesis system.

The resurrection plant Myrothamnus flabellifolia can survive extreme drought and desiccation conditions, and quickly recover after rewatering. However, little is known about the mechanism underlying the drought tolerance of M. flabellifolia. In this study, MfbHLH104 was cloned and introduced into Arabidopsis thaliana due to the lack of a transgenic system for M. flabellifolia. MfbHLH104 is localized in the nucleus. Its N-terminal region has transactivation ability in yeast, and the C-terminal region may inhibit the transactivation ability. Overexpressing MfbHLH104 significantly increased drought and salt tolerance of A. thaliana at both seedling and adult stages. It enhanced leaf water retention capacity by decreasing water loss rate and increasing drought- and abscisic acid (ABA) -induced stomatal closure. Additionally, it boosted osmolyte accumulation and ROS scavenging ability by up-regulating genes associated with osmolyte biosynthesis and antioxidant enzymes, and enhancing antioxidant enzyme activities. The expression of ABA-responsive genes were also promoted by MfbHLH104. Remarkably, RNA-seq analysis indicated that MfbHLH104 significantly up-regulated 32 genes (FDR < 0.05 and fold change ≥1.5) involved in photosynthesis related pathways (KEGG pathway No: ko00195, ko00196) under drought, which account for 18.7% of the total up-regulated genes and the most enriched KEGG pathways. This result suggested that it may help to maintain the stability of the photosynthesis system under drought conditions.

Mechanistic Insight into the Enantioselective Degradation of Esterase QeH to (R)/(S)-Quizalofop-Ethyl with Molecular Dynamics Simulation Using a Residue-Specific Force Field.

The enantioselective mechanism of the esterase QeH against the two enantiomers of quizalofop-ethyl (QE) has been primitively studied using computational and experimental approaches. However, it is still unclear how the esterase QeH adjusts its conformation to adapt to substrate binding and promote enzyme-substrate interactions in the catalytic kinetics. The equilibrium processes of enzyme-substrate interactions and catalytic dynamics were reproduced by performing independent molecular dynamics (MD) runs on the QeH-(R)/(S)-QE complexes with a newly developed residue-specific force field (RSFF2C). Our results indicated that the benzene ring of the (R)-QE structure can simultaneously form anion-π and cation-π interactions with the side-chain group of Glu328 and Arg384 in the binding cavity of the QeH-(R)-QE complex, resulting in (R)-QE being closer to its catalytic triplet system (Ser78-Lys81-Tyr189) with the distances measured for the hydroxyl oxygen atom of the catalytic Ser78 of QeH and the carbonyl carbon atom of (R)-QE of 7.39 Å, compared to the 8.87 Å for (S)-QE, whereas the (S)-QE structure can only form an anion-π interaction with the side chain of Glu328 in the QeH-(S)-QE complex, being less close to its catalytic site. The computational alanine scanning mutation (CAS) calculations further demonstrated that the π-π stacking interaction between the indole ring of Trp351 and the benzene ring of (R)/(S)-QE contributed a lot to the binding stability of the enzyme-substrate (QeH-(R)/(S)-QE). These results facilitate the understanding of their catalytic processes and provide new theoretical guidance for the directional design of other key enzymes for the initial degradation of aryloxyphenoxypropionate (AOPP) herbicides with higher catalytic efficiencies.

N-Heterocyclic Carbene Enabled Copper Catalyzed Asymmetric Synthesis of Pyrimidinyl Phosphine with both Axial and P-Stereogenicity.

P-stereogenic phosphines, renowned for their utility as ligands and catalysts, have been instrumental in the field of asymmetric catalysis. However, the catalytic asymmetric synthesis of chiral ligands possessing both axial and phosphine chirality remains a significant challenge. Here, we present the successful demonstration of a Cu-catalyzed asymmetric C-P construction using in situ generated secondary phosphine and heteroaryl chloride. By introducing a chiral NHC ligand and an achiral diphosphine auxiliary ligand, we effectively alleviated the poisoning effect caused by phosphine(III) compounds and suppressed the nonenantioselective background reaction. The reaction exhibited excellent enantioselectivity, with up to 96 % ee, and good diastereoselectivity, with up to 14 : 1 dr, when employing less sterically hindered secondary phosphines. This particular substrate poses a significant challenge due to its strong poisoning effect in copper catalysis.

Glucose-responsive, self-healing, wet adhesive and multi-biofunctional hydrogels for diabetic wound healing.

Diabetic wounds are serious clinical complications which manifest wet condition due to the mass exudate, along with disturbed regulation of inflammation, severe oxidative stress and repetitive bacterial infection. Existing treatments for diabetic wounds remain unsatisfactory due to the lack of ideal dressings that encompass mechanical performance, adherence to moist tissue surfaces, quick repair, and diverse therapeutic benefits. Herein, we fabricated a wet adhesive, self-healing, glucose-responsive drug releasing hydrogel with efficient antimicrobial and pro-healing properties for diabetic wound treatment. PAE hydrogel was constructed with poly(acrylic acid-co-acrylamide) (AA-Am) integrated with a dynamic E-F crosslinker, which consisted of epigallocatechin gallate (EGCG) and 4-(2-acrylamidoethylcarbamoyl)-3-fluorophenylboronic acid (AFPBA). Due to the dynamic crosslinking nature of boronate esters, abundant catechol groups and hydrogen bonding, PAE hydrogel demonstrated excellent mechanical properties with about 1000 % elongation, robust adhesion to moist tissues, fast self-healing, and absorption of biofluids of 10 times of its own weight. Importantly, PAE hydrogel exhibited sustained and glucose-responsive release of EGCG. Together, the bioactive PAE hydrogel had effective antibacterial, antioxidative, and anti-inflammatory properties in vitro, and accelerated diabetic wound healing in rats via reducing tissue-inflammatory response, enhancing angiogenesis, and reprogramming of macrophages. Overall, this versatile hydrogel provides a straightforward solution for the treatment of diabetic wound, and shows potential for other wound-related application scenarios.

Microalgae-derived hydrogels/membranes for phosphorus removal and recovery from aquaculture tailwater: Waste utilization and phosphorus recycling.

Efficient removal and recovery of phosphorus from aquaculture tailwater is challenging due to increasing strict water environment restrictions. This study presents a sustainable approach by using microalgae-waste-derived hydrogels/membranes for phosphorus adsorption and microalgae cultivation. Waste from Euglena gracilis (or Haematococcus pluvialis), modified with magnesium, was converted into biochars (abbreviated as MEBC or MHBC). This biochars were then combined with sodium alginate to fabricate hydrogels and with polyvinyl chloride to create membranes. Due to the almost 100 % phosphorus removal of MEBC (or MHBC) biochar, the as-obtained hydrogels/membranes demonstrated excellent phosphate adsorption, reducing total phosphorus in real aquaculture tailwater from 11 mg/L to 0. Additionally, the phosphorus-saturated hydrogel served as a phosphorus source for microalgae cultivation, while the membranes facilitated microalgae harvesting with a water flux over 40 L/m2/h. This study provides an eco-friendly solution for using microalgae-waste-derived materials to effectively address phosphorus removal and recovery challenges in aquaculture tailwater.

Phytoremediation of Pb-polluted soil using bermudagrass: Effect of mowing frequencies.

Plant lead (Pb) tolerance and accumulation are key characteristics affecting phytoremediation efficiency. Bermudagrass is an excellent candidate for the remediation of Pb-polluted soil, and it needs to be mowed regularly. Here, we explored the effect of different mowing frequencies on the remediation of Pb-contaminated soil using bermudagrass. Mowing was found to decrease the biomass and photosynthetic efficiency of bermudagrass under Pb stress, thereby inhibiting its growth. Although mowing exacerbated membrane peroxidation, successive mowing treatments alleviated peroxidation damage by regulating enzymatic and nonenzymatic systems. A comprehensive evaluation of Pb tolerance revealed that all the mowing treatments reduced the Pb tolerance of bermudagrass, and a once-per-month mowing frequency had a less negative effect on Pb tolerance than did more frequent mowing. In terms of Pb enrichment, mowing significantly increased the Pb concentration, total Pb accumulation, translocation factor (TF), and bioenrichment factor (BCF) of bermudagrass. The total Pb accumulation was greatest under the once-a-month treatment, while the TF and BCF values were greatest under the three-times-a-month mowing treatment. Additionally, the decrease in soil pH and DOC were significantly correlated with the soil available Pb content and plant Pb accumulation parameters. The results showed that changes in the rhizosphere are crucial factors regulating Pb uptake in bermudagrass during mowing. Overall, once-a-month mowing minimally affects Pb tolerance and maximizes Pb accumulation, making it the optimal mowing frequency for soil Pb remediation by bermudagrass. This study provides a novel approach for the remediation of Pb-contaminated soil with bermudagrass based on mowing.

Individuals with genetic high-risk for psychosis experience impaired coping styles compared with healthy controls.

BACKGROUND: Individuals with schizophrenia tend to have negative coping styles and low levels of self-esteem, but it is unclear whether coping styles and self-esteem levels are altered in people in the prodromal phase of psychosis. AIMS: The study was designed to assess the role of coping style and self-esteem in the context of different phases of schizophrenia. METHODS: Recurrent Schizophrenia (ReSch), first-episode schizophrenia patients (FEP), genetic-high risk for psychosis (GHR) patients, and healthy controls (HC) (40 per group) were subjected to in-person clinical interviews. The results of these interviews were then used to gauge coping style and self-esteem using the Coping Styles Questionnaire (CSQ) and the Rosenberg's Self-Esteem Scale (RSES). Data were analyzed through ANCOVAs and logistic regression analyses. RESULTS: The results found that positive coping style (CSQ problem-solving and CSQ seeking for help) generally decline with progression through the HC, GHR, and FEP groups, while negative coping style (CSQ fantasy, CSQ repression and CSQ self-blame) generally increase with progression through the HC, GHR, and FEP groups (except that GHR group was slightly lower than HC group in CSQ self-blame). Results for members of ReSch group were in line with those of members of the FEP group in coping style. At the level of self-esteem, the GHR group was similar to the HC group and significantly higher than the FEP group and the ReSch group. Logistic regression analyses indicated that GHR group patients exhibited increased negative coping styles (CSQ fantasy) relative to members of the HC group, but had greater Positive coping style (CSQ problem-solving) than did members of the FEP group. DISCUSSION: These findings suggest that both GHR individuals experience impaired negative coping styles which expands the understanding of the psychological characteristics of the prodromal group. Further explorations are warranted to develop optimal psychosocial interventions.

Latent profiles of narrative competence and professional identity among nursing students: A cross-sectional analytic study based on the Ring theory of personhood.

AIM: To identify latent profiles of narrative competence in nursing students and examine the association between the potential competence profiles and professional identity from a person-centred perspective. BACKGROUND: According to the Ring theory of personhood, nursing students can develop their professional identities from individual, relational and social aspects through interaction with patients, as well as listening to, understanding and responding to patients' disease narratives. However, few studies have examined the relationship between narrative competence and professional identity through the quantitative method. DESIGN: A cross-sectional analytic study. METHODS: A total of 472 nursing students responded to the survey between March and May 2023. The Professional Identity Questionnaire for Nurse Students and the Narrative Competence Scale were given to participants. Latent profile analysis was conducted to identify narrative competence profiles. The Bolck-Croon-Hagenaars method was used to analyse whether these latent profiles for narrative competence affected nursing students' general, individual, interpersonal and social professional identities. RESULTS: Latent profiles were identified as "low narrative competence" (12.1 %), "relatively low narrative competence" (39.9 %), "moderate narrative competence" (40.1 %) and "high narrative competence" (7.9 %). The profiles only show level differences rather than combinations of competence areas. These profiles had varying effects on the nursing students' general professional identities, as well as their individual, relational and social professional identities. CONCLUSION: This study highlights the significance of providing tailored guidance and support to nursing students, taking into account their unique narrative competency profile, to promote the formation of professional identity from individual, relational and social aspects. Nursing educators should effectively distinguish nursing students with inadequate narrative competence and value patients' disease narratives to promote narrative competence and professional identity.

A Novel Ubiquitin Ligase Adaptor PTPRN Suppresses Seizure Susceptibility through Endocytosis of NaV1.2 Sodium Channels.

Intrinsic plasticity, a fundamental process enabling neurons to modify their intrinsic properties, plays a crucial role in shaping neuronal input-output function and is implicated in various neurological and psychiatric disorders. Despite its importance, the underlying molecular mechanisms of intrinsic plasticity remain poorly understood. In this study, a new ubiquitin ligase adaptor, protein tyrosine phosphatase receptor type N (PTPRN), is identified as a regulator of intrinsic neuronal excitability in the context of temporal lobe epilepsy. PTPRN recruits the NEDD4 Like E3 Ubiquitin Protein Ligase (NEDD4L) to NaV1.2 sodium channels, facilitating NEDD4L-mediated ubiquitination, and endocytosis of NaV1.2. Knockout of PTPRN in hippocampal granule cells leads to augmented NaV1.2-mediated sodium currents and higher intrinsic excitability, resulting in increased seizure susceptibility in transgenic mice. Conversely, adeno-associated virus-mediated delivery of PTPRN in the dentate gyrus region decreases intrinsic excitability and reduces seizure susceptibility. Moreover, the present findings indicate that PTPRN exerts a selective modulation effect on voltage-gated sodium channels. Collectively, PTPRN plays a significant role in regulating intrinsic excitability and seizure susceptibility, suggesting a potential strategy for precise modulation of NaV1.2 channels' function.

Geriatric nutritional risk index is associated with the occurrence of acute kidney injury in critically ill patients with acute heart failure.

Background: During the acute heart failure (AHF), acute kidney injury (AKI) is highly prevalent in critically ill patients. The occurrence of the latter condition increases the risk of mortality in patients with acute heart failure. The current research on the relationship between nutritional risk and the occurrence of acute kidney injury in patients with acute heart failure is very limited. Methods: This retrospective cohort study utilized data from the Medical Information Mart for Intensive Care IV (MIMIC-IV, version 2.1) database. We included adult patients with AHF who were admitted to the intensive care unit in the study. Results: A total of 1310 critically ill patients with acute heart failure were included. The AUC of geriatric nutritional risk index (GNRI) (0.694) is slightly superior to that of controlling nutritional status (CONUT) (0.656) and prognostic nutritional index (PNI) (0.669). The Log-rank test revealed a higher risk of acute kidney injury in patients with high nutritional risk (p < 0.001). Multivariate COX regression analysis indicated that a high GNRI (adjusted HR 0.62, p < 0.001) was associated with a reduced risk of AKI during hospitalization in AHF patients. The final subgroup analysis demonstrated no significant interaction of GNRI in all subgroups except for diabetes subgroup and ventilation subgroup (P for interaction: 0.057-0.785). Conclusion: Our study findings suggest a correlation between GNRI and the occurrence of acute kidney injury in patients hospitalized with acute heart failure.

Structural mechanism of voltage-gated sodium channel slow inactivation.

Voltage-gated sodium (NaV) channels mediate a plethora of electrical activities. NaV channels govern cellular excitability in response to depolarizing stimuli. Inactivation is an intrinsic property of NaV channels that regulates cellular excitability by controlling the channel availability. The fast inactivation, mediated by the Ile-Phe-Met (IFM) motif and the N-terminal helix (N-helix), has been well-characterized. However, the molecular mechanism underlying NaV channel slow inactivation remains elusive. Here, we demonstrate that the removal of the N-helix of NaVEh (NaVEhΔN) results in a slow-inactivated channel, and present cryo-EM structure of NaVEhΔN in a potential slow-inactivated state. The structure features a closed activation gate and a dilated selectivity filter (SF), indicating that the upper SF and the inner gate could serve as a gate for slow inactivation. In comparison to the NaVEh structure, NaVEhΔN undergoes marked conformational shifts on the intracellular side. Together, our results provide important mechanistic insights into NaV channel slow inactivation.

Anti-Hu antibody associated paraneoplastic neurological syndrome in a child with ganglioneuroblastoma: A rare case report and literature review.

RATIONALE: Paraneoplastic neurological syndrome with anti-Hu antibody (Hu-PNS) is a neurological disorder that occur in patients with malignancy. The syndrome has a wide range of presentations and can present before diagnosis of primary malignancy. Familiarity with these paraneoplastic neurological syndromes can help early recognition and take appropriate regimens. PATIENTS CONCERNS: Diagnosis and treatment of Hu-PNS. DIAGNOSES: This is retrospective study that analyzed the clinical data of this case. Through retrospective analysis and targeted antibody screening, serum anti-Hu antibody was detected. Subsequent spinal imaging revealed a mass in the paraspinal region, which was confirmed as ganglioneuroblastoma by pathologic examination. INTERVENTIONS: The child was treated with a course of intravenous immunoglobulin and radical surgical operation without chemotherapy. OUTCOMES: The neurological symptoms were gradually improved and no signs indicate disease progression or tumor recurrence. LESSONS: Hu-PNS has rarely been reported in children with ganglioneuroblastomas. They can mimic non-neoplastic processes, making detection and diagnosis difficult. Serum and/or cerebrospinal fluid onconeural antibody can strongly indicate occult cancers. Early detection of paraneoplastic neurological syndromes can help take appropriate regimens and improve prognosis.

Genome-wide association exploratory studies in individuals with ultra-high risk for schizophrenia in Chinese Han nationality in two years follow-up: A subpopulation study.

BACKGROUND: Although ultra-high risk for schizophrenia (UHR) is related to both genetic and environment factors, the precise pathogenesis is still unknow. To date, few studies have explored the Genome-Wide Association Studies (GWAS) in UHR or HR individuals especially in Han population in China. METHODS: In this study, a GWAS analysis for 36 participants with UHR and 43 with HR were performed, and all deletion variations in 22q11 region were also compared. RESULTS: Sixteen individuals with UHR (44.4%) and none with HR converted into schizophrenia in follow-up after two years. Six loci including neurexin-1(NRXN1) (rs1045881), dopamine D1 receptor (DRD1) (rs686, rs4532), chitinase-3-like protein 1 (CHI3L1) (rs4950928), velocardiofacial syndrome (ARVCF) (rs165815), dopamine D2 receptor (DRD2) (rs1076560) were identified higher expression with significant difference in individuals converted into schizophrenia after two years. The Family with Sequence Similarity 230 Member H (FAM230H) gene in the 22q11 region were also found high expression in UHR group. CONCLUSIONS: Further expansion of sample size and validation studies are needed to explore the pathogenesis of these risk loci in UHR conversion into schizophrenia in the future.