Observing Proton-Electron Mixed Conductivity in Graphdiyne.

Mixed conducting materials with both ionic and electronic conductivities have gained prominence in emerging applications. However, exploring material with on-demand ionic and electronic conductivities remains challenging, primarily due to the lack of correlating macroscopic conductivity with atom-scale structure. Here, the correlation of proton-electron conductivity and atom-scale structure in graphdiyne is explored. Precisely adjusting the conjugated diynes and oxygenic functional groups in graphdiyne yields a tunable proton-electron conductivity on the order of 103. In addition, a wet-chemistry lithography technique for uniform preparation of graphdiyne on flexible substrates is provided. Utilizing the proton-electron conductivity and mechanical tolerance of graphdiyne, bimodal flexible devices serving as capacitive switches and resistive sensors are created. As a proof-of-concept, a breath-machine interface for sentence-based communication and self-nursing tasks with an accuracy of 98% is designed. This work represents an important step toward understanding the atom-scale structure-conductivity relationship and extending the applications of mixed conducting materials to assistive technology.

Genetic variability in stroke patients: CYP2C19 polymorphisms unraveled.

OBJECTIVE: To study the distribution characteristics of CYP2C19 polymorphisms in patients suffering from stroke in Han Chinese patients. METHOD: PCR and DNA microarray chip technology were used to detect the CYP2C19 genotype of 549 patients with stroke, and the genotype, allele frequency and metabolic type of patients with different sexes, ages and types of infarctions and the independent risk factors for clopidogrel resistance were analyzed. RESULTS: Six genotypes were detected in these 549 patients. A total of 233 (42.44%) patients had the heterozygous allele *1/*2, which was the most prevalent, followed by the homozygous wild-type allele *1/*1 (191, 34.79%). A total of 30 (5.46%) patients possessed the heterozygous allele *1/*3, and 65 (11.84%) patients had the homozygous mutant allele *2/*2. Twenty-nine (5.28%) patients had the compound heterozygous mutant allele *2/*3, and only 1 patient had the homozygous mutant allele *3/*3. The distribution of genotypes, alleles, and metabolic types did not change significantly (P > 0.05) by sex, age, or type of stroke. In addition, no independent risk factors for clopidogrel resistance were found in this analysis. CONCLUSION: The distribution of CYP2C19 genotypes, allele frequencies, and metabolic types in patients with stroke in Han Chinese patients were not correlated with sex, age, or infarction type. The possibilities of hyperglycemia, hypercholesterolemia, hypertriglyceridemia, hypo-HDL-cholesterolemia, hyper-LDL-cholesterolemia and high blood pressure were not statistically associated with CYP2C19 genotypes. CYP2C19 gene polymorphism detection is recommended for patients who are available, and during treatment, the CYP2C19 genotype can be used to guide personalized precise medication use in patients with stroke.

A unique Levey-Jennings control chart used for internal quality control in human papillomavirus detection.

OBJECTIVE: The purpose of this study was to provide an updated estimate of the prevalences of different types of human papillomavirus (HPV) in females in Chaoshan District and to establish an internal quality control (IQC) method for excluding false-positive results in HPV detection by using the Levey-Jennings control chart. METHOD: HPV types were detected in 23,762 cervical samples by using PCR membrane hybridization. The means and standard deviations (SDs) of the positive rates were calculated, the Levey-Jennings chart was plotted, and the rules for "out of control" and "warning" were established. A set of standardized IQC for HPV DNA tests was developed based on the values and Levey-Jennings charts. RESULT: In 466 batches, the positive rate exceeded the 1 + 2SD rule 24 times, but there was no consecutive exceedance, which was considered "in control". When the positive rate exceeded the 1 + 3SD rule 8 times with consecutive exceedance, it was considered "out of control". Further examination revealed that detections showing "out of control" had an undesirable random error, indicating that contamination may occur due to improper operation. CONCLUSION: This unique Levey-Jennings control chart is a practical method for eliminating false-positive results in HPV DNA detection and should be widely applicable in molecular diagnostic laboratories.

Case Report: Successful Management of a 29-Day-Old Infant With Severe Hyperlipidemia From a Novel Homozygous Variant of GPIHBP1 Gene.

Background: Severe hyperlipidemia is characterized by markedly elevated blood triglyceride levels and severe early-onset cardiovascular diseases, pancreatitis, pancreatic necrosis or persistent multiple organ failure if left untreated. It is a rare autosomal recessive metabolic disorder originated from the variants of lipoprotein lipase gene, and previous studies have demonstrated that most cases with severe hyperlipidemia are closely related to the variants of some key genes for lipolysis, such as LPL, APOC2, APOA5, LMF1, and GPIHBP1. Meanwhile, other unidentified causes also exist and are equally worthy of attention. Methods: The 29-day-old infant was diagnosed with severe hyperlipidemia, registering a plasma triglyceride level as high as 25.46 mmol/L. Whole exome sequencing was conducted to explore the possible pathogenic gene variants for this patient. Results: The infant was put on a low-fat diet combined with pharmacological therapy, which was successful in restraining the level of serum triglyceride and total cholesterol to a low to medium range during the follow-ups. The patient was found to be a rare novel homozygous duplication variant-c.45_48dupGCGG (Pro17Alafs*22) in GPIHBP1 gene-leading to a frameshift which failed to form the canonical termination codon TGA. The mutant messenger RNA should presumably produce a peptide consisting of 16 amino acids at the N-terminus, with 21 novel amino acids on the heels of the wild-type protein. Conclusions: Our study expands on the spectrum of GPIHBP1 variants and contributes to a more comprehensive understanding of the genetic diagnosis, genetic counseling, and multimodality therapy of families with severe hyperlipidemia. Our experience gained in this study is also contributory to a deeper insight into severe hyperlipidemia and highlights the importance of molecular genetic tests.

Predicting the risk of suicide attempt in a depressed population: Development and assessment of an efficient predictive nomogram.

The purpose of this study was to develop and validate a user-friendly suicide attempt risk nomogram in depression, supporting timely interventions by clinicians. We collected clinical data of 273 depressed patients from January 2020 to January 2021. Suicide attempt was assessed conducting the Mini International Neuropsychiatric Interview. First, optimized features were filtrated through the least absolute shrinkage and selection operator regression analysis. Subsequently, we selected variables with nonzero coefficients and entered them into multiple logistic regression model and nomogram function to construct a visual predicting suicide attempt model. Additionally, the C-index, calibration plot and decision curve analysis, were applied to assess discrimination, calibration, and clinical practicability. Finally, the bootstrapping validation was applied to assess internal validation. Finally, eleven clinical features are screened out in the prediction nomogram. The model presented tiptop calibration and pleasant discrimination with a C-index of 0.853. A towering C-index value, up to 0.799, could also be attained in the interval validation analysis. In addition, decision curve analysis exhibited that our predictive model is clinically effective when the threshold is no less than 1%. These results demonstrate this predictive model was helpful for clinicians assessing the inpatient's suicide attempt recently and implementing individualized treatment strategies.

Copper-Catalyzed Tandem Cross-Coupling/Thermally Promoted [2 + 2] Cycloaddition of 1,6-Enynes and Diazo Compounds To Assemble Methylenecyclobutane-Fused Ring System.

An unprecedented copper-catalyzed tandem reaction of 1,6-enynes with diazo compounds via a cross-coupling/[2 + 2] cycloaddition sequence was reported. A library of methylenecyclobutane-fused ring systems including cyclobuta[b]indolines, cyclobuta[b]benzofuran, benzo[b]cyclobuta[d]thiophene, and bicyclo[3.2.0] structures were obtained in moderate to excellent yields under very mild reaction conditions. The reaction exhibited high proximal-regioselectivity and diastereoselectivity. Moreover, 1,6-allenene has proven to be the key intermediate and proceeds via a thermally promoted [2 + 2] cycloaddition in the absence of copper catalyst.

Cell count-based parameters and algorithms for thalassaemia trait screening in the southern Chinese population.

INTRODUCTION: Thalassaemia trait (TT) is potential to be missed clinically, especially normocytic thalassaemia. We aimed to establish discriminant functions (DFs) and an algorithm for detecting microcytic or normocytic TT in epidemiological screening. METHODS: The receiver operating characteristics (ROC) curve analysis was used to determine the diagnostic performance of the proposed formulas in differentiating TT and nonthalassaemia (non-TT). DFs combined the two blood count parameters with the highest performance, based on the area under the curve (AUC) value, into mathematical formulas, using logistic regression. The diagnostic efficacy of DFs was subsequently evaluated in 761 participants, and reliability (including adjusted agreement [AA] and Kappa values) and validity (including sensitivity, specificity, likelihood ratio and Youden's Index) were calculated. RESULTS: Among microcytic participants, the proposed DFs showed good diagnostic performance (in females: AUC = 0.892 [DF1 = 0.015 × RDW-CV/RBC - 0.096 × RDW-SD/RBC + 1.29], in males: AUC = 0.861 [DF2=-0.025 × RDW-SD/RBC - 0.035 × MCV/RBC + 1.415]). Youden's Index, AA and Kappa values for microcytic TT detection were 0.72, 0.86, and 0.72 and 0.63, 0.81 and 0.63 for females and males, respectively. In normocytic participants with RDW-CV/RBC ≤ 3.54, DF3=-0.38 × MCH-0.02 × MCHC+17.37 achieved AUC = 0.857 in females, whereas DF4 = 0.007 × MCV-0.113 × MCH+2.829 achieved AUC = 0.969 in males. The Youden's Index, AA and Kappa values for the proposed DFs for thalassaemia detection were 0.69, 0.84 and 0.67 in females, 0.76, 0.91 and 0.71 in males, respectively. CONCLUSION: The proposed DFs performed well in the detection of TT among participants with microcytic and normocytic parameters and could be utilized in epidemiological study for TT.

Development of an Axon-Guiding Aligned Nanofiber-Integrated Compartmentalized Microfluidic Neuron Culture System.

Microfluidic-based neuron cell culture systems have recently gained a lot of attention due to their efficiency in supporting the spatial and temporal control of cellular microenvironments. However, the lack of axon guidance is the key limitation in current culture systems. To combat this, we have developed electrospun aligned nanofiber-integrated compartmentalized microfluidic neuron culture systems (NIMSs), where the nanofibers have enabled axonal guidance and stability. The resulting platform significantly improved axon alignment, length, and stability for both rat primary embryonic motor neurons (MNs) and dorsal root ganglia (DRG) neurons compared to the conventional glass-based microfluidic systems (GMSs). The results showed that axonal growth covered more than two times the area on the axonal chamber of NIMSs compared to the area covered for GMSs. Overall, this platform can be used as a valuable tool for fundamental neuroscience research, drug screening, and biomaterial testing.

Palladium(II)-Catalyzed Oxidative Decarboxylative [2 + 2 + 1] Annulation of Cinnamic Acids with Alkynes: Access to Polysubstituted Pentafulvenes.

An unprecedented palladium(II)-catalyzed oxidative decarboxylative [2 + 2 + 1] annulation of cinnamic acids with alkynes has been developed for the synthesis of polysubstituted pentafulvenes. Ag2CO3 and DMSO are essential for the reaction. This protocol features readily available starting materials, a wide substrate scope, and moderate to excellent yields. Moreover, various significant frameworks can be easily obtained from the late-stage transformations of pentafulvenes via oxidation, reduction, and Scholl-type reaction.

Nanotunnels within Poly(3,4-ethylenedioxythiophene)-Carbon Nanotube Composite for Highly Sensitive Neural Interfacing.

Neural electrodes are developed for direct communication with neural tissues for theranostics. Although various strategies have been employed to improve performance, creating an intimate electrode-tissue interface with high electrical fidelity remains a great challenge. Here, we report the rational design of a tunnel-like electrode coating comprising poly(3,4-ethylenedioxythiophene) (PEDOT) and carbon nanotubes (CNTs) for highly sensitive neural recording. The coated electrode shows a 50-fold reduction in electrochemical impedance at the biologically relevant frequency of 1 kHz, compared to the bare gold electrode. The incorporation of CNT significantly reinforces the nanotunnel structure and improves coating adhesion by ∼1.5 fold. In vitro primary neuron culture confirms an intimate contact between neurons and the PEDOT-CNT nanotunnel. During acute in vivo nerve recording, the coated electrode enables the capture of high-fidelity neural signals with low susceptibility to electrical noise and reveals the potential for precisely decoding sensory information through mechanical and thermal stimulation. These findings indicate that the PEDOT-CNT nanotunnel composite serves as an active interfacing material for neural electrodes, contributing to neural prosthesis and brain-machine interface.

Pd-Catalyzed Oxidative Annulation of Aryl Ethers with Alkynes: Synthesis of Functionalized Spirocycles and Naphthalenes.

Palladium-catalyzed dearomative [2+2+1] annulations of aryl ethers with alkynes are reported via para-selective C-H functionalization, providing highly functionalized spirocyclohexadienones in moderate to excellent yields under mild reaction conditions. Importantly, mechanistic investigation indicated an unusual C-O bond cleavage was involved. Moreover, polyarylated naphthalenes could be obtained via oxidative [2+2+2] annulation by tuning aryl ethers from monomethoxybenzenes to polymethoxybenzenes under an identical catalytic system.

Synthesis of 3-Azabicyclo[m.2.0] Ring Systems via a Copper-Catalyzed Cascade Reaction of Diazo Compounds with 1,n-Allenynes.

A copper-catalyzed cascade reaction of diazo compounds with 1,n-allenynes (n = 6,7) was reported, which provides efficient access to various functionalized 3-azabicyclo[m.2.0] frameworks (m = 5,6) in moderate to excellent yields under mild reaction conditions. The reaction proceeds through intermolecular cross-coupling to form bisallene intermediates, followed by subsequent intramolecular [2+2] cycloaddition.

Severe forms of Johanson-Blizzard syndrome caused by two novel compound heterozygous variants in UBR1: Clinical manifestations, imaging findings and molecular genetics.

Johanson-Blizzard Syndrome (JBS) is a rare autosomal recessive genetic disorder characterized by exocrine pancreatic insufficiency, distinct abnormal facial appearance and varying degrees of growth retardation. Variants in UBR1 gene are considered to be responsible for the syndrome. Here, we describe a 3-year old boy, who visited our clinic for severe growth retardation and frequent oily diarrhea. The physical examination revealed nasal alae aplasia, scalp defect, and maldescent of left testicle. Transabdominal ultrasound and computed tomography scan of his abdomen demonstrated complete fatty replacement of the pancreas. The clinical, laboratory, and imaging findings strongly suggest the diagnosis of hereditary pancreatitis. Whole exome sequencing revealed two rare compound heterozygous variants, c.2511T > G (p.H837Q) and c.1188T > G (p.Y396X), in the UBR1 gene of this boy, so, the diagnosis of JBS was established. This is the first report of Chinese patient with JBS, and our study indicates that transabdominal ultrasound and computed tomography are two useful and noninvasive imaging methods for the diagnosis and evaluation of JBS, and identification of these two novel variants expands the database of UBR1 gene variants. Furthermore, with the availability of the identification technology for these variants, prenatal diagnosis could be offered for future pregnancies.

Copper-Catalyzed Tandem Cross-Coupling/[2 + 2] Cycloaddition of 1,6-Allenynes with Diazo Compounds to 3-Azabicyclo[5.2.0] Ring Systems.

An unprecedented copper-catalyzed tandem cross-coupling/[2 + 2] cycloaddition of 1,6-allenynes with diazo compounds was reported, chemo- and regioselectively providing 3-azabicyclo[5.2.0] frameworks in moderate to excellent yields under mild reaction conditions. Moreover, the products readily convert to highly functionalized quinolines via oxidative radical rearrangement.

Rhodium-Catalyzed Regiodivergent [3 + 2] and [5 + 2] Cycloadditions of Quinolinium Ylides with Alkynes.

Rhodium-catalyzed regiodivergent [3 + 2] and [5 + 2] cycloadditions of quinolinium ylides with alkynes are reported, providing highly functionalized five-membered indolizine derivatives and seven-membered 1,4-oxazepine compounds, respectively, in moderate to excellent yields under mild reaction conditions. Importantly, quinolinium ylides are derived from donor-acceptor diazo compounds, and different types of donor-acceptor diazo compounds exhibit distinct selectivity and reactivity for the reactions. The [3 + 2] cycloadditions involve an unusual 1,3-ester migration process.

Bionanotube/Poly(3,4-ethylenedioxythiophene) Nanohybrid as an Electrode for the Neural Interface and Dopamine Sensor.

Poly(3,4-ethylene dioxythiophene) (PEDOT) is a promising conductive material widely used for interfacing with tissues in biomedical fields because of its unique properties. However, obtaining high charge injection capability and high stability remains challenging. In this study, pristine carbon nanotubes (CNTs) modified by dopamine (DA) self-polymerization on the surface polydopamine (PDA@CNTs) were utilized as dopants of PEDOT to prepare hybrid films through electrochemical deposition on the indium tin oxide (ITO) electrode. The PDA@CNTs-PEDOT film of the nanotube network topography exhibited excellent stability and strong adhesion to the ITO substrate compared with PEDOT and PEDOT/ p-toulene sulfonate. The PDA@CNTs-PEDOT-coated ITO electrodes demonstrated lower impedance and enhanced charge storage capacity than the bare ITO. When applying exogenous electrical stimulation (ES), robust long neurites sprouted from the dorsal root ganglion (DRG) neurons cultured on the PDA@CNTs-PEDOT film. Moreover, ES promoted Schwann cell migration out from the DRG spheres and enhanced myelination. The PDA@CNTs-PEDOT film served as an excellent electrochemical sensor for the detection of DA in the presence of biomolecule interferences. Results would shed light into the advancement of conducting nanohybrids for applications in the multifunctional bioelectrode in neuroscience.

Advances in injectable self-healing biomedical hydrogels.

In recent years, implantable biomaterials have attracted significant interest owing to their potentials for use in the therapy of physical defects and traumas. Among the implantable biomaterials, hydrogels have received increasing attention for their tunable structures and good rheological behavior. However, the mechanical failures of traditional gel materials during normal operation remain a serious issue. To overcome this problem, hydrogel materials with self-healing and injectable abilities have been developed, with their potential for autonomous self-recovery and minimally invasive implantation. In this paper, the progress of injectable self-healing hydrogels is presented by combining developments in the fundamental knowledge of polymer designs and discussions on the practical biomedical applications of the materials. The mechanisms of different types of self-healing hydrogels are introduced first and their performances are then discussed, followed by a review of the self-healing hydrogels with injectability. The applications of the injectable self-healing hydrogels are discussed in the final section. STATEMENT OF SIGNIFICANCE: This paper provides an overview of the progress of a smart material, injectable self-healing hydrogel, during the past ten years and mainly focuses on its recent development. This paper presents developments in the fundamental knowledge in polymer designs and discussions on the practical biomedical application of the materials, which sheds more light on the advancement of injectable self-healing hydrogels. This paper should be of interest to the readers who are curious about the advances of injectable self-healing hydrogels.

Severe forms of complete androgen insensitivity syndrome caused by a p.Q65X novel mutation in androgen receptor: Clinical manifestations, imaging findings and molecular genetics.

Androgen insensitivity syndrome (AIS), a rare X-linked recessive genetic disorder with a normal 46, XY karyotype, is caused by defect of androgen receptor gene (AR) leading to resistance of the target tissues to androgenic hormones. There is a wide spectrum of clinical presentations of AIS, ranging from male infertility, hypospadias to completely normal female external genitalia. Here, we describe a 15-year old, phenotypically female individual, who visited our clinic for primary amenorrhea. The physical examination revealed normal female external genitalia, normal breast development, as well as sparse pubic hair and absence of axillary hair. A short blind vagina pouch was noticed in gynecological examination apart from the absence of cervix and uterus. Serum testosterone measured a considerable high level, and the karyotype was indicative of a normal male (46, XY). Transabdominal ultrasound (US) and magnetic resonance imaging (MRI) confirmed the absence of uterus, ovaries and fallopian tubes, only with a small blind-ending vagina observed. The clinical, laboratory, imaging, and genetic findings strongly suggest the diagnosis of complete androgen insensitivity syndrome (CAIS). Mutational analysis of the AR gene revealed a novel small insertion mutation c.192_193insTAGCAG(Q65X) in exon 1, which gives rise to a truncated nonfunctional protein, resulting in the loss of the remaining 856 C-terminus amino acid residues. This study indicates that US and MRI are two useful and noninvasive imaging methods for the diagnosis and evaluation of CAIS, and identification of this novel mutation expands the database of AR gene mutations. Furthermore, with the availability of the identification technology for this mutation, prenatal diagnosis could be offered for future pregnancies.

Electrospun nanofibers facilitate better alignment, differentiation, and long-term culture in an in vitro model of the neuromuscular junction (NMJ).

The neuromuscular junction (NMJ) is a specialized synapse between motor neurons and the muscle fibers they innervate. Due to the complexity of various signalling molecules and pathways, in vivo NMJs are difficult to study. Therefore, in vitro motor neuron-muscle co-culture plays a pivotal role in studying the mechanisms of NMJ formation associated with neurodegenerative diseases. There is a growing need to develop novel methodologies that can be used to develop long-term cultures of NMJs. To date, there have been few studies on NMJ development and long-term maintenance of the system, which is also the main challenge for the current in vitro models of NMJs. In this study, we demonstrate a long-term co-culture system of primary embryonic motor neurons from Sprague-Dawley rats and C2C12 cells on both random and aligned electrospun polylactic acid (PLA) nanofibrous scaffolds. This is the first study to explore the role of electrospun nanofibers in the long-term maintenance of NMJs. PLA nanofibrous scaffolds provide better contact guidance for C2C12 cells aligning along the fibers, thus guiding myotube formation. We can only maintain the co-culture system on a conventional glass substrate for 2 weeks, whilst 55% and 70% of the cells still survived on random and aligned PLA substrates after 7 weeks. Our nanofiber-based long-term co-culture system is used as an important tool for the fundamental research of NMJs.

The cellular response of nerve cells on poly-l-lysine coated PLGA-MWCNTs aligned nanofibers under electrical stimulation.

Tissue engineering scaffold provide an effective alternative for peripheral nerve repair. Nanofibrous nerve conduits fabricated with various synthetic and natural materials have great potential to support nerve regeneration as a bridge between adjacent ends. The physical, chemical and electrical properties of the scaffolds affect the outcome of nerve regeneration and recovery of function. In this paper, a surface modified, electrically conductive, aligned nanofibrous scaffold composed of poly(lactic-co-glycolic acid) (PLGA) and multi-walled carbon nanotubes (MWCNTs), referred to as L-PC_A was fabricated for nerve regeneration. The morphology, surface chemistry and hydrophilicity of nanofibers were characterized by Scanning Electron Microscopy (SEM), Energy-dispersive X-ray (EDX) and water contact angle, respectively. The mechanical property of the nanofibrous scaffold was also evaluated using a universal materials tester. The effects of these scaffolds on PC12 cell adhesion, proliferation and neuronal differentiation were all evaluated. A hydrophilic surface was created by poly-l-lysine coating, which was able to provide a better environment for cell attachment. Furthermore aligned fibers were proved to be able to guide PC12 cells and DRG neurons growing along the fiber direction and be beneficial for neurite outgrowth. The cellular responses of PC12 cells and DRG neurons on L-PC_A scaffold under electrical stimulation were evaluated by neurofilament proteins expression. As a result, the PC12 cells and DRG neurons stimulated with electrical shock showed longer neurite length, indicating that electrical stimulation with a voltage of 40 mV based on the scaffold with MWCNTs could enhance the neurite extension. Moreover, the cellular response of Schwann cells including cell attachment, proliferation and MBP expression were also enhanced with the synergistic effect of aligned nanofibers and electrical stimulation. In summary, the L-PC_A nanofibrous scaffold supported the cellular response of nerve cells in terms of cell proliferation, differentiation, neurite outgrowth, and myelination in the presence of electrical stimulation, which could be a potential candidate for nerve regeneration application.