scNanoHi-C: a single-cell long-read concatemer sequencing method to reveal high-order chromatin structures within individual cells.

The high-order three-dimensional (3D) organization of regulatory genomic elements provides a topological basis for gene regulation, but it remains unclear how multiple regulatory elements across the mammalian genome interact within an individual cell. To address this, herein, we developed scNanoHi-C, which applies Nanopore long-read sequencing to explore genome-wide proximal high-order chromatin contacts within individual cells. We show that scNanoHi-C can reliably and effectively profile 3D chromatin structures and distinguish structure subtypes among individual cells. This method could also be used to detect genomic variations, including copy-number variations and structural variations, as well as to scaffold the de novo assembly of single-cell genomes. Notably, our results suggest that extensive high-order chromatin structures exist in active chromatin regions across the genome, and multiway interactions between enhancers and their target promoters were systematically identified within individual cells. Altogether, scNanoHi-C offers new opportunities to investigate high-order 3D genome structures at the single-cell level.

Long-read-based single sperm genome sequencing for chromosome-wide haplotype phasing of both SNPs and SVs.

Although localized haploid phasing can be achieved using long read genome sequencing without parental data, reliable chromosome-scale phasing remains a great challenge. Given that sperm is a natural haploid cell, single-sperm genome sequencing can provide a chromosome-wide phase signal. Due to the limitation of read length, current short-read-based single-sperm genome sequencing methods can only achieve SNP haplotyping and come with difficulties in detecting and haplotyping structural variations (SVs) in complex genomic regions. To overcome these limitations, we developed a long-read-based single-sperm genome sequencing method and a corresponding data analysis pipeline that can accurately identify crossover events and chromosomal level aneuploidies in single sperm and efficiently detect SVs within individual sperm cells. Importantly, without parental genome information, our method can accurately conduct de novo phasing of heterozygous SVs as well as SNPs from male individuals at the whole chromosome scale. The accuracy for phasing of SVs was as high as 98.59% using 100 single sperm cells, and the accuracy for phasing of SNPs was as high as 99.95%. Additionally, our method reliably enabled deduction of the repeat expansions of haplotype-resolved STRs/VNTRs in single sperm cells. Our method provides a new opportunity for studying haplotype-related genetics in mammals.

Molecular basis underlying default mode network functional abnormalities in postpartum depression with and without anxiety.

Although Postpartum depression (PPD) and PPD with anxiety (PPD-A) have been well characterized as functional disruptions within or between multiple brain systems, however, how to quantitatively delineate brain functional system irregularity and the molecular basis of functional abnormalities in PPD and PPD-A remains unclear. Here, brain sample entropy (SampEn), resting-state functional connectivity (RSFC), transcriptomic and neurotransmitter density data were used to investigate brain functional system irregularity, functional connectivity abnormalities and associated molecular basis for PPD and PPD-A. PPD-A exhibited higher SampEn in medial prefrontal cortex (MPFC) and posterior cingulate cortex (PPC) than healthy postnatal women (HPW) and PPD while PPD showed lower SampEn in PPC compared to HPW and PPD-A. The functional connectivity analysis with MPFC and PPC as seed areas revealed decreased functional couplings between PCC and paracentral lobule and between MPFC and angular gyrus in PPD compared to both PPD-A and HPW. Moreover, abnormal SampEn and functional connectivity were associated with estrogenic level and clinical symptoms load. Importantly, spatial association analyses between functional changes and transcriptome and neurotransmitter density maps revealed that these functional changes were primarily associated with synaptic signaling, neuron projection, neurotransmitter level regulation, amino acid metabolism, cyclic adenosine monophosphate (cAMP) signaling pathways, and neurotransmitters of 5-hydroxytryptamine (5-HT), norepinephrine, glutamate, dopamine and so on. These results reveal abnormal brain entropy and functional connectivities primarily in default mode network (DMN) and link these changes to transcriptome and neurotransmitters to establish the molecular basis for PPD and PPD-A for the first time. Our findings highlight the important role of DMN in neuropathology of PPD and PPD-A.

Molecular mechanisms underlying human spatial cognitive ability revealed with neurotransmitter and transcriptomic mapping.

Mental rotation, one of the cores of spatial cognitive abilities, is closely associated with spatial processing and general intelligence. Although the brain underpinnings of mental rotation have been reported, the cellular and molecular mechanisms remain unexplored. Here, we used magnetic resonance imaging, a whole-brain spatial distribution atlas of 19 neurotransmitter receptors, transcriptomic data from Allen Human Brain Atlas, and mental rotation performances of 356 healthy individuals to identify the genetic/molecular foundation of mental rotation. We found significant associations of mental rotation performance with gray matter volume and fractional amplitude of low-frequency fluctuations in primary visual cortex, fusiform gyrus, primary sensory-motor cortex, and default mode network. Gray matter volume and fractional amplitude of low-frequency fluctuations in these brain areas also exhibited significant sex differences. Importantly, spatial correlation analyses were conducted between the spatial patterns of gray matter volume or fractional amplitude of low-frequency fluctuations with mental rotation and the spatial distribution patterns of neurotransmitter receptors and transcriptomic data, and identified the related genes and neurotransmitter receptors associated with mental rotation. These identified genes are localized on the X chromosome and are mainly involved in trans-synaptic signaling, transmembrane transport, and hormone response. Our findings provide initial evidence for the neural and molecular mechanisms underlying spatial cognitive ability.

A dichromatic plasmonic ELISA CD81 protein sensor for ultrasensitive detection of preeclampsia.

Preeclampsia (PE) seriously affects pregnant women and fetuses' health and causes maternal near-misses. CD81 has been confirmed to be a novel PE biomarker with great potential. Herein, a hypersensitive dichromatic biosensor based on the plasmonic enzyme-linked immunosorbent assay (plasmonic ELISA) is proposed initially for the application of CD81 in early screening for PE. In this work, a novel chromogenic substrate [(HAuCl4)-(N-methylpyrrolidone)-(Na3C6H5O7)] is designed based on the H2O2 dual catalysis reduction pathway of Au ions. The two reduction pathways of Au ions are controlled by H2O2 which ensures that the synthesis and growth of AuNPs are sensitive to H2O2. The amount of H2O2 correlates with the concentration of CD81 and directs the production of different-sized AuNPs in this sensor. Blue solutions are generated when analytes are present. When analytes are absent, solutions turn red. Therefore, due to different absorption peaks in red and blue, bimodal detection can be performed, and then two detection signals can be generated, one on signal at 550 nm and another off signal at 600 nm. This method exhibits a linear response to the logarithmic CD81 concentrations in the range of 0.1-1000 pg mL-1 with detection limits of 86 fg mL-1 and 152 fg mL-1 at two wavelengths. The false positive rate is low due to the nonspecific coloration caused by serum, which produces a more intense color contrast. The results indicate that the proposed dichromatic sensor could be used as a visual sensing platform for the direct detection of CD81 in biological samples and demonstrate its potential in preeclampsia diagnosis.

Equity and trends in general practitioners' allocation in China: based on ten years of data from 2012 to 2021.

BACKGROUND: General practitioners (GP) are the gatekeepers of residents' health, 2021 is the 10th year of the establishment of the GP system in China. This study aims to assess the equity and trends of GP allocation in China from 2012 to 2021, summarize the efforts and progress of GPs in China during the decade, predict the development trend of GPs in mainland China in the next 5 years to provide a reference for regional health planning and rational allocation of GPs in China. METHODS: Data from 2012 to 2021 on GPs in 22 provinces, 5 autonomous regions, and 4 municipalities directly under the central government in mainland China (excluding Hong Kong, Macao, and Taiwan) are collected by us. Gini coefficient, Lorenz curve and health resource agglomeration degree (HRAD) were used to analyze the equity of the allocation of GPs in China from different dimensions, a Grey prediction model was used to forecast the number of GPs in 2022-2026. RESULTS: The number of GPs in mainland China increased from 109 794 to 434 868 from 2012 to 2021, with 3.08 GPs per 10 000 people in 2021. The Gini coefficient of GPs allocation by population in China decreased from 0.312 to 0.147 from 2012 to 2021, while the Gini coefficient of geographic dimension remained between 0.700 and 0.750. Compared with the degree of curvature of the Lorenz curve in the geographic dimension, the degree of curvature of the population and economic dimension were smaller. In 2021, the HRAD in the Eastern region was 4.618, the Central region was 1.493, with different degrees of imbalance among regions, the HRAD/PAD (population agglomeration degree) in the Eastern, Central and Western regions were 1.196, 0.880 and 0.821, respectively. GPs in the Eastern region is still concentrated, while the Central and Western regions were at a similar level, GPs were more scarce. The GM (1,1) model predicts that the number of GPs in mainland China will reach about 720 000 in 2026, the number of GPs per 10 000 people will reach 4.9. CONCLUSION: After a decade of development, the number of GPs in China has increased significantly. It has reached the goal of the GP system when it was first established. However, the equity of the geographical dimension, both in terms of Gini coefficient and HRAD, has great differences between different regions. The average Gini coefficient at the geographic dimension is 0.723. The average HRAD index was 4.969 in the East and 0.293 in the West. The Western region has the problem of insufficient GP allocation in both population and geographical dimension. In the future, the number of GPs in China will continue to grow rapidly with the support of policies. The "2030" goal, proposed in 2018, is expected to be achieved by 2026. Due to certain factors (such as COVID-19), the actual situation may be different from the predicted results.

Genetic regulation of m6A RNA methylation and its contribution in human complex diseases.

N6-methyladenosine (m6A) has been established as the most prevalent chemical modification in message RNA (mRNA), playing an essential role in determining the fate of RNA molecules. Dysregulation of m6A has been revealed to lead to abnormal physiological conditions and cause various types of human diseases. Recent studies have delineated the genetic regulatory maps for m6A methylation by mapping the quantitative trait loci of m6A (m6A-QTLs), thereby building up the regulatory circuits linking genetic variants, m6A, and human complex traits. Here, we review the recent discoveries concerning the genetic regulatory maps of m6A, describing the methodological and technical details of m6A-QTL identification, and introducing the key findings of the cis- and trans-acting drivers of m6A. We further delve into the tissue- and ethnicity-specificity of m6A-QTL, the association with other molecular phenotypes in light of genetic regulation, the regulators underlying m6A genetics, and importantly, the functional roles of m6A in mediating human complex diseases. Lastly, we discuss potential research avenues that can accelerate the translation of m6A genetics studies toward the development of therapies for human genetic diseases.

Neuroprotective effects of gypenosides on LPS-induced anxiety and depression-like behaviors.

AIM: Depression, a prevalent mental disorder, significantly impairs the quality of life and social functioning. Targeting neuroinflammation is a promising therapeutic approach, highlighting the need for natural neuroprotective agents. Gypenosides (Gyp) from Gynostemma pentaphyllum exhibit anxiolytic and antidepressant effects, yet the underlying mechanisms remain unclear. We investigated whether Gyp, isolated and purified by our laboratory, can exert neuroprotective effects by modulating neuroinflammation in the hippocampus and prefrontal cortex (PFC) of mice with LPS-induced anxiety and depression, thereby ameliorating behavioral phenotypes. METHODS: LPS (1 mg/kg, i.p.) was used to induce anxiety and depression-like behaviors. Gyp was administered at 50, 100, or 200 mg/kg in pretreatment, with fluoxetine hydrochloride (Flu) as a positive control, for 10 consecutive days. RESULTS: Gyp, especially at 100 mg/kg, significantly ameliorated LPS-induced anxiety and depression in mice, normalizing cytokine expression in the hippocampus and PFC, with IL-1ß showing the most pronounced regulation (Hippocampus: RatioGyp-100/LPS = 30.73 %, PFC: RatioGyp-100/LPS = 55.89 %). Gyp also reversed LPS-induced neuronal loss and necrosis, reduced glial cell activation, and prevented the transition of microglia to the M1 phenotype. Mechanistically, Gyp suppressed the activation of the NLRP3 inflammasome in the PFC, and modulated hippocampal synaptic protein loss, thereby mediating neuroinflammation. CONCLUSIONS: Gyp improved anxiety and depression in LPS-induced mice, which may be achieved by balancing systemic inflammatory levels, regulating glial cell activation and phenotypic polarization, regulating hippocampal synaptic plasticity, and suppressing the NLRP3/Caspase-1/ASC signaling pathway in the PFC.

Synergistic pathways for health investment and economic development in China: a fuzzy-set qualitative comparative analysis.

Background: System coordination is an effective way to achieve high-quality development, and the debate on the interaction between health investment and economic development is still ongoing. To strengthen previous research and offer feasible advice and references for relevant stakeholders, we provide empirical evidence for exploring intersystem coordination and enhancement pathways using data from China. Methods: Based on the data published by the National Bureau of Statistics of China, the current status of the interaction and coordination between health investment and economic development in China was measured by calculating the comprehensive evaluation index, relative development degree, and coupling coordination degree. Subsequently, a fuzzy-set qualitative comparative analysis method was introduced to explore pathways for enhancing system interaction and coordination. Results: There are obvious inter-provincial and regional differences between health investment and economic development in China. Provinces in the west and north are lagging in economic development, while provinces in the east and south are lagging in health investment. There is a clear synergy between health investment and economic development, and there is still much room for improving the degree of coupling coordination between systems. The five conditional configurations derived from the fuzzy-set qualitative comparative analysis yield three pathways for enhancing system coordination: a health expenditure-driven path, an economic development-driven path, and a balanced health investment and economic development-driven path. Conclusion: Health expenditure is sufficient for high coordination, and the level and equity of investment in health expenditure should be improved. The gross regional product is a necessary and sufficient condition for high coordination, and consideration must be given to strengthening the regional economic support capacity. Health investment and economic development can drive the coordinated development of the system in a balanced way. This enlightens us to give full play to the positive synergy between health investment and economic development based on promoting the benign interaction of subsystems.

Single-Cell Chromatin Accessibility Analysis Reveals the Epigenetic Basis and Signature Transcription Factors for the Molecular Subtypes of Colorectal Cancers.

Colorectal cancer is a highly heterogeneous disease, with well-characterized subtypes based on genome, DNA methylome, and transcriptome signatures. To chart the epigenetic landscape of colorectal cancers, we generated a high-quality single-cell chromatin accessibility atlas of epithelial cells for 29 patients. Abnormal chromatin states acquired in adenomas were largely retained in colorectal cancers, which were tightly accompanied by opposite changes of DNA methylation. Unsupervised analysis on malignant cells revealed two epigenetic subtypes, exactly matching the iCMS classification, and key iCMS-specific transcription factors (TFs) were identified, including HNF4A and PPARA for iCMS2 tumors and FOXA3 and MAFK for iCMS3 tumors. Notably, subtype-specific TFs bind to distinct target gene sets and contribute to both interpatient similarities and diversities for both chromatin accessibilities and RNA expressions. Moreover, we identified CpG-island methylator phenotypes and pinpointed chromatin state signatures and TF regulators for the CIMP-high subtype. Our work systematically revealed the epigenetic basis of the well-known iCMS and CIMP classifications of colorectal cancers. SIGNIFICANCE: Our work revealed the epigenetic basis of the well-known iCMS and CIMP classifications of colorectal cancers. Moreover, interpatient minor similarities and major diversities of chromatin accessibility signatures of TF target genes can faithfully explain the corresponding interpatient minor similarities and major diversities of RNA expression signatures of colorectal cancers, respectively. This article is featured in Selected Articles from This Issue, p. 897.

Aberrant individual large-scale functional network connectivity and topology in chronic insomnia disorder with and without depression.

Insomnia is increasingly prevalent with significant associations with depression. Delineating specific neural circuits for chronic insomnia disorder (CID) with and without depressive symptoms is fundamental to develop precision diagnosis and treatment. In this study, we examine static, dynamic and network topology changes of individual large-scale functional network for CID with (CID-D) and without depression to reveal their specific neural underpinnings. Seventeen individual-specific functional brain networks are obtained using a regularized nonnegative matrix factorization technique. Disorders-shared and -specific differences in static and dynamic large-scale functional network connectivities within or between the cognitive control network, dorsal attention network, visual network, limbic network, and default mode network are found for CID and CID-D. Additionally, CID and CID-D groups showed compromised network topological architecture including reduced small-world properties, clustering coefficients and modularity indicating decreased network efficiency and impaired functional segregation. Moreover, the altered neuroimaging indices show significant associations with clinical manifestations and could serve as effective neuromarkers to distinguish among healthy controls, CID and CID-D. Taken together, these findings provide novel insights into the neural basis of CID and CID-D, which may facilitate developing new diagnostic and therapeutic approaches.

Molecular basis underlying changes of brain entropy and functional connectivity in major depressive disorders after electroconvulsive therapy.

INTRODUCTION: Electroconvulsive therapy (ECT) is widely used for treatment-resistant depression. However, it is unclear whether/how ECT can be targeted to affect brain regions and circuits in the brain to dynamically regulate mood and cognition. METHODS: This study used brain entropy (BEN) to measure the irregular levels of brain systems in 46 major depressive disorder (MDD) patients before and after ECT treatment. Functional connectivity (FC) was further adopted to reveal changes of functional couplings. Moreover, transcriptomic and neurotransmitter receptor data were used to reveal genetic and molecular basis of the changes of BEN and functional connectivities. RESULTS: Compared to pretreatment, the BEN in the posterior cerebellar lobe (PCL) significantly decreased and FC between the PCL and the right temporal pole (TP) significantly increased in MDD patients after treatment. Moreover, we found that these changes of BEN and FC were closely associated with genes' expression profiles involved in MAPK signaling pathway, GABAergic synapse, and dopaminergic synapse and were significantly correlated with the receptor/transporter density of 5-HT, norepinephrine, glutamate, etc. CONCLUSION: These findings suggest that loops in the cerebellum and TP are crucial for ECT regulation of mood and cognition, which provides new evidence for the antidepressant effects of ECT and the potential molecular mechanism leading to cognitive impairment.

Simultaneous de novo calling and phasing of genetic variants at chromosome-scale using NanoStrand-seq.

The successful accomplishment of the first telomere-to-telomere human genome assembly, T2T-CHM13, marked a milestone in achieving completeness of the human reference genome. The upcoming era of genome study will focus on fully phased diploid genome assembly, with an emphasis on genetic differences between individual haplotypes. Most existing sequencing approaches only achieved localized haplotype phasing and relied on additional pedigree information for further whole-chromosome scale phasing. The short-read-based Strand-seq method is able to directly phase single nucleotide polymorphisms (SNPs) at whole-chromosome scale but falls short when it comes to phasing structural variations (SVs). To shed light on this issue, we developed a Nanopore sequencing platform-based Strand-seq approach, which we named NanoStrand-seq. This method allowed for de novo SNP calling with high precision (99.52%) and acheived a superior phasing accuracy (0.02% Hamming error rate) at whole-chromosome scale, a level of performance comparable to Strand-seq for haplotype phasing of the GM12878 genome. Importantly, we demonstrated that NanoStrand-seq can efficiently resolve the MHC locus, a highly polymorphic genomic region. Moreover, NanoStrand-seq enabled independent direct calling and phasing of deletions and insertions at whole-chromosome level; when applied to long genomic regions of SNP homozygosity, it outperformed the strategy that combined Strand-seq with bulk long-read sequencing. Finally, we showed that, like Strand-seq, NanoStrand-seq was also applicable to primary cultured cells. Together, here we provided a novel methodology that enabled interrogation of a full spectrum of haplotype-resolved SNPs and SVs at whole-chromosome scale, with broad applications for species with diploid or even potentially polypoid genomes.

Abnormal large-scale resting-state functional networks in anti-N-methyl-D-aspartate receptor encephalitis.

Background: Patients with anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis often experience severe symptoms. Resting-state functional MRI (rs-fMRI) has revealed widespread impairment of functional networks in patients. However, the changes in information flow remain unclear. This study aims to investigate the intrinsic functional connectivity (FC) both within and between resting-state networks (RSNs), as well as the alterations in effective connectivity (EC) between these networks. Methods: Resting-state functional MRI (rs-fMRI) data were collected from 25 patients with anti-NMDAR encephalitis and 30 healthy controls (HCs) matched for age, sex, and educational level. Changes in the intrinsic functional connectivity (FC) within and between RSNs were analyzed using independent component analysis (ICA). The functional interaction between RSNs was identified by granger causality analysis (GCA). Results: Compared to HCs, patients with anti-NMDAR encephalitis exhibited lower performance on the Wisconsin Card Sorting Test (WCST), both in terms of correct numbers and correct categories. Additionally, these patients demonstrated decreased scores on the Montreal Cognitive Assessment (MoCA). Neuroimaging studies revealed abnormal intra-FC within the default mode network (DMN), increased intra-FC within the visual network (VN) and dorsal attention network (DAN), as well as increased inter-FC between VN and the frontoparietal network (FPN). Furthermore, aberrant effective connectivity (EC) was observed among the DMN, DAN, FPN, VN, and somatomotor network (SMN). Conclusion: Patients with anti-NMDAR encephalitis displayed noticeable deficits in both memory and executive function. Notably, these patients exhibited widespread impairments in intra-FC, inter-FC, and EC. These results may help to explain the pathophysiological mechanism of anti-NMDAR encephalitis.

Personalized functional network mapping for autism spectrum disorder and attention-deficit/hyperactivity disorder.

Autism spectrum disorder (ASD) and Attention-deficit/hyperactivity disorder (ADHD) are two typical neurodevelopmental disorders that have a long-term impact on physical and mental health. ASD is usually comorbid with ADHD and thus shares highly overlapping clinical symptoms. Delineating the shared and distinct neurophysiological profiles is important to uncover the neurobiological mechanisms to guide better therapy. In this study, we aimed to establish the behaviors, functional connectome, and network properties differences between ASD, ADHD-Combined, and ADHD-Inattentive using resting-state functional magnetic resonance imaging. We used the non-negative matrix fraction method to define personalized large-scale functional networks for each participant. The individual large-scale functional network connectivity (FNC) and graph-theory-based complex network analyses were executed and identified shared and disorder-specific differences in FNCs and network attributes. In addition, edge-wise functional connectivity analysis revealed abnormal edge co-fluctuation amplitude and number of transitions among different groups. Taken together, our study revealed disorder-specific and -shared regional and edge-wise functional connectivity and network differences for ASD and ADHD using an individual-level functional network mapping approach, which provides new evidence for the brain functional abnormalities in ASD and ADHD and facilitates understanding the neurobiological basis for both disorders.

Crosstalk between epitranscriptomic and epigenomic modifications and its implication in human diseases.

Crosstalk between N6-methyladenosine (m6A) and epigenomes is crucial for gene regulation, but its regulatory directionality and disease significance remain unclear. Here, we utilize quantitative trait loci (QTLs) as genetic instruments to delineate directional maps of crosstalk between m6A and two epigenomic traits, DNA methylation (DNAme) and H3K27ac. We identify 47 m6A-to-H3K27ac and 4,733 m6A-to-DNAme and, in the reverse direction, 106 H3K27ac-to-m6A and 61,775 DNAme-to-m6A regulatory loci, with differential genomic location preference observed for different regulatory directions. Integrating these maps with complex diseases, we prioritize 20 genome-wide association study (GWAS) loci for neuroticism, depression, and narcolepsy in brain; 1,767 variants for asthma and expiratory flow traits in lung; and 249 for coronary artery disease, blood pressure, and pulse rate in muscle. This study establishes disease regulatory paths, such as rs3768410-DNAme-m6A-asthma and rs56104944-m6A-DNAme-hypertension, uncovering locus-specific crosstalk between m6A and epigenomic layers and offering insights into regulatory circuits underlying human diseases.

In vitro sensitivities of Plasmodium falciparum isolates from the China-Myanmar border to piperaquine and association with polymorphisms in candidate genes.

The recent reports of resistance in Plasmodium falciparum to artemisinin derivatives and their partner drugs demand intensive studies toward understanding the molecular mechanisms of resistance. In this study, we examined the in vitro susceptibility of 63 P. falciparum field isolates collected from the China-Myanmar border area to chloroquine (CQ) and piperaquine (PPQ). Parasite isolates remained highly resistant to CQ, with the geometric mean 50% inhibitory concentration (IC50) of 252.7 nM and a range of 51.9 to 1,052.0 nM. In comparison, these parasites had a geometric mean IC50 of 28.4 nM for PPQ, with a fairly wide range of 5.3 to 132.0 nM, suggesting that certain parasite isolates displayed relatively high levels of resistance to PPQ. Interestingly, within the 4 years of study, the parasites exhibited a continuous decline in susceptibilities to both CQ and PPQ, and there was a significant correlation between responses to CQ and PPQ (Pearson correlation coefficient = 0.79, P < 0.0001). Consistent with the CQ-resistant phenotype, all parasites carried the pfcrt K76T mutation, and most parasites had the CVIET type that is prevalent in Southeast Asia. In contrast, pfmdr1 mutations were relatively rare, and no gene amplification was detected. Only the pfmdr1 N1042D mutation was associated with resistance to CQ. For the pfmrp1 gene, four substitutions reached relatively high prevalence of >22%, and the I876V mutation was associated with reduced sensitivity to CQ. However, we could not establish a link between PPQ responses and the polymorphisms in the three genes associated with quinoline drug resistance.

Deciphering Structural Origins of Highly Reversible Lithium Storage in High Entropy Oxides with In Situ Transmission Electron Microscopy.

Configurational entropy-stabilized single-phase high-entropy oxides (HEOs) have been considered revolutionary electrode materials with both reversible lithium storage and high specific capacity that are difficult to fulfill simultaneously by conventional electrodes. However, precise understanding of lithium storage mechanisms in such HEOs remains controversial due to complex multi-cationic oxide systems. Here, distinct reaction dynamics and structural evolutions in rocksalt-type HEOs upon cycling are carefully studied by in situ transmission electron microscopy (TEM) including imaging, electron diffraction, and electron energy loss spectroscopy at atomic scale. The mechanisms of composition-dependent conversion/alloying reaction kinetics along with spatiotemporal variations of valence states upon lithiation are revealed, characterized by disappearance of the original rocksalt phase. Unexpectedly, it is found from the first visualization evidence that the post-lithiation polyphase state can be recovered to the original rocksalt-structured HEOs via reversible and symmetrical delithiation reactions, which is unavailable for monometallic oxide systems. Rigorous electrochemical tests coupled with postmortem ex situ TEM and bulk-level phase analyses further validate the crucial role of structural recovery capability in ensuring the reversible high-capacity Li-storage in HEOs. These findings can provide valuable guidelines to design compositionally engineer HEOs for almighty electrodes of next-generation long-life energy storage devices.

Cerebellum drives functional dysfunctions in restless leg syndrome.

OBJECTIVE: Restless legs syndrome (RLS) has serious effects on patients' sleep quality, physical and mental health. However, the pathophysiological mechanisms of RLS remain unclear. This study utilized both static and dynamic functional activity and connectivity analyses approaches as well as effective connectivity analysis to reveal the neurophysiological basis of RLS. METHODS: The resting-state functional MRI (rs-fMRI) data from 32 patients with RLS and 33 age-, and gender-matched healthy control (HC) were collected. Dynamic and static amplitude of low frequency fluctuation (ALFF), functional connectivity (FC), and Granger causality analysis (GCA) were employed to reveal the abnormal functional activities and couplings in patients with RLS. RESULTS: RLS patients showed over-activities in left parahippocampus and right cerebellum, hyper-connectivities of right cerebellum with left basal ganglia, left postcentral gyrus and right precentral gyrus, and enhanced effective connectivity from right cerebellum to left postcentral gyrus compared to HC. CONCLUSIONS: Abnormal cerebellum-basal ganglia-sensorimotor cortex circuit may be the underlying neuropathological basis of RLS. Our findings highlight the important role of right cerebellum in the onset of RLS and suggest right cerebellum may be a potential target for precision therapy.

Stable nitronyl nitroxide monoradical MATMP as novel monomer of reversible addition fragmentation chain transfer (RAFT) polymerization for ultrasensitive DNA detection.

In this work, it came up a hydrophilic and stable nitronyl nitroxide monoradical 4-methacryloyloxy-2,2,6,6-tetramethylpiperidine 1-oxyl freeradical (MATMP) as new monomer of polymerization for DNA detection. The detection limit was over 1,000,000 times lower than 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) derivatives as electrochemical labels alone. Within this approach, a single biomolecule can be converted into the strong electrochemical signal, therefore lung cancer DNA can be detected at low concentration. For the first step, the HS-PNA probe was fixed on the surface of the Au electrode. After the target DNA was captured by complementary base pairing, 4-cyano-4-(phenylcarbonothioylthio) pentanoic acid (CPAD), chain transfer agent of RAFT polymerization, was bonded to target DNA as reaction via coordination bond of Zr4+. Electroactive polymers had grown by means of surface initiated thermally RAFT polymerization with MATMP as monomer. MATMP polymer significantly improves the electrochemical signal. This method can detect DNA from 0.01 fM to 10 pM, and detection limit is 1.51 aM. The sensitivity of this method is greater than that in most other reported signal amplification strategies of DNA biosensor, which indicates that it is appropriate for single nucleotide polymorphism analysis and will broaden prospects for biological molecules detection application.