AlphaFold 3 - Aided Design of DNA Motifs To Assemble into Triangles.

Self-assembly of biomolecules provides a powerful tool for a wide range of applications in nanomedicine, biosensing and imaging, vaccines, computation, nanophotonics, etc. The key is to rationally design building blocks and the intermolecule interactions. Along this line, structural DNA nanotechnology has rapidly developed by limiting DNA secondary structures to primarily well-established, B-form DNA duplexes, which can be readily and reliably predicted. As the field evolves, more sophisticated structural elements must be introduced. While increasing the structural complexity, they bring challenges to predicting DNA nanostructures. In the past, a brutal and tedious error-and-trial approach has often been used to solve this problem. Here, we report a case study of applying AlphaFold 3 to model the structural elements to facilitate DNA nanostructure design. This protocol is expected to be generally applicable and greatly facilitates the further development of structural DNA nanotechnology.

A connectome-based model of delusion in schizophrenia using functional connectivity under working memory task.

Delusion is an important feature of schizophrenia, which may stem from cognitive biases. Working memory (WM) is the core foundation of cognition, closely related to delusion. However, the knowledge of neural mechanisms underlying the relationship between WM and delusion in schizophrenia is poorly investigated. Two hundred and thirty patients with schizophrenia (dataset 1: n = 130; dataset 2: n = 100) were enrolled and scanned for an N-back WM task. We constructed the WM-related whole-brain functional connectome and conducted Connectome-based Predictive Modelling (CPM) to detect the delusion-related networks and built the correlation model in dataset 1. The correlation between identified networks and delusion severity was tested in a separate, heterogeneous sample of dataset 2 that mainly includes early-onset schizophrenia. The identified delusion-related network has a strong correlation with delusion severity measured by the NO.20 item of SAPS in dataset 1 (r = 0.433, p = 2.7 × 10-7, permutation-p = 0.035), and can be validated in the same dataset by using another delusion measurement, that is, the P1 item of PANSS (r = 0.362, p = 0.0005). It can be validated in another independent dataset 2 (NO.20 item of SAPS for r = 0.31, p = 0.0024, P1 item of PANSS for r = 0.27, p = 0.0074). The delusion-related network comprises the connections between the default mode network (DMN), cingulo-opercular network (CON), salience network (SN), subcortical, sensory-somatomotor network (SMN), and visual networks. We successfully established correlation models of individualized delusion based on the WM-related functional connectome and showed a strong correlation between delusion severity and connections within the DMN, CON, SMN, and subcortical network.

Wearable device-measured moderate to vigorous physical activity and risk of degenerative aortic valve stenosis.

BACKGROUND AND AIMS: Physical activity has proven effective in preventing atherosclerotic cardiovascular disease, but its role in preventing degenerative valvular heart disease (VHD) remains uncertain. This study aimed to explore the dose-response association between moderate to vigorous physical activity (MVPA) volume and the risk of degenerative VHD among middle-aged adults. METHODS: A full week of accelerometer-derived MVPA data from 87 248 UK Biobank participants (median age 63.3, female: 56.9%) between 2013 and 2015 were used for primary analysis. Questionnaire-derived MVPA data from 361 681 UK Biobank participants (median age 57.7, female: 52.7%) between 2006 and 2010 were used for secondary analysis. The primary outcome was the diagnosis of incident degenerative VHD, including aortic valve stenosis (AS), aortic valve regurgitation (AR), and mitral valve regurgitation (MR). The secondary outcome was VHD-related intervention or mortality. RESULTS: In the accelerometer-derived MVPA cohort, 555 incident AS, 201 incident AR, and 655 incident MR occurred during a median follow-up of 8.11 years. Increased MVPA volume showed a steady decline in AS risk and subsequent AS-related intervention or mortality risk, levelling off beyond approximately 300 min/week. In contrast, its association with AR or MR incidence was less apparent. The adjusted rates of AS incidence (95% confidence interval) across MVPA quartiles (Q1-Q4) were 11.60 (10.20, 13.20), 7.82 (6.63, 9.23), 5.74 (4.67, 7.08), and 5.91 (4.73, 7.39) per 10 000 person-years. The corresponding adjusted rates of AS-related intervention or mortality were 4.37 (3.52, 5.43), 2.81 (2.13, 3.71), 1.93 (1.36, 2.75), and 2.14 (1.50, 3.06) per 10 000 person-years, respectively. Aortic valve stenosis risk reduction was also observed with questionnaire-based MVPA data [adjusted absolute difference Q4 vs. Q1: AS incidence, -1.41 (-.67, -2.14) per 10 000 person-years; AS-related intervention or mortality, -.38 (-.04, -.88) per 10 000 person-years]. The beneficial association remained consistent in high-risk populations for AS, including patients with hypertension, obesity, dyslipidaemia, and chronic kidney disease. CONCLUSIONS: Higher MVPA volume was associated with a lower risk of developing AS and subsequent AS-related intervention or mortality. Future research needs to validate these findings in diverse populations with longer durations and repeated periods of activity monitoring.

Molecular and structural basis of an ATPase-nuclease dual-enzyme anti-phage defense complex.

Coupling distinct enzymatic effectors emerges as an efficient strategy for defense against phage infection in bacterial immune responses, such as the widely studied nuclease and cyclase activities in the type III CRISPR-Cas system. However, concerted enzymatic activities in other bacterial defense systems are poorly understood. Here, we biochemically and structurally characterize a two-component defense system DUF4297-HerA, demonstrating that DUF4297-HerA confers resistance against phage infection by cooperatively cleaving dsDNA and hydrolyzing ATP. DUF4297 alone forms a dimer, and HerA alone exists as a nonplanar split spiral hexamer, both of which exhibit extremely low enzymatic activity. Interestingly, DUF4297 and HerA assemble into an approximately 1 MDa supramolecular complex, where two layers of DUF4297 (6 DUF4297 molecules per layer) linked via inter-layer dimerization of neighboring DUF4297 molecules are stacked on top of the HerA hexamer. Importantly, the complex assembly promotes dimerization of DUF4297 molecules in the upper layer and enables a transition of HerA from a nonplanar hexamer to a planar hexamer, thus activating their respective enzymatic activities to abrogate phage infection. Together, our findings not only characterize a novel dual-enzyme anti-phage defense system, but also reveal a unique activation mechanism by cooperative complex assembly in bacterial immunity.

Potential Correlation between Tea Intake and the Risk of Amyotrophic Lateral Sclerosis: A Mendelian Randomization Study.

INTRODUCTION: There were limited observation studies on the association between tea intake and amyotrophic lateral sclerosis (ALS) with inconsistent results. This study aimed to determine the potential relationship between tea intake and ALS by a two-sample Mendelian randomization (MR) analysis. METHODS: We identified 41 independent SNPs strongly associated with tea intake from 448,060 participants of European ancestry in the UK Biobank. Summary statistics associated with ALS were also obtained from the UK Biobank including 20,806 cases and 59,804 controls. The study used MR analysis to assess the potential effect of tea consumption on ALS, and several methods such as sensitivity analyses and MR-pleiotropy residual sum and outlier method were performed to further test the robustness of our findings. RESULTS: The F statistic was more than 10 in each SNP, which meets the first assumption for the MR study. Using the inverse variance weighted MR analysis as the primary method, we found that a one standard deviation increase in tea consumption was associated with a 14% lower risk of ALS (OR = 0.86, 95% CI = 0.74-0.99, p < 0.05). Sensitivity analyses detected no potential pleiotropy and directional heterogeneity. CONCLUSION: Our MR study supported the potential relationship between tea intake and ALS risk, suggesting the potential advantages of tea intake for preventing ALS. Future clinical trials and research are needed to further validate the results and elucidate possible mechanisms.

Clinical and genetic characteristics of 1672 cases of amyotrophic lateral sclerosis in China: a single-center retrospective study.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. In recent years, continuous discoveries of new ALS-causing genes have enhanced the understanding of the genotype-phenotype relationship in ALS, aiding in disease progression prediction and providing a more comprehensive basis for genetic diagnosis. METHODS: A total of 1672 ALS patients who visited the Neurology Department of Peking Union Medical College Hospital between January 2014 and December 2022 and met the revised El Escorial diagnostic criteria were included. Clinical data were collected, whole exome sequencing and dynamic mutation screening of the C9ORF72 gene were performed, and the clinical phenotypes and genotypes of the patients were analyzed. RESULTS: The average age of onset for the 1672 ALS patients was 52.6 ± 11.2 years (range 17-85 years), with a median disease duration of 14 months at the time of visit (interquartile range 9-24 months, range 2-204 months). The male to female ratio was 833:839. The patients included 297 (17.8%) with bulbar onset, 198 (11.8%) with flail arm/leg syndrome, 89 (5.3%) with familial ALS, and 52 (3.1%) with concomitant frontotemporal dementia (FTD). Pathogenic variants associated with ALS were detected in 175 patients (10.5% of the cohort), with the most common mutations being SOD1, FUS, and ANXA11. Among patients with familial ALS, 56.2% (50/89) had genetic mutations, compared to 7.9% (125/1583) in sporadic ALS cases. From the perspective of phenotype-genotype correlation, (1) In ALS-FTD patients, the most common genetic mutations were ANXA11 and C9ORF72 repeat expansions. Patients with flail arm/leg syndrome more frequently carried mutations in SOD1, ANXA11, and hnRNPA1; (2) Despite genetic heterogeneity, it was observed that mutations in FUS and NEK1 were more common in males, and patients with FUS mutations had a younger age of onset; mutations in SOD1 and SQSTM1 were more likely to present with lower limb onset. CONCLUSION: This study provides comprehensive data on the genetic characteristics of ALS patients in China through large-scale clinical data and genetic analysis of 1672 cases. Differences in age of onset, onset site, and clinical phenotype among ALS patients with different genotypes can help clinicians better predict disease progression and provide a basis for precise diagnosis and individualized treatment.

Multimodal neuroimaging exploration of the mechanisms of sleep quality deterioration after SARS-CoV-2 Omicron infection.

BACKGROUND: To evaluate the neurological alterations induced by Omicron infection, to compare brain changes in chronic insomnia with those in exacerbated chronic insomnia in Omicron patients, and to examine individuals without insomnia alongside those with new-onset insomnia. METHODS: In this study, a total of 135 participants were recruited between January 11 and May 4, 2023, including 26 patients with chronic insomnia without exacerbation, 24 patients with chronic insomnia with exacerbation, 40 patients with no sleep disorder, and 30 patients with new-onset insomnia after infection with Omicron (a total of 120 participants with different sleep statuses after infection), as well as 15 healthy controls who were never infected with Omicron. Neuropsychiatric data, clinical symptoms, and multimodal magnetic resonance imaging data were collected. The gray matter thickness and T1, T2, proton density, and perivascular space values were analyzed. Associations between changes in multimodal magnetic resonance imaging findings and neuropsychiatric data were evaluated with correlation analyses. RESULTS: Compared with healthy controls, gray matter thickness changes were similar in the patients who have and do not have a history of chronic insomnia groups after infection, including an increase in cortical thickness near the parietal lobe and a reduction in cortical thickness in the frontal, occipital, and medial brain regions. Analyses showed a reduced gray matter thickness in patients with chronic insomnia compared with those with an aggravation of chronic insomnia post-Omicron infection, and a reduction was found in the right medial orbitofrontal region (mean [SD], 2.38 [0.17] vs. 2.67 [0.29] mm; P < 0.001). In the subgroups of Omicron patients experiencing sleep deterioration, patients with a history of chronic insomnia whose insomnia symptoms worsened after infection displayed heightened medial orbitofrontal cortical thickness and increased proton density values in various brain regions. Conversely, patients with good sleep quality who experienced a new onset of insomnia after infection exhibited reduced cortical thickness in pericalcarine regions and decreased proton density values. In new-onset insomnia patients post-Omicron infection, the thickness in the right pericalcarine was negatively correlated with the Self-rating Anxiety Scale (r = - 0.538, P = 0.002, PFDR = 0.004) and Self-rating Depression Scale (r = - 0.406, P = 0.026, PFDR = 0.026) scores. CONCLUSIONS: These findings help us understand the pathophysiological mechanisms involved when Omicron invades the nervous system and induces various forms of insomnia after infection. In the future, we will continue to pay attention to the dynamic changes in the brain related to insomnia caused by Omicron infection.

The neural compensation phenomenon in schizophrenia with mild attention deficits during working memory task.

BACKGROUND: Working memory (WM) and attention are essential cognitive processes, and their interplay is critical for efficient information processing. Schizophrenia often exhibits deficits in both WM and attention, contributing to function impairments. This study aims to investigate the neural mechanisms underlying the relationship between WM impairments and attention deficits in schizophrenia. METHODS: We assessed the functional-MRI scans of the 184 schizophrenias with different attention deficits (mild=133; severe=51) and 146 controls during an N-back WM task. We explored their whole-brain functional connectome profile by adopting the voxel-wise degree centrality (DC). Linear analysis was conducted to explore the associations among attention deficit severity, altered DC, and WM performance in patients. RESULTS: We observed that all patients showed decreased DC in the pre-supplementary area (pre-SMA), and posterior cerebellum compared to the controls, and schizophrenia patients with mild attention deficits showed decreased DC in the supramarginal gyrus, insula, and precuneus compared with the other 2 groups. DC values of the detected brain regions displayed U-shaped or inverted U-shaped curves, rather than a linear pattern, in response to increasing attention deficits. The linear analysis indicated that altered DC of the pre-SMA can modulate the relationship between attention deficits and WM performance. CONCLUSION: The U-shaped or inverted U-shaped pattern in response to increasing attention deficits may reflect a compensation mechanism in schizophrenia with mild attention deficits. This notion is also supported by the linear analysis that schizophrenia patients with mild attention deficits can improve their WM performance by increasing the DC value of the pre-SMA.

Structure-function analysis of the ATPase domain of African swine fever virus topoisomerase.

Type II topoisomerase utilizes the energy from ATP hydrolysis to alter DNA topology during genome replication and transcription. The ATPase domain of this enzyme is required for ATP hydrolysis and plays a crucial role in coupling DNA binding and ATP turnover with the DNA strand passage reaction. The African swine fever virus (ASFV) specifically encodes a topoisomerase II (topo II), which is critical for viral replication and an attractive target for antiviral development. Here, we present a high-resolution crystal structure of the ASFV topo II ATPase domain complexed with the substrate analog AMPPNP. Structural comparison reveals that the ASFV topo II ATPase domain shares a conserved overall structure with its homologs from eukaryotes and prokaryotes but also has three characteristic regions, including the intra-molecular interface formed by the ATP-lid and QTK loop as well as helix α9, the K-loop in the transducer domain, and the antennae-like α-helix at the ATP binding domain. Mutating the key residues within these three regions impairs or abolishes the basal and DNA-stimulated ATPase activities and reduces or eliminates the relaxation activity of the holoenzyme. Our data indicate that all three regions are functionally important for the ATPase and relaxation activities and strongly suggest that ATP hydrolysis, DNA binding, and strand passage are highly coupled and managed by the allosteric coordination of multiple domains of the type II topoisomerase. Moreover, we find a promising druggable pocket in the dimeric interface of the ASFV topo II ATPase domain, which will benefit future anti-ASFV drug development. IMPORTANCE: The ATPase domain of type II topoisomerase provides energy by hydrolyzing ATP and coordinates with the DNA-binding/cleavage domain to drive and control DNA transport. The precise molecular mechanisms of how these domains respond to DNA binding and ATP hydrolysis signals and communicate with each other remain elusive. We determine the first high-resolution crystal structure of the ATPase domain of African swine fever virus (ASFV) topo II in complex with AMPPNP and biochemically investigate its function in ATPase and DNA relaxation activities. Importantly, we find that mutations at three characteristic regions of the ASFV ATPase domain produce parallel effects on the basal/DNA-stimulated ATPase and relaxation activities, implying the tight coupling of the ATP hydrolysis and strand passage process. Therefore, our data provide important implications for understanding the strand passage mechanism of the type II topoisomerase and the structural basis for developing ATPase domain-targeting antivirals against ASFV.

Influence of TMX2-CTNND1 polymorphism on cortical thickness in schizophrenia patients and unaffected siblings: an exploratory study based on target region sequencing.

OBJECTIVE: The advancement of neuroimaging and genetic research has revealed the presence of morphological abnormalities and numerous risk genes, along with their associations. We aimed to estimate magnetic resonance imaging-derived cortical thickness across multiple brain regions. METHODS: The cortical thickness of 129 schizophrenia patients, 42 of their unaffected siblings, and 112 healthy controls was measured and the candidate genes were sequenced. Comparisons were made of cortical thickness (including 68 regions of the Desikan-Killiany Atlas) and genetic variants (in 108 risk genes for schizophrenia) among the three groups, and correlation analyses were performed regarding cortical thickness, clinical symptoms, cognitive tests (such as the N-back task and the logical memory test), and genetic variants. RESULTS: Schizophrenia patients had significantly thinner bilateral frontal, temporal, and parietal gyri than healthy controls and unaffected siblings. Association analyses in target genes showed that four single nucleotide variants (SNVs) were significantly associated with schizophrenia, including thioredoxin-related transmembrane protein 2-catenin, cadherin-associated protein, delta 1 (SNV20673) (positive false discovery rate [PFDR] = 0.008) and centromere protein M (rs35542507, rs41277477, rs73165153) (PFDR = 0.030). Additionally, cortical thickness in the right pars triangularis was lower in carriers of the SNV20673 variant than in non-carriers (PFDR = 0.048). Finally, a positive correlation was found between right pars triangularis cortical thickness and logical memory in schizophrenia patients (r = 0.199, p = 0.032). CONCLUSIONS: This study identified regional morphological abnormalities in schizophrenia, including the right homologue of Broca's area, which was associated with a risk variant that affected delta-1 catenin and logical memory. These findings suggest a potential association between candidate gene loci, cortical thickness, and schizophrenia.

Altered orientation dispersion index of white matter in individuals with insomnia during the COVID-19 pandemic: A study combining neuroimaging technique and Mendelian randomization.

STUDY OBJECTIVES: Coronavirus disease 2019 (COVID-19) can lead to insomnia. However, associations between COVID-19-caused insomnia and white matter (WM) changes are unclear. METHODS: All subjects had ever been infected with COVID-19. We investigated 89 insomniacs (29 chronic insomniacs, 33 new-onset insomniacs, 27 aggravated insomniacs) and 44 matched non-insomnia participants. Neurite orientation dispersion and density imaging (NODDI) was performed to identify micro-structural alterations of WM, and twelve scales related to sleeping status, memory, attention, learning, emotional status, and executive functions were used. Then, correlations between insomnia/cognitive-behavioral functions and diffusion metrics were tested. To eliminate influence of pre-COVID-19 factors on insomnia, causal relationships between COVID-19 and WM changes were validated by Mendelian randomization (MR) analysis. The significant brain regions of COVID-19-caused insomnia were intersected results of tract-based spatial statistics (TBSS) and MR analyses. RESULTS: Compared to non-insomnia group, insomnia group and its subgroups including post-COVID-19 aggravated or unchanged chronic insomnia group had higher orientation dispersion index (ODI) in extensive brain regions. The left superior longitudinal fasciculus (SLF), left posterior thalamic radiation (PTR), and left cingulate gyrus (CG) were specific brain regions in COVID-19-induced insomnia aggravation. After Bonferroni correction, partial correlation analyses within insomnia group showed that ODI in left SLF was positively correlated with Pittsburgh sleep quality index (PSQI), insomnia severity index (ISI), and self-rating anxiety scale (SAS) scores; ODI in the left PTR was positively correlated with PSQI and ISI scores. CONCLUSIONS: This study is a continuation of our previous research, which provided potential biomarkers for COVID-19-induced insomnia.

Influence of TMX2-CTNND1 polymorphism on cortical thickness in schizophrenia patients and unaffected siblings: an exploratory study based on target region sequencing

Objective: The advancement of neuroimaging and genetic research has revealed the presence of morphological abnormalities and numerous risk genes, along with their associations. We aimed to estimate magnetic resonance imaging-derived cortical thickness across multiple brain regions. Methods: The cortical thickness of 129 schizophrenia patients, 42 of their unaffected siblings, and 112 healthy controls was measured and the candidate genes were sequenced. Comparisons were made of cortical thickness (including 68 regions of the Desikan-Killiany Atlas) and genetic variants (in 108 risk genes for schizophrenia) among the three groups, and correlation analyses were performed regarding cortical thickness, clinical symptoms, cognitive tests (such as the N-back task and the logical memory test), and genetic variants. Results: Schizophrenia patients had significantly thinner bilateral frontal, temporal, and parietal gyri than healthy controls and unaffected siblings. Association analyses in target genes showed that four single nucleotide variants (SNVs) were significantly associated with schizophrenia, including thioredoxin-related transmembrane protein 2-catenin, cadherin-associated protein, delta 1 (SNV20673) (positive false discovery rate [PFDR] = 0.008) and centromere protein M (rs35542507, rs41277477, rs73165153) (PFDR = 0.030). Additionally, cortical thickness in the right pars triangularis was lower in carriers of the SNV20673 variant than in non-carriers (PFDR = 0.048). Finally, a positive correlation was found between right pars triangularis cortical thickness and logical memory in schizophrenia patients (r = 0.199, p = 0.032). Conclusions: This study identified regional morphological abnormalities in schizophrenia, including the right homologue of Broca's area, which was associated with a risk variant that affected delta-1 catenin and logical memory. These findings suggest a potential association between candidate gene loci, cortical thickness, and schizophrenia.

Discovery of a selective TC-PTP degrader for cancer immunotherapy.

T-cell protein tyrosine phosphatase (TC-PTP), encoded by PTPN2, has emerged as a promising target for cancer immunotherapy. TC-PTP deletion in B16 melanoma cells promotes tumor cell antigen presentation, while loss of TC-PTP in T-cells enhances T-cell receptor (TCR) signaling and stimulates cell proliferation and activation. Therefore, there is keen interest in developing TC-PTP inhibitors as novel immunotherapeutic agents. Through rational design and systematic screening, we discovered the first highly potent and selective TC-PTP PROTAC degrader, TP1L, which induces degradation of TC-PTP in multiple cell lines with low nanomolar DC50s and >110-fold selectivity over the closely related PTP1B. TP1L elevates the phosphorylation level of TC-PTP substrates including pSTAT1 and pJAK1, while pJAK2, the substrate of PTP1B, is unaffected by the TC-PTP degrader. TP1L also intensifies interferon gamma (IFN-γ) signaling and increases MHC-I expression. In Jurkat cells, TP1L activates TCR signaling through increased phosphorylation of LCK. Furthermore, in a CAR-T cell and KB tumor cell co-culture model, TP1L enhances CAR-T cell mediated tumor killing efficacy through activation of the CAR-T cells. Thus, we surmise that TP1L not only provides a unique opportunity for in-depth interrogation of TC-PTP biology but also serves as an excellent starting point for the development of novel immunotherapeutic agents targeting TC-PTP.

Development of Molecular Dynamics and Research Progress in the Study of Slag.

Molecular dynamics is a method of studying microstructure and properties by calculating and simulating the movement and interaction of molecules. The molecular dynamics simulation method has become an important method for studying the structural and dynamic characteristics of slag systems and can make up for the shortcomings of existing detection methods and experiments. Firstly, this paper analyzes the development process and application fields of molecular dynamics, summarizes the general simulation steps and software algorithms of molecular dynamics simulation methods, and discusses the advantages and disadvantages of the algorithms and the common functions of the software. Secondly, the research status and application progress of molecular dynamics simulation methods in the study of phosphate, silicate, aluminate and aluminosilicate are introduced. On this basis, a method of combining molecular dynamics simulation with laboratory experiments is proposed, which will help obtain more accurate simulation results. This review provides theoretical guidance and a technical framework for the effective analysis of the microstructure of different slag systems via molecular dynamics, so as to finally meet the needs of iron and steel enterprises in producing high-quality steel grades.

Cryo-EM structures of African swine fever virus topoisomerase.

IMPORTANCE: African swine fever virus (ASFV) is a highly contagious virus that causes lethal hemorrhagic diseases known as African swine fever (ASF) with a case fatality rate of 100%. There is an urgent need to develop anti-ASFV drugs. We determine the first high-resolution structures of viral topoisomerase ASFV P1192R in both the closed and open C-gate forms. P1192R shows a similar overall architecture with eukaryotic and prokaryotic type II topoisomerases, which have been successful targets of many antimicrobials and anticancer drugs, with the most similarity to yeast topo II. P1192R also exhibits differences in the details of active site configuration, which are important to enzyme activity. These two structures offer useful structural information for antiviral drug design and provide structural evidence to support that eukaryotic type IIA topoisomerase likely originated from horizontal gene transfer from the virus.

Polygenic risk for schizophrenia and the language network: Putative compensatory reorganization in unaffected siblings.

Language-related symptoms, such as disorganized, impoverished speech and communicative behaviors, are one of the core features of schizophrenia. These features most strongly correlate with cognitive deficits and polygenic risk among various symptom dimensions of schizophrenia. Nevertheless, unaffected siblings with genetic high-risk fail to show consistent deficits in language network (LN), indicating that either (1) polygenic risk has no notable effect on LN and/or (2) siblings show compensatory changes in opposing direction to patients. To answer this question, we related polygenic risk scores (PRS) to the region-level, tract-level, and systems-level structure (cortical thickness and fiber connectivity) of LN in 182 patients, 48 unaffected siblings and 135 healthy controls. We also studied the relationships between symptoms, language-related cognition, social functioning and LN structure. We observed a significantly lower thickness in LN (especially the Broca's, Wernicke's area and their right homologues) in patients. Siblings had a distinctly higher thickness in parts of the LN and a more pronounced small-world-like structural integration within the LN. Patients with reduced LN thickness had higher PRS, more disorganization and impoverished speech with lower language-related cognition and social functioning. We conclude that the genetic susceptibility and putative compensatory changes for schizophrenia operate, in part, via key regions in the Language Network.

Health-related quality of life of Chinese patients with chronic kidney disease: a study based on four EQ-5D-3L value sets.

Provide reference data on which EQ-5D-3L value set should be used with Chinese patients with chronic kidney disease (CKD); assess differences in health-related quality of life (HRQoL) based on the use of the Chinese (from 2014 and 2018), the UK, and the Japanese value sets; and examine differences in utility scores for key preventive influencing factors. Data from 373 patients with CKD recruited for a cross-sectional multicenter HRQoL survey were used. Differences among utility scores based on the four value sets were determined using Wilcoxon signed rank test. Intra-class correlation coefficient (ICCs) and Bland-Altman plots were used to evaluate consistency among utility scores and Tobit regression model was used to analyze the influencing factors of utility scores. There were significant differences between utility scores based on the four value sets, with the Chinese 2018 value set yielding the highest utility (0.957). ICCs between the value sets for China 2014, the UK, and Japan were all greater than 0.9, whereas the ICCs between the value sets for China 2018 and the other three were all less than 0.7. The influencing factors of utility scores included CKD stages, age, education level, city, and primary renal disease. This was the first study to report findings on the health utility of patients with CKD based on the two Chinese EQ-5D-3L value sets. Overall, the Chinese value sets performed similarly to the other two value sets (UK and Japan) commonly used in the Chinese population; however, value sets for different countries were not interchangeable. In Chinese contexts, the two value sets for China were recommended and the choice of which one should consider whether the value set of choice was established with a sample that is consistent with the targeted population.

Comparison of the chloroplast genomes and phylogenomic analysis of Elaeocarpaceae.

Background: Elaeocarpaceae is a vital family in tropical and subtropical forests. Compared with the important position of Elaeocarpaceae species in forest ecosystem and the concern of medicinal value, the most research on Elaeocarpaceae are classification and taxonomy. Molecular systematics has corrected the morphological misjudgment, and it belongs to Oxalidales. Phylogenetic and divergence time estimates of Elaeocarpaceae is mostly constructed by using chloroplast gene fragments. At present, although there are reports on the chloroplast structure of Elaeocarpaceae, a comprehensive analysis of the chloroplast structure of Elaeocarpaceae is lacking. Methods: To understand the variation in chloroplast sequence size and structure in Elaeocarpaceae, the chloroplast genomes of nine species were sequenced using the Illumina HiSeq 2500 platform and further assembled and annotated with Elaeocarpus japonicus and Sloanea sinensis (family Elaeocarpaceae) as references. A phylogenomic tree was constructed based on the complete chloroplast genomes of the 11 species representing five genera of Elaeocarpaceae. Chloroplast genome characteristics were examined by using Circoletto and IRscope software. Results: The results revealed the following: (a) The 11 sequenced chloroplast genomes ranged in size from 157,546 to 159,400 bp. (b) The chloroplast genomes of Elaeocarpus, Sloanea, Crinodendron and Vallea lacked the rpl32 gene in the small single-copy (SSC) region. The large single-copy (LSC) region of the chloroplast genomes lacked the ndhK gene in Elaeocarpus, Vallea stipularis, and Aristotelia fruticosa. The LSC region of the chloroplast genomes lacked the infA gene in genus Elaeocarpus and Crinodendron patagua. (c) Through inverted repeat (IR) expansion and contraction analysis, a significant difference was found between the LSC/IRB and IRA/LSC boundaries among these species. Rps3 was detected in the neighboring regions of the LSC and IRb regions in Elaeocarpus. (d) Phylogenomic analysis revealed that the genus Elaeocarpus is closely related to Crinodendron patagua on an independent branch and Aristotelia fruticosa is closely related to Vallea stipularis, forming a clade with the genus Sloanea. Structural comparisons showed that Elaeocarpaceae diverged at 60 Mya, the genus Elaeocarpus diverged 53 Mya and that the genus Sloanea diverged 0.44 Mya. These results provide new insight into the evolution of the Elaeocarpaceae.

Two new species of Polyalthiopsis (Annonaceae) based on morphological characters and phylogenetic evidence, with a supplementary description of P. chinensis from China.

Two new species of Polyalthiopsis (Annonaceae), P. nigra Y.H. Tan & Bin Yang from Guangxi and Yunnan Provinces and P. xui Y.H. Tan & Bin Yang from Yunnan Province, are described and illustrated. P. nigra is morphologically similar to P. chinensis in having narrowly elliptic-oblong, lemon to yellowish green petals, but differs by having obovoid monocarps, a higher number of leaf secondary veins, leaf blades usually widest above the middle, and a lower ratio of leaf blade length to width. P. xui is morphologically similar to P. floribunda in having axillary inflorescences, 1-3(-4) flowers, elliptic leaves, and elliptic-ovate petals, but differs in the numbers of carpels per flower and ovules per carpel. The molecular phylogenetic analysis using five plastid markers confirm that the two new species belong to the genus Polyalthiopsis and show clear interspecific divergences between P. nigra and P. xui and between them and other species in the genus. Detailed descriptions, colored photographs, and habitat and distribution data for the two new species are provided. In addition, the fruit morphology of P. chinensis is described for the first time, based on living collections. Geographical distributions and a diagnostic key for all Polyalthiopsis species are also presented.

Comparison of neurofilament light and heavy chain in spinal muscular atrophy and amyotrophic lateral sclerosis: A pilot study.

BACKGROUND: Spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) were two major motor neuron diseases with similar symptoms and poor outcomes. This study aimed to identify potential biomarkers in disease monitoring and differential diagnosis of adult SMA patients with sporadic ALS patients. METHODS: This was a pilot study with ten adult SMA patients and ten ALS patients consecutively enrolled during hospitalization. Serum and cerebrospinal fluid (CSF) samples were collected for assessment of neurofilament light (NFL) and phosphorylated neurofilament heavy chain (pNFH). Serum creatine kinase (CK) and creatinine (Cr) were also compared between groups. The receiver operating characteristic (ROC) curves were used to identify differentiated values among ALS and SMA patients. RESULTS: Serum Cr, CSF NFL, and CSF pNFH levels of ALS patients were significantly higher than those of the adult SMA patients (p < .01). Serum CK and Cr were strongly correlated with baseline ALSFRS-R scores in SMA patients (p < .001). The ROC curves revealed an area under the curve (AUC) of 0.94 in serum Cr with a cut-off value of 44.5 µmol/L (Sensitivity 90%, Specificity 90%). AUC from the ROC curve of CSF NFL and CSF pNFH were 1.0 and 0.84, with cut-off values of 1275 pg/mL and 0.395 ng/mL, respectively (Sensitivity and Specificity of 100% and 100% in CSF NFL; Sensitivity and Specificity of 90% and 80% in CSF pNFH). CONCLUSION: CSF NFL and pNFH might be useful biomarkers for differential diagnosis of adult SMA and ALS.