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Abstract YTHDC1, a reader of N6-methyladenosine (m6A) modifications on RNA, is posited to exert significant influence over RNA metabolism. Despite its recognized importance, the precise function and underlying mechanisms of YTHDC1 in the preservation of normal hematopoietic stem cell (HSCs) homeostasis remain elusive. Here, we investigated the role of YTHDC1 in normal hematopoiesis and HSCs maintenance in vivo. Utilizing conditional Ythdc1 knockout mice and Ythdc1/Mettl3 double knockout mice, we demonstrated that YTHDC1 is required for HSCs maintenance and self-renewal by regulating microRNA maturation. YTHDC1 deficiency resulted in HSCs apoptosis. Furthermore, we uncovered that YTHDC1 interacts with HP1BP3, a nuclear RNA binding protein involved in microRNA maturation. Deletion of YTHDC1 brought about significant alterations in microRNA levels. However, over-expression of mir-125b, mir-99b, and let-7e partially rescued the functional defect of YTHDC1-null HSCs. Taken together, these findings indicated that the nuclear protein YTHDC1-HP1BP3-microRNA maturation axis is essential for the long-term maintenance of HSCs.

Abstract The serine/arginine-rich splicing factors (SRSFs) play an important role in regulating the alternative splicing of precursor RNA (pre-RNA). During this procedure, introns are removed from the pre-RNA, while the exons are accurately joined together to produce mature mRNA. In addition, SRSFs also involved in DNA replication and transcription, mRNA stability and nuclear export, and protein translation. It is reported that SRSFs participate in hematopoiesis, development, and other important biological process. They are also associated with the development of several diseases, particularly cancers. While the basic physiological functions and the important roles of SRSFs in solid cancer have been extensively reviewed, a comprehensive summary of their significant functions in normal hematopoiesis and hematopoietic malignancies is currently absent. Hence, this review presents a summary of their roles in normal hematopoiesis and hematopoietic malignancies. Graphical Abstract

Lysine succinylation (Ksu) has recently emerged as a protein modification that regulates diverse functions in various biological processes. However, the systemically and precise role of lysine succinylation in erythropoiesis remains to be fully elucidated. In this study, we noted a prominent increase of succinyl-CoA and lysine succinylation during human erythroid differentiation. To explore the functional significance of succinylation, we inhibited succinylation by either knock downing key succinyltransferases or overexpressing desuccinylases. Succinylation inhibition led to suppressed cell proliferation, increased apoptosis, and disrupted erythroid differentiation. In vivo overexpression of the desuccinylases SIRT5 delayed erythroid differentiation. Furthermore, integrative proteome and succinylome analysis identifies 939 succinylated proteins with 3,562 Ksu sites, distributed across various cellular compartments and involved in multiple cellular processes. Significantly, inconsistencies between protein expression levels and succinylation levels were observed, indicating that the succinylation of certain proteins may function independently of expression. Mechanistically, we implicated KAT2A-mediated succinylation of histone H3 K79, leading to chromatin remodeling and subsequently erythropoiesis regulation. Specially, we identified CYCS as a key regulator of erythropoiesis, which depends on its succinylation sites K28/K40. Taken together, our comprehensive investigation of the succinylation landscape during erythropoiesis provides valuable insights into its regulatory role and offer potential implications for erythroid-related diseases.

Acute myeloid leukemia (AML), a highly heterogeneous myeloid malignancy, remains a challenge in terms of proper risk stratification. In this study, we developed a novel pyroptosis prognostic model based on pyroptosis-related gene pairs, which exhibited excellent prognostic performance across multiple cohorts (N = 1506) and accurately predicted both adult and pediatric AML prognosis. Additionally, we integrated the pyroptosis risk model with other clinical risk factors to construct a highly operational nomogram. Moreover, our findings indicate a significant correlation between elevated pyroptosis risk scores and increased stemness of AML. Using CIBERSORT immune analysis, we found a decreased proportion of resting NK cells and activated mast cells in the high-risk group. Through analyzing the correlation between chemotherapy drug response sensitivity and risk scores, we found that AZD1332 and BPD-0008900 were extremely sensitive in the high-risk group.

Abstract Interstitial lung diseases (ILDs), or diffuse pulmonary lung disease, are a subset of lung diseases that primarily affect lung alveoli and the space around interstitial tissue and bronchioles. It clinically manifests as progressive dyspnea, and patients often exhibit a varied decrease in pulmonary diffusion function. Recently, variants in telomere biology-related genes have been identified as genetic lesions of ILDs. Here, we enrolled 82 patients with interstitial pneumonia from 2017 to 2021 in our hospital to explore the candidate gene mutations of these patients via whole-exome sequencing. After data filtering, a novel heterozygous mutation (NM_025099: p.Gly131Arg) of CTC1 was identified in two affected family members. As a component of CST (CTC1-STN1-TEN1) complex, CTC1 is responsible for maintaining telomeric structure integrity and has also been identified as a candidate gene for IPF, a special kind of chronic ILD with insidious onset. Simultaneously, real-time PCR revealed that two affected family members presented with short telomere lengths, which further confirmed the effect of the mutation in the CTC1 gene. Our study not only expanded the mutation spectrum of CTC1 and provided epidemiological data on ILDs caused by CTC1 mutations but also further confirmed the relationship between heterozygous mutations in CTC1 and ILDs, which may further contribute to understanding the mechanisms underlying ILDs.

This research explores the dynamic common correlated effects of financial inclusion on foreign direct investment (FDI) in East Asia and Pacific (EAP) countries. Traditional econometric methodologies overlook cross-sectional dependence and heterogeneity among countries, resulting in biased estimates. As a result, we use a unique method called DCCE, which can effectively address these problems. The short run and long-run estimates reveal that financial inclusion positively and significantly influences FDI in higher-income and overall EAP countries. Furthermore, in lower-income EAP countries, financial inclusion has an insignificant correlation with FDI, which becomes significant when an interaction term for institutional performance and financial inclusion is included. Hence, governments and policy makers in EAP economies should try to increase financial inclusion in order to attain an optimal and sustainable level of FDI inflows to enhance economic growth.

In development over 70 years, magnetotelluric (MT) sounding, a high-resolution technique for subsurface electrical resistivity imaging, has been widely applied in resource exploration in the Earth. The key factors of the metallogenic system of metallic mineral deposits can be closely correlated to the electrical anomalies of the lithosphere. In this paper, we review the relationship between the electrical resistivity model of the lithosphere and the metallogenic system. At the beginning, we indicate why the electrical parameters relate to the metallogenic system in all geophysical parameters. The advantage of MT sounding in sketching an electrical resistivity model of the lithosphere is subsequently discussed, and some methods of data processing, analysis and inversion are also introduced. Furthermore, we summarize how to bridge the relationship between the electrical resistivity model of the lithosphere and metallogenic system, and analyze the influence of the rheological variation estimated from conductivity in the lithosphere on mineralization. In the end, we list some typical cases of the application of MT sounding in mineral exploration, and also give some suggestions for future work. This study is aimed at providing guidance in discussing the metallogenic system using an electrical resistivity model.

Background: Heterozygous mutations in the dehydrodolichol diphosphate synthase (DHDDS) gene are one of the causes generating developmental and epileptic encephalopathies. So far, only eleven mutations in the DHDDS gene have been identified. The mutation spectrum of the DHDDS gene in the Chinese population remains unclear.Methods: In this study, we enrolled a Chinese family with myoclonus and/or epilepsy and intellectual disability. The epilepsy and myoclonic tremor were improved after deep brain stimulation (DBS) of the subthalamic nucleus (STN) treatment. Whole exome sequencing and Sanger sequencing were employed to explore the genetic variations of the family.Results: Subsequent to data filtering, we identified a recurrent pathogenic mutation (NM_001243564.1, c.113G>A/p.R38H) in the DHDDS gene in the proband. Sanger sequencing further validated that the presence of the mutation in his affected mother but absent in the health family members. Further bioinformatics analysis revealed that this mutation (p.R38H), located in an evolutionarily conserved region of DHDDS, was predicted to be deleterious.Discussion: In this report, we present the first case of intractable epilepsy and/or myoclonus caused by p.R38H mutation of the DHDDS gene in the Chinese population. Furthermore, this study represents the third report of autosomal dominant familial inheritance of DHDDS mutation worldwide.

Leukemia stem cells (LSC) represent a crucial and rare subset of cells present in acute myeloid leukemia (AML); they play a pivotal role in the initiation, maintenance, and relapse of this disease. Targeting LSC holds great promise for preventing AML relapse and improving long-term outcomes. However the precise molecular mechanisms governing LSC self-renewal are still poorly understood. Here, we present compelling evidence that the expression of miR-30e-5p, a potential tumor-suppressive microRNA, is significantly lower in AML samples than in healthy bone marrow samples. Forced expression of miR- 30e effectively inhibits leukemogenesis, impairs LSC self-renewal, and delays leukemia progression. Mechanistically, Cyb561 acts as a direct target of miR-30e-5p in LSC, and its deficiency restricts the self-renewal of LSC by activating reactive oxygen series signaling and markedly prolongs recipients’ survival. Moreover, genetic or pharmacological overexpression of miR-30e-5p or knockdown of Cyb561 suppresses the growth of human AML cells. In conclusion, our findings establish the crucial role of the miR-30e-5p/Cyb561/ROS axis in finely regulating LSC self-renewal, highlighting Cyb561 as a potential therapeutic target for LSC-directed therapies.

Clonal hematopoiesis plays a critical role in the initiation and development of hematologic malignancies. In patients with del(5q) myelodysplastic syndrome (MDS), the transcription factor FOXM1 is frequently downregulated in CD34+ cells. In this study, we demonstrated that Foxm1 haploinsufficiency disturbed normal hematopoiesis and conferred a competitive repopulation advantage for a short period. However, it impaired the long-term self-renewal capacity of hematopoietic stem cells, recapitulating the phenotypes of abnormal hematopoietic stem cells observed in patients with MDS. Moreover, heterozygous inactivation of Foxm1 led to an increase in DNA damage in hematopoietic stem/progenitor cells (HSPCs). Foxm1 haploinsufficiency induced hematopoietic dysplasia in a mouse model with LPS-induced chronic inflammation and accelerated AML-ETO9a–mediated leukemogenesis. We have also identified Parp1, an important enzyme that responds to various types of DNA damage, as a target of Foxm1. Foxm1 haploinsufficiency decreased the ability of HSPCs to efficiently repair DNA damage by downregulating Parp1 expression. Our findings suggest that the downregulation of the Foxm1-Parp1 molecular axis may promote clonal hematopoiesis and reduce genome stability, contributing to del(5q) MDS pathogenesis.

Abstract We aimed to comprehensively investigate the proteomic profile and underlying biological function of exosomal proteins associated with B-cell acute lymphoblastic leukemia. Exosomes were isolated from plasma samples collected from five patients with B-ALL and five healthy individuals, and their protein content was quantitatively analyzed by liquid chromatography with tandem mass spectrometry. A total of 342 differentially expressed proteins were identified in patients with B-ALL. The DEPs were mainly associated with protein metabolic processes and protein activity regulation and were significantly enriched in the Notch and autophagy pathways. Furthermore, we found that ADAM17 and ATG3 were upregulated in patients with B-ALL and enriched in the Notch and autophagy pathways, respectively. Further western blot analysis of exosomes collected from additional 18 patients with B-ALL and 10 healthy controls confirmed that both ADAM17 and ATG3 were overexpressed in exosomes derived from patients with B-ALL (p

Background: CODAS syndrome (MIM 600373) is a multi-system developmental disorder characterized by cerebral, ocular, dental, auricular, and skeletal anomalies. CODAS syndrome is rare in the world and no cases have been reported in Chinese population so far. Mutations in the LONP1 gene can contribute to CODAS syndrome, while the underlying molecular mechanisms requires further investigation.Method: We described a Chinese boy who has suffered from cognition impairment, cataracts, caries, abnormal auricle and skeletal anomalies since birth. The patient’s parents are non-consanguineous and healthy. Whole-exome sequencing (WES) was employed to explore the genetic entity of this family.Results: A compound heterozygous missense mutation (NM_004793: c.2009C>T/p.A670V and c.2014C>T/p.R672C) of LONP1 was identified in the patient. Considering the clinical phenotypes and genetic results, the patient was diagnosed as CODAS syndrome.Conclusion: Here we reported the first case with CODAS syndrome in Chinese population. WES identified a compound heterozygous missense mutation of LONP1 gene in the patients. Our study not only provided data for genetic counseling and clinical diagnosis to this family, but also expanded the clinical spectrum of LONP1-related CODAS syndrome.

Background: Hyperhomocysteinemia (HHcy) is a risk factor for thromboembolic disease. Defects in one-carbon metabolism (1-CM)-related genes, such as methylenetetrahydrofolate reductase (MTHFR), methylenetetrahydrofolate dehydrogenase, cyclohydrolase, and formyltetrahydrofolate synthetase 1 (MTHFD1), can cause HHcy and may also affect the efficacy of folic acid therapy. The details of mechanisms are yet to be further investigated.Method: We described a Chinese family with hereditary HHcy. The proband suffered from severe thromboembolic disease and experienced failure of folic acid therapy. Two sons of the proband were also diagnosed with HHcy but were sensitive to folic acid therapy. Whole-exome sequencing (WES) was conducted to evaluate the genetic lesion of this family.Results: Compound heterozygous variants (a common polymorphism, p. A222V, and a novel variant, p. C631*fs*1) of the MTHFR gene and a homozygous missense variant (p. K134R) of the MTHFD1 gene were identified in the proband. The two sons, with successful intervention, only harbored the homozygous p. A222V variant of the MTHFR gene.Conclusion: The clinical manifestations and genetic research synergistically confirmed the diagnosis of HHcy and clarified the failure of folic acid therapy in the proband caused by doubly bi-allelic variants of the MTHFR and MTHFD1 genes. Our study increased our understanding of the molecular basis of 1-CM-related gene defects on folic acid therapy in HHcy.

ABSTRACT The harvesting of straw by the flail knife type straw cutting device will cause loose contacts between straw roots and soil, affecting the straw feed's impurity content. In this study, a theoretical analysis of the straw cutting process was conducted to explore the factors influencing the root-soil disturbance. A pulling force test device was designed to test the pulling force of the corn stalk. The response surface method was used to study the effects of various factors on the straw pulling force under different conditions of draft angles (20°, 30°, 40°), soil moisture content (15.23%, 17.62%, 20.47%), and different straw root diameters. The test results showed that the straw pulling force was directly proportional to the straw root diameter and inversely proportional to the soil moisture content. The straw pulling force decreased first and then increased with the increase of the draft angle. According to the established second-order regression model, when the draft angle was 28.5°, the soil moisture content was 20.47%, the root diameter was 22 mm, the minimum pulling force of straw was 189.635N. The test results can provide a reference for the design of straw feed harvester.

Introduction: Antibody–drug conjugates (ADCs) produce unparalleled efficacy in refractory neoplasms but can also lead to serious toxicities. Although ADC-related sepsis has been reported, the clinical features are not well characterized in real-world studies.Objective: The aim of this study was to identify the association between ADCs and sepsis using FAERS data and uncover the clinical characteristics of ADC-related sepsis.Methods: We performed disproportionality analysis using FAERS data and compared rates of sepsis in cancer patients receiving ADCs vs. other regimens. Associations between ADCs and sepsis were assessed using reporting odds ratios (RORs) and information component (IC). For each treatment group, we detected drug interaction signals, and conducted subgroup analyses (age, gender, and regimens) and sensitivity analyses.Results: A total of 24,618 cases were reported with ADCs between Q1, 2004 and Q3, 2021. Sepsis, septic shock, multiple organ dysfunction syndrome, and other sepsis-related toxicities were significantly associated with ADCs than other drugs in this database. Sepsis and multiple organ dysfunction syndrome have the highest safety concerns with ADCs compared with other anticancer monotherapies. Gemtuzumab ozogamicin and inotuzumab ozogamicin showed increased safety risks than other ADCs. For the top nine ADC-related sepsis, males showed higher sepsis safety concern than females (p

BackgroundDesmin is an intermediate filament protein that plays a critical role in the stabilization of the sarcomeres and cell contacts in the cardiac intercalated disk. Mutated DES gene can cause hereditary cardiomyopathy with heterogeneous phenotypes, while the underlying molecular mechanisms requires further investigation.MethodsWe described a Chinese family present with cardiomyopathy and sudden cardiac death (SCD). Whole-exome sequencing (WES) and bioinformatics strategies were employed to explore the genetic entity of this family.ResultsAn unknown heterozygote missense variant (c.1300G > A; p. E434K) of DES gene was identified. The mutation cosegregates in this family. The mutation was predicted as pathogenic and was absent in our 200 healthy controls.ConclusionWe identified a novel DES mutation (p. E434K) in a Chinese family with cardiomyopathy and SCD. Our study not only provided a new case for the study of the relationship between DES mutations and hereditary cardiomyopathy but also broadened the spectrum of DES mutations.

Rhodotorula glutinis, as a member of the family Sporidiobolaceae, is of great value in the field of biotechnology. However, the evolutionary relationship of R. glutinis X-20 with Rhodosporidiobolus, Sporobolomyces, and Rhodotorula are not well understood, and its metabolic pathways such as carotenoid biosynthesis are not well resolved. Here, genome sequencing and comparative genome techniques were employed to improve the understanding of R. glutinis X-20. Phytoene desaturase (crtI) and 15-cis-phytoene synthase/lycopene beta-cyclase (crtYB), key enzymes in carotenoid pathway from R. glutinis X-20 were more efficiently expressed in S. cerevisiae INVSc1 than in S. cerevisiae CEN.PK2-1C. High yielding engineered strains were obtained by using synthetic biology technology constructing carotenoid pathway in S. cerevisiae and optimizing the precursor supply after fed-batch fermentation with palmitic acid supplementation. Genome sequencing analysis and metabolite identification has enhanced the understanding of evolutionary relationships and metabolic pathways in R. glutinis X-20, while heterologous construction of carotenoid pathway has facilitated its industrial application.

Preaxial polydactyly (PPD) is a common congenital abnormality with an incidence of 0.8–1.4% in Asians, characterized by the presence of extra digit(s) on the preaxial side of the hand or foot. PPD is genetically classified into four subtypes, PPD type I–IV. Variants in six genes/loci [including GLI family zinc finger 3 (GLI3), ZPA regulatory sequence (ZRS), and pre-ZRS region] have been identified in PPD cases. Among these loci, ZRS is, perhaps, the most special and well known, but most articles only reported one or a few cases. There is a lack of reports on the ZRS-variant frequency in patients with PPD. In this study, we recruited 167 sporadic or familial cases (including 154 sporadic patients and 13 families) with PPD from Central-South China and identified four ZRS variants in four patients (2.40%, 4/167), including two novel variants (ZRS131A > T/chr7:g.156584439A > T and ZRS474C > G/chr7:g.156584096C > G) and two known variants (ZRS428T > A/chr7:g.156584142T > A and ZRS619C > T/chr7:g.156583951C > T). ZRS131A > T and ZRS428T > A were detected in PPD I cases and ZRS474C > G and ZRS619C > T combinedly acted to cause PPD II. The detectable rate of ZRS variants in PPD I was 1.60% (2/125), while PPD II was significantly higher (9.52%, 2/21). Three bilateral PPD cases harbored ZRS variants (13.64%, 3/22), suggesting that bilateral PPD was more possibly caused by genetic etiologies. This study identified two novel ZRS variants, further confirmed the association between ZRS and PPD I and reported a rare PPD II case resulted from the compound heterozygote of ZRS. This investigation preliminarily evaluated a ZRS variants rate in patients with PPD and described the general picture of PPD in Central-South China.

BackgroundSudden cardiac death (SCD), based on sudden cardiac ejection cessation, is an unexpected death. Primary cardiomyopathies, including dilated cardiomyopathy (DCM), are one of main causes of SCD. The DCM is characterized by a cardiac dilatation and a reduced systolic function with a prevalence of 1/250 in adults. The DCM has been reported with more than 60 disease-causing genes, and MYBPC3 variants are one of the most common and well-known causes of DCM.MethodsWe identified a 29-year-old female who died of SCD. We performed a whole-exome sequencing (WES) to detect her genetic etiology and used minigene modeling and immunohistochemistry staining to verify the pathogenicity.ResultsWe determined that the woman died of SCD caused by DCM due to an identified novel synonymous variant of MYBPC3 (NM_000256.3: c.24A>C, p.P8P) in the deceased. The variant can result in abnormal splicing, which was confirmed by minigene models and immunohistochemistry staining.ConclusionWe may have identified the first deleterious synonymous variant of MYBPC3 in an SCD case and verified its significant impact on RNA splicing. Our description enriched the spectrum of MYBPC3 variants and emphasized the significance of synonymous variants that are always disregarded in genetic screening.

FOXM1 is a known transcription factor which promotes cell proliferation in cancer cells. Here, the authors show that FOXM1 is required for the maintenance of quiescence and self-renewal of leukemia stem cells in MLL-AF9-rearranged acute myeloid leukemia patient and mouse models.

Polyketides are an important class of structurally diverse natural products derived from a precursor molecule consisting of a chain of alternating ketone and methylene groups. These compounds have attracted the worldwide attention of pharmaceutical researchers since they are endowed with a wide array of biological properties. As one of the most common filamentous fungi in nature, Aspergillus spp. is well known as an excellent producer of polyketide compounds with therapeutic potential. By extensive literature search and data analysis, this review comprehensively summarizes Aspergillus-derived polyketides for the first time, regarding their occurrences, chemical structures and bioactivities as well as biosynthetic logics.

7q terminal deletion syndrome is a rare condition presenting with multiple congenital malformations, including abnormal brain and facial structures, developmental delay, intellectual disability, abnormal limbs, and sacral anomalies. At least 40 OMIM genes located in the 7q34-7q36.3 region act as candidate genes for these phenotypes, of which SHH, EN2, KCNH2, RHEB, HLXB9, EZH2, MNX1 and LIMR1 may be the most important. In this study, we discuss the case of a 2.5-year-old male patient with multiple malformations, congenital brain dysplasia, developmental delay, and intellectual disability. A high-resolution genome-wide single nucleotide polymorphism array and real-time polymerase chain reaction were performed to detect genetic lesions. A de novo 9.4 Mb deletion in chromosome region 7q35-7q36.3 (chr7:147,493,985–156,774,460) was found. This chromosome region contains 68 genes, some of which are candidate genes for each phenotype. To the best of our knowledge, this is a rare case report of 7q terminal deletion syndrome in a Chinese patient. Our study identifies a rare phenotype in terms of brain structure abnormalities and cerebellar sulcus widening in patients with deletion in 7q35-7q36.3.

Hypokalemic periodic paralysis (HypoPP) is a rare autosomal dominant disorder characterized by episodic flaccid paralysis with concomitant hypokalemia. More than half of patients were associated with mutations in CACNA1S that encodes the alpha-1-subunit of the skeletal muscle L-type voltage-dependent calcium channel. Mutations in CACNA1S may alter the structure of CACNA1S and affect the functions of calcium channels, which damages Ca2+-mediated excitation-contraction coupling. In this research, we identified and described a Chinese HypoPP patient with a novel frameshift mutation in CACNA1S [NM_000069.2: c.1364delA (p.Asn455fs)] by targeted sequencing. This study would expand the spectrum of CACNA1S mutations, further our understanding of HypoPP, and provided a new perspective for selecting effective treatments.

Idiopathic focal segmental glomerulosclerosis (FSGS) is a relatively frequent kidney disorder that manifest clinically as proteinuria and progressive loss of renal function. Genetic factors play a dominant role in the occurrence of FSGS. CD2-associated protein (CD2AP) is an adapter molecule and is essential for the slit-diaphragm assembly and function. Mutations in the CD2AP gene can contribute to FSGS development. Here, we describe a Chinese family of four generations with unexplained proteinuria. The proband, a 12-year-old boy, was diagnosed as FSGS. Whole-exome sequencing (WES) revealed an unknown frameshift insertion mutation (p.K579Efs*7) of CD2AP gene that leads to a truncation of CD2AP protein. Bioinformatics strategies predicted that the novel mutation was pathogenic. The mutation was absent in either healthy family members or our 200 healthy controls. In summary, we used WES to explore the genetic lesion of FSGS patients and identified a novel mutation in CD2AP gene. This work broadens the mutation spectrum of CD2AP gene and provides data for genetic counseling to additional FSGS patients.

Inherited macrothrombocytopenia (IMTP) is a rare disorder characterized by a reduced platelet count and abnormally large platelets. The main clinical symptom of IMTP is mild bleeding in some patients. At present, more than 30 genes have been identified in patients with syndromic and non-syndromic IMTP. In this study, a 3-year-old boy and his mother who presented with mild epistaxis and/or gingival bleeding were diagnosed as having IMTP. Wen then selected whole sequencing to explore the genetic lesion of the patients. After data filtering and mutation validation, a novel frameshift mutation (NM_001130004: c.398_399insTGCG, p.F134AfsX60) of α-actin 1 (ACTN1) was identified in the proband and his mother but absent in other unaffected individuals. Previous studies have proven that mutations in ACTN1 may lead to IMTP with mild to absent bleeding phenotype. The novel mutation, resulting in a truncated protein in exon 4 of the ACTN1 gene, was absent in the public database, such as 1000G and genomAD. Further Western blot revealed that the expression of α-actin 1 in the proband was decreased overtly, which indicated that the novel frameshift mutation may induce non-sense-mediated mRNA decay. In summary, this study not only broadened the variants spectrum of ACTN1 gene, which may contribute to the genetic counseling of IMTP, but also confirmed the diagnosis of IMTP, which may help the management and prognosis for the family members.

Abstract Ectopic Viral Integration site 1 (EVI1) upregulation is implicated in 10–25% of pediatric acute myeloid leukemia (AML) and has an inferior outcome with current chemotherapy regimens. Here we report that EVI1 upregulation is associated with methylation of the miR-9 promoter and correlated with downregulation of miR-9 in human AML cell lines and bone marrow (BM) cells from pediatric patients. Reactivation of miR-9 by hypomethylating agents and forced expression of miR-9 in EVI1high leukemia cell lines and primary leukemia cells results in apoptosis and decreased proliferation of EVI1high leukemia cells. Furthermore, re-expression of miR-9 delays disease progression in EVI1high leukemia-xenograft mice. Our results suggest that EVI1-induced hypermethylation and downregulation of the miR-9 plays an important role in leukemogenesis in EVI-1high pediatric AML, indicating that hypomethylating agents may be a potential therapeutic strategy for EVI1high pediatric AML.

The brain–computer interface (BCI) is a system that is designed to provide communication channels to anyone through a computer. Initially, it was suggested to help the disabled, but actually had been proposed a wider range of applications. However, the cross-subject recognition in BCI systems is difficult to break apart from the individual specific characteristics, unsteady characteristics, and environmental specific characteristics, which also makes it difficult to develop highly reliable and highly stable BCI systems. Rapid serial visual presentation (RSVP) is one of the most recent spellers with a clean, unified background and a single stimulus, which may evoke event-related potential (ERP) patterns with less individual difference. In order to build a BCI system that allows new users to use it directly without calibration or with less calibration time, RSVP was employed as evoked paradigm, then correlation analysis rank (CAR) algorithm was proposed to improve the cross-individual classification and simultaneously use as less training data as possible. Fifty-eight subjects took part in the experiments. The flash stimulation time is 200 ms, and the off time is 100 ms. The P300 component was locked to the target representation by time. The results showed that RSVP could evoke more similar ERP patterns among subjects compared with matrix paradigm. Then, the included angle cosine was calculated and counted for averaged ERP waveform between each two subjects. The average matching number of all subjects was 6 for the matrix paradigm, while for the RSVP paradigm, the average matching number range was 20 when the threshold value was set to 0.5, more than three times as much larger, quantificationally indicating that ERP waveforms evoked by the RSVP paradigm produced smaller individual differences, and it is more favorable for cross-subject classification. Information transfer rates (ITR) were also calculated for RSVP and matrix paradigms, and the RSVP paradigm got the average ITR of 43.18 bits/min, which was 13% higher than the matrix paradigm. Then, the receiver operating characteristic (ROC) curve value was computed and compared using the proposed CAR algorithm and traditional random selection. The results showed that the proposed CAR got significantly better performance than the traditional random selection and got the best AUC value of 0.8, while the traditional random selection only achieved 0.65. These encouraging results suggest that with proper evoked paradigm and classification methods, it is feasible to get stable performance across subjects for ERP-based BCI. Thus, our findings provide a new approach to improve BCI performances.

Students' valuing of academic content impacts their engagement in learning and plays a pivotal role in shaping their future academic and career choices. Fortunately, practicing educators can integrate many readily applicable strategies into teaching to enhance students' valuing of academic content. Drawing from expectancy-value theory, Eric M. Anderman, Yue Sheng, and Wonjoon Cha present five evidence-based instructional strategies with concrete examples that aim to enhance students' valuing of academic content. These strategies can be implemented with minimal additional work for teachers and at little or no additional financial cost to schools.

Current studies have got a series of satisfying accuracies in EEG-based emotion classification, but most of the classifiers used in previous studies are totally time-limited. To produce generalizable results, the emotion classifier should be stable over days, in which the day-to-day variations of EEG should be appropriately handled. To improve the generalization of EEG-based emotion recognition over time by learning multiple-days information which embraces the day-to-day variations, in this paper, 17 subjects were recruited to view several video clips to experience different emotion states, and each subject was required to perform five sessions in 5 days distributed over 1 month. Support vector machine was built to perform a classification, in which the training samples may come from 1, 2, 3, or 4 days' sessions but have a same number, termed learning 1-days information (L1DI), learning 2-days information (L2DI), learning 3-days information (L3DI), and learning 4-days information (L4DI) conditions, respectively. The results revealed that the EEG variability could impair the performance of emotion classifier dramatically, and learning more days' information to construct a classifier could significantly improve the generalization of EEG-based emotion recognition over time. Mean accuracies were 62.78, 67.92, 70.75, and 72.50% at L1DI, L2DI, L3DI, and L4DI conditions, respectively. Features at L4DI condition were ranked by modified RFE, and features providing better contribution were applied to obtain the performances of all conditions, results showed that the performance of SVMs trained and tested with the feature subset were all improved for L1DI, L2DI (*p < 0.05), L3DI (**p < 0.01), and L4DI (*p < 0.05) conditions. It could be a substantial step forward in the development of emotion recognition from EEG signals because it may enable a classifier trained on one time to handle another.

Our previous work found that DMH1 (4-[6-(4-isopropoxyphenyl)pyrazolo [1,5-a]pyrimidin-3-yl]quinoline) was a novel autophagy inhibitor. Here, we aimed to investigate the effects of DMH1 on chemotherapeutic drug-induced autophagy as well as the efficacy of chemotherapeutic drugs in different cancer cells. We found that DMH1 inhibited tamoxifen- and cispcis-diaminedichloroplatinum (II) (CDDP)-induced autophagy responses in MCF-7 and HeLa cells, and potentiated the anti-tumor activity of tamoxifen and CDDP for both cells. DMH1 inhibited 5-fluorouracil (5-FU)-induced autophagy responses in MCF-7 and HeLa cells, but did not affect the anti-tumor activity of 5-FU for these two cell lines. DMH1 itself did not induce cell death in MCF-7 and HeLa cells, but inhibited the proliferation of these cells. In conclusion, DMH1 inhibits chemotherapeutic drug-induced autophagy response and the enhancement of efficacy of chemotherapeutic drugs by DMH1 is dependent on the cell sensitivity to drugs.

Objectives: It has been reported recently that gamma measures of the electroencephalogram (EEG) might provide information about the candidate biomarker of mental diseases like schizophrenia, Alzheimer’s disease, affective disorder and so on, but as we know it is a difficult issue to induce visual and tactile evoked responses at high frequencies. Although a high-frequency response evoked by auditory senses is achievable, the quality of the recording response is not ideal, such as relatively low signal-to-noise ratio (SNR). Recently, auditory steady-state responses (ASSRs) play an essential role in the field of basic auditory studies and clinical uses. However, how to improve the quality of ASSRs is still a challenge which researchers have been working on. This study aims at designing a more comfortable and suitable evoked paradigm and then enhancing the quality of the ASSRs in healthy subjects so as to further apply it in clinical practice. Methods: Chirp and click stimuli with 40 Hz and 60 Hz were employed to evoke the gamma-ASSR respectively, and the sound adjusted to 45 dB sound pressure level (SPL). Twenty healthy subjects with normal-hearing participated, and 64-channel EEGs were simultaneously recorded during the experiment. Event-related spectral perturbation (ERSP) and SNR of the ASSRs were measured and analyzed to verify the feasibility and adaptability of the proposed evoked paradigm. Results: The results showed that the evoked paradigm proposed in this study could enhance ASSRs with strong feasibility and adaptability. (1) ASSR waves in time domain indicated that 40 Hz stimuli could significantly induce larger peak-to-peak values of ASSRs compared to 60 Hz stimuli (p < 0.01**); ERSP showed that obvious ASSRs were obtained at each lead for both 40 Hz and 60 Hz, as well as the click and chirp stimuli. (2) The SNR of the ASSRs were ⁻3.23 ± 1.68, ⁻2.44 ± 2.90, ⁻4.66 ± 2.09, and ⁻3.53 ± 3.49 respectively for 40 Hz click, 40 Hz chirp, 60 Hz click and 60 Hz chirp, indicating the chirp stimuli could induce significantly better ASSR than the click, and 40 Hz ASSRs had the higher SNR than 60 Hz (p < 0.01**). Limitation: In this study, sample size was small and the age span was not large enough. Conclusions: This study verified the feasibility and adaptability of the proposed evoked paradigm to improve the quality of the gamma-ASSR, which is significant in clinical application. The results suggested that 40 Hz ASSR evoked by chirp stimuli had the best performance and was expected to be used in clinical practice, especially in the field of mental diseases such as schizophrenia, Alzheimer’s disease, and affective disorder.