LiBis: an ultrasensitive alignment augmentation for low-input bisulfite sequencing.

The cell-free DNA (cfDNA) methylation profile in liquid biopsy has been utilized to diagnose early-stage disease and estimate therapy response. However, typical clinical procedures are capable of purifying only very small amounts of cfDNA. Whole-genome bisulfite sequencing (WGBS) is the gold standard for measuring DNA methylation; however, WGBS using small amounts of fragmented DNA introduces a critical challenge for data analysis, namely a low-mapping ratio. The resulting low sequencing depth and low coverage of CpG sites genome-wide is a bottleneck for the clinical application of cfDNA-based WGBS assays. We developed LiBis (Low-input Bisulfite Sequencing), a novel method for low-input WGBS data alignment. By dynamically clipping initially unmapped reads and remapping clipped fragments, we judiciously rescued those reads and uniquely aligned them to the genome. By substantially increasing the mapping ratio by up to 88%, LiBis dramatically improved the number of informative CpGs and the precision in quantifying the methylation status of individual CpG sites. LiBis significantly improved the cost efficiency of low-input WGBS experiments by dynamically removing contamination introduced by random priming. The high sensitivity and cost effectiveness afforded by LiBis for low-input samples will allow the discovery of genetic and epigenetic features suitable for downstream analysis and biomarker identification using liquid biopsy.

Ubiquitous Topological States of Phonons in Solids: Silicon as a Model Material.

Research on topological physics of phonons has attracted enormous interest but demands appropriate model materials. Our ab initio calculations identify silicon as an ideal candidate material containing extraordinarily rich topological phonon states. In silicon, we identify various topological nodal lines characterized by quantized Berry phase π, which gives drumhead surface states observable from any surface orientations. Remarkably, a novel type of topological nexus phonon is discovered which is featured by double Fermi-arc-like surface states but requires neither inversion nor time-reversal symmetry breaking. Versatile topological states can be created from the nexus phonons, such as Hopf nodal links by strain. Furthermore, we generalize the symmetry analysis to other centrosymmetric systems and find numerous candidate materials, demonstrating the ubiquitous existence of topological phonons in solids. These findings open up new opportunities for studying topological phonons in realistic materials and their influence on surface physics.

The Association Between Relative Deprivation, Depression, and Youth Suicide: Evidence From a Psychological Autopsy Study.

OBJECTIVE: Suicide is a serious public health concern in China. In the present study, we investigated the specific mechanisms underlying relative deprivation and suicide in rural China. METHODS: A large psychological autopsy study was conducted in rural China, in which 392 suicides and 416 community-living controls were consecutively recruited. Multiple logistic regression analysis was used to assess the relationship between relative deprivation and suicide, with depression as a potential mediator. RESULTS: Young people who experienced relative deprivation were at a greater risk of suicide and depression. Depression plays a mediating role in the relationship between relative deprivation and suicide. LIMITATIONS: Due to the limitations of the data, we cannot know whether there is mutual causation between relative deprivation and depression. The self-reported relative deprivation may also produce some influence on the results. CONCLUSIONS: The current findings demonstrate the importance of relative deprivation as one of the four sources of psychological strain to explain how relative status is associated with suicide. The findings also can be translated into the clinical and preventive practice for suicide.

Evaluation of an EZH2 inhibitor in patient-derived orthotopic xenograft models of pediatric brain tumors alone and in combination with chemo- and radiation therapies.

Brain tumors are the leading cause of cancer-related death in children. Tazemetostat is an FDA-approved enhancer of zeste homolog (EZH2) inhibitor. To determine its role in difficult-to-treat pediatric brain tumors, we examined EZH2 levels in a panel of 22 PDOX models and confirmed EZH2 mRNA over-expression in 9 GBM (34.6 ± 12.7-fold) and 11 medulloblastoma models (6.2 ± 1.7 in group 3, 6.0 ± 2.4 in group 4) accompanied by elevated H3K27me3 expression. Therapeutic efficacy was evaluated in 4 models (1 GBM, 2 medulloblastomas and 1 ATRT) via systematically administered tazemetostat (250 and 400 mg/kg, gavaged, twice daily) alone and in combination with cisplatin (5 mg/kg, i.p., twice) and/or radiation (2 Gy/day × 5 days). Compared with the untreated controls, tazemetostat significantly (Pcorrected < 0.05) prolonged survival times in IC-L1115ATRT (101% at 400 mg/kg) and IC-2305GBM (32% at 250 mg/kg, 45% at 400 mg/kg) in a dose-dependent manner. The addition of tazemetostat with radiation was evaluated in 3 models, with only one [IC-1078MB (group 4)] showing a substantial, though not statistically significant, prolongation in survival compared to radiation treatment alone. Combining tazemetostat (250 mg/kg) with cisplatin was not superior to cisplatin alone in any model. Analysis of in vivo drug resistance detected predominance of EZH2-negative cells in the remnant PDOX tumors accompanied by decreased H3K27me2 and H3K27me3 expressions. These data supported the use of tazemetostat in a subset of pediatric brain tumors and suggests that EZH2-negative tumor cells may have caused therapy resistance and should be prioritized for the search of new therapeutic targets.

The role of the extension region on the structural and physicochemical characteristics of the α-subunit of ß-conglycinin: implications of pH value and ionic strength.

BACKGROUND: To clarify the role of the extension region on the structure-functional relationship of the α-subunit of ß-conglycinin, α-subunit and its segment of the core region (αc-subunit) were expressed via an Escherichia coli system. Their physicochemical properties were compared under acid, neutral or alkaline conditions (pH 4.0, 7.0, and 8.0) and high or low ionic strength (µ = 0.05 and 0.5), respectively. RESULTS: The results showed that the extension region contributed to increasing thermal stability, especially at low ionic strength under acidic and neutral conditions. The extension region stabilized the α-subunit with high solubility, low turbidity, and small particle size under neutral and alkaline conditions, whereas these impacts were suppressed at a high ionic strength and acidic conditions. Surface hydrophobicity of the α-subunit decreased under acidic and alkaline conditions without being interfered with by ionic strength. CONCLUSION: It can be concluded that the extension region played different roles under different pH and ionic strength conditions. These factors should be specified carefully and speculated individually to explore the more detailed and profound nature of ß-conglycinin at the submolecular level. The results could benefit a better understanding of the relationship between domain structure and functions of soybean protein. © 2022 Society of Chemical Industry.

One-pot conversion of wheat straw into biobased chemicals in methanol/water medium using cheap mixed acid catalyst.

BACKGROUND: Environmental concerns and the diminishing availability of unrenewable resources have spurred research into the use of agricultural waste as a feedstock for industrial applications. Efficient conversion of wheat straw into biobased chemicals is an important way to realize the potential value of renewable agricultural biomass. This study investigated one-pot conversion of wheat straw into two notable platform chemicals, levulinic acid (LA) and methyl levulinate (ML). RESULTS: A mixed acid catalyst system, including 1% H2 SO4 and 0.015 mol L-1 Al2 (SO4 )3 , was an efficient catalyst for the conversion of wheat straw due to the combination of Brønsted acid and Lewis acid. A ratio of wheat straw to methanol of 5 g/50 mL was identified as the preferred solid/liquid ratio, and a methanol/H2 O medium with 25% water content aided the simultaneous production of LA and ML from wheat straw. Under optimum conditions, the maximum total yield of LA and ML reached 23.01% at 220 °C and 3 h. The kinetics of biobased chemical formation and the reaction pathways in methanol/water were investigated. CONCLUSION: The presence of water in the methanol/H2 O medium affected the distribution of products and promoted hydrolysis reactions. The methanol/H2 O medium not only inhibited the side reactions but also promoted the degradation of wheat straw and increased the total yield of LA and ML. This study provides a feasible method for the conversion of wheat straw to prepare biobased chemicals. © 2021 Society of Chemical Industry.

Religion, Psychological Strain, and Suicidality in China: A Preliminary Study.

BACKGROUND: There is a lack of religiosity studies in China especially in relation to mental health and suicidality. In this research, we focus our studies on medical workers of which some studies reported to have higher stress, and to pilot our studies in this adult age-group. DATA AND METHODOLOGY: Data were obtained by a questionnaire survey in a large public hospital in a big metropolitan city of China. The final sample consisted of 1012 respondents with 237 (23.4%) being male and 775 (76.6%) being female. The respondents were of three groups: (1) Believers (n = 34; 3.5%); (2) Non-Believers or Atheists (n = 547; 55.8%); and (3) Agnostics or Fence-Sitters (n = 400; 40.8%). Suicidality was measured by the NCS-Suicidality Scale, and standard measures were employed for other major variables. FINDINGS: In line with other recent studies in China, the religion rate among the urban adults remained low (3.5%). However, about 40.8% of the respondents chose "don't know" and could be fence-sitters on the issue of religious belief. Many of them are involved in various folk beliefs which may not be considered as religious. The religious believers were at higher risk of suicidality and depression than the atheists and the fence-sitters. However, the fence-sitters were higher than the believers and atheists on psychological strains, and they were higher on depression compared to the atheists. CONCLUSION: The religious believers and religious fence-sitters have higher psychopathologic risks and suicidal risk than the atheist group. Religion as of low prevalence in Chinese societies is a social value deviant from the norm and its practitioners are likely to be marginalized or stigmatized. The Strain Theory of Suicide is used for detailed explanations.

Feeling matters: perceived social support moderates the relationship between personal relative deprivation and depressive symptoms.

BACKGROUND: Little research describes the mechanisms underlying depressive symptoms and personal relative deprivation in Chinese populations. METHODS: In this study, the respondents were (N = 914) residents of Beijing (17-59 years old) and robust multiple linear regressions were used to assess the main relationship between relative deprivation and depressive symptoms and social support as a potential moderator for that relationship. RESULTS: Individuals who reported higher personal relative deprivation had greater depressive symptoms than those who reported lower personal relative deprivation. Perceived social support buffered the relationship between depressive symptoms and personal relative deprivation. CONCLUSIONS: The findings of this current study demonstrate the importance of relative deprivation for psychological strain and income in explaining how socioeconomic indices correlate with depressive symptoms. They also demonstrate the need to acknowledge the interaction of perceived social support and personal relative deprivation for influencing depression.

Ependymoma Presenting as a -Rim-Enhancing Lesion in the Brainstem.

INTRODUCTION: The posterior fossa is the most common intracranial location for pediatric ependymoma. While ependymoma usually arises from the ventricular lining of the fourth ventricle as a solid mass, it rarely originates from the brainstem. Grade II ependymomas also infrequently appear as a cavitary ring-enhancing lesion. CASE PRESENTATION: We describe a case of a 6-year-old boy with an ependymoma arising within the medulla with imaging features of a thick-walled rim-enhancing cavitary lesion. A stereotactic biopsy was obtained which confirmed a grade II ependymoma. The patient received focal proton beam radiation therapy and is doing well with no concerns for disease progression at 28 months after diagnosis. CONCLUSION: Posterior fossa ependymomas typically arise from ependymal cells within the fourth ventricle or foramina of Luschka. They rarely invade or arise within the brainstem parenchyma. Our case had atypical imaging findings in addition to the atypical tumor location. The lesion was described as a thick-walled rim-enhancing focal cystic necrotic lesion centered within the medulla with surrounding nonenhancing expansile infiltrative changes. Ring-enhancing lesions can be seen in patients with anaplastic ependymoma, but is not commonly reported in grade II ependymomas. In summary, this report highlights a unique case of a posterior fossa ependymoma in a pediatric patient arising in an atypical brainstem location as well as having unique imaging features.

Displacement Induced Off-On Fluorescent Biosensor Targeting IDO1 Activity in Live Cells.

We show how the macrocyclic host cucurbit[8]uril (CB[8]) and a fluorescent dye form a biosensing ensemble while its cavity simultaneously traps tryptophan, the upstream substrate of IDO1 enzymes, therefore providing a label-free method to monitor the activity of IDO1 in real time. Incubation of malignant HeLa and HepG2 cells overexpressing IDO1 with the associative biosensor resulted in its spontaneous uptake and a fluorescence switch-on response in situ, which can be traced to the displacement of tryptophan from CB[8] upon IDO1-catalyzed oxidation. The results, for the first time, establish a supramolecular sensing concept for the detection of intracellular enzymatic activity in live cells, thus allowing direct cell-based analysis and inhibitor screening compatible with commercial instruments including microplate reader, fluorescent microscopy, and flow cytometry.

Variability of blood eosinophils in patients in a clinic for severe asthma.

BACKGROUND: Blood eosinophils are used to determine eligibility for agents targeting IL-5 in patients with uncontrolled asthma. However, little is known about the variability of blood eosinophil measures in these patients before treatment initiation. OBJECTIVE: To characterize variability and patterns of variability of blood eosinophil levels in a real-world clinic for severe asthmatics. METHODS: Retrospective review of blood eosinophils measured over a 5-year period in patients enrolled in an urban clinic. Repeated measures of blood eosinophil levels in individuals were evaluated, and cluster analysis was performed to characterize patients by eosinophil patterns. Clinical characteristics associated with eosinophil levels and patterns of variability were analysed. RESULTS: Patients treated in the Bellevue Hospital Asthma Clinic within a 3-month period were identified (n = 219). Blood eosinophil measures were obtained over the previous 5 years. Only 6% (n = 13) of patients had levels that were consistently above 300 cells/µL. Nearly 50% (n = 104) had eosinophil levels that traversed the threshold of 300 cells/µL. In contrast, 102 (46%) had levels that never reached the threshold of 300 cells/µL. Cluster analyses revealed three clusters with differing patterns of levels and variability. There was a suggestion of decreased clinical control and increased atopy in the cluster with the greatest variability in blood eosinophil measures. CONCLUSION: In an urban clinic for patients referred for uncontrolled asthma, blood measures of eosinophils were variable and showed differing patterns of variability. These data reinforce the need to perform repeated eosinophil blood measures for appropriate designation for therapeutic intervention.

Impulsivity Kills Some Who Did Not Plan to Die by Suicide: Evidence From Chinese Rural Youths.

This study aimed to compare the mental disorders, psychological factors, and suicidal intent between high- and low-impulsivity Chinese rural young suicides. Rural young women and men aged 15 to 34 years who died by suicide and various risk factors were examined. The data were obtained using psychological autopsy method with instruments as Dysfunctional Impulsivity Scale, the Structured Clinical Interview for DSM-III-R, Beck Hopeless Scale, Social Support Index, Coping Response Inventory, Hamilton Depression Rating Scale, and Beck Suicide Intent Scale. Compared with low-impulsivity suicides, the high-impulsivity suicides were younger, had less mental disorders, owned less social support, scored lower on approach coping and higher on avoidance coping, and scored a lower score on the Suicide Intent Scale. Characteristics of high-impulsivity suicides differed significantly from low-impulsivity suicides in rural China. It was important to develop different prevention and intervention strategies to reduce the suicide rate in China.

Cost-effectiveness and Improved Parent and Provider Satisfaction With Outpatient Management of Pediatric Oncology Patients, With Low-risk Fever and Neutropenia.

On the basis of significant evidence for safety, the international pediatric fever and neutropenia committee recommends the identification and management of patients with "low-risk fever and neutropenia" (LRFN), outpatient with oral antibiotics, instead of traditional inpatient management. The aim of our study was to compare the cost-per-patient with these 2 strategies, and to evaluate parent and provider satisfaction with the outpatient management of LRFN. Between March 2016 and February 2017, 17 LRFN patients (median absolute neutrophil count, 90/µL) were managed at a single institution, per new guidelines. Fifteen patients were discharged on presentation or at 24 to 48 hours postadmission on oral levofloxacin, and 2 were inadvertently admitted off protocol. The mean cost of management for the postimplementation cohort was compared with a historic preimplementation control group. Satisfaction surveys were completed by parents and health care providers of LRFN patients. The mean total cost of an LRFN episode was $12,500 per patient preimplementation and $6168 postimplementation, a decrease of $6332 (51%) per patient. All parents surveyed found outpatient follow-up easy; most (12/14) parents and all (16/16) providers preferred outpatient management. Outpatient management of LRFN patients was less costly, and was preferred by a majority of parents and all health care providers, compared with traditional inpatient management.

The Association Between Depression, Suicidal Ideation and Psychological Strains in College Students: A Cross-National Study.

OBJECTIVE: This study examined the differences of psychological strains between Chinese and American college students and discussed how strains may influence individuals' suicidal ideation and depression. PARTICIPANTS/METHODS: A total of 539 college students (298 from China and 241 from the U.S.) were recruited in March 2016 to complete the survey study. Multiple linear regressions were used in data analysis. RESULTS: Students in America had higher scores on depression and stress than students in China, while students in China rated higher on suicidal ideation than students in America. In contrast of students in America facing more coping strains, students in China were confronting more value strains in their life. CONCLUSION: The cross-cultural variations in the effect of psychological strains have been substantiated in current study, indicating that understanding the psychological strains in different cultural contexts is necessary for the early intervention and prevention in college aged populations.

Correction to: The Association Between Depression, Suicidal Ideation and Psychological Strains in College Students: A Cross-National Study.

The original version of the article unfortunately contained an error in acknowledgement section. The corrected acknowledgement is: This research was supported by a grant of Beijing Natural Science Foundation (9174046), for which the first author is PI.

Preservation of KIT genotype in a novel pair of patient-derived orthotopic xenograft mouse models of metastatic pediatric CNS germinoma.

Metastatic intracranial germinoma is difficult to treat. Although the proto-oncogene KIT is recognized as one of the most frequent genetic abnormalities in CNS germinoma, the development of new target therapeutic agents for CNS germinoma is hampered by the lack of clinically-relevant animal models that replicate the mutated or over-expressed KIT. CNS germinoma tumor cells from five pediatric patients were directly implanted into the brains of Rag2/severe combined immune deficiency mice. Once established, the xenograft tumors were sub-transplanted in vivo in mouse brains. Characterization of xenograft tumors were performed through histologic and immunohistochemical staining, and KIT mutation analysed with quantitative pyro-sequencing. Expression of putative cancer stem cell markers (CD133, CD15, CD24, CD44, CD49f) was analyzed through flow cytometry. Two patient-derived orthotopic xenograft (PDOX) models (IC-6999GCT and IC-9302GCT) were established from metastatic germinoma and serially sub-transplanted five times in mouse brains. Similar to the original patient tumors, they both exhibited faint expression (+) of PLAP, no expression (-) of ß-HCG and strong (+++) expression of KIT. KIT mutation (D816H), however, was only found in IC-9320GCT. This mutation was maintained during the five in vivo tumor passages with an increased mutant allele frequency compared to the patient tumor. Expression of putative cancer stem cell markers CD49f and CD15 was also detected in a small population of tumor cells in both models. This new pair of PDOX models replicated the key biological features of pediatric intracranial germinoma and should facilitate the biological and pre-clinical studies for metastatic intracranial germinomas.

Improvement in severe lower respiratory symptoms and small airway function in World Trade Center dust exposed community members.

OBJECTIVE: Longitudinal assessment of lower respiratory symptoms (LRS) in community members with World Trade Center (WTC) exposures. METHODS: Adult members of a treatment program with complete standardized visits were evaluated (n = 798). Association of demographic characteristics, mental health symptoms and lung function with trajectory of LRS between initial and monitoring visit was evaluated. RESULTS: Severe LRS were present in 70% at initial and 63% at monitoring visit. Initial severe LRS were associated with WTC dust cloud exposure and mental health symptoms. Spirometry measures were not associated with LRS severity or trajectory; improvement in LRS was associated with improved lung function measured with forced oscillometry techniques. CONCLUSION: Many community patients in a WTC treatment program had severe LRS associated with exposures and mental health symptoms. Improvement in LRS was associated with improvement in measures of small airway function. Am. J. Ind. Med. 59:777-787, 2016. © 2016 Wiley Periodicals, Inc.

Salsolinol Damaged Neuroblastoma SH-SY5Y Cells Induce Proliferation of Human Monocyte THP-1 Cells Through the mTOR Pathway in a Co-culture System.

Despite extensive efforts to study the inflammatory process in the central nervous system of Parkinson's disease (PD) patients, little is known about the role of peripheral blood mononuclear cells (PBMCs) in PD. In the present study, we used an in vitro co-culture system to study the role of the human monocyte cell line THP-1 in medium conditioned by the neuroblastoma cell line SH-SY5Y damaged with the endogenous neurotoxin 1-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline (Salsolinol, Sal) in co-culture with the human glioma cell line U87. For this purpose, SH-SY5Y and U87 co-cultures were treated with Sal, and this conditioned medium containing mediators, including the potential effector CCL2, was isolated and applied to THP-1 cells. This treatment resulted in approximately 19 % cell proliferation as well as activation of mTOR and induction of phosphorylated 4E-BP1, S6K1, PI3K, and AKT proteins. Treatment with rapamycin, an mTOR inhibitor, attenuated the proliferation of THP-1 cells. U87 glial cells were essential for this as medium conditioned without them had no effect on THP-1 cells. These results suggest a positive effect of THP-1 cells on Sal-induced neurotoxicity in a cellular model of PD and this is likely mediated by the enhancement of cell proliferation through activation of the mTOR signaling pathway. Hence, PBMCs and their mTOR signaling pathway could be of therapeutic benefit in treating the endogenous neurotoxin-induced neuroinflammation in PD.

Intranasal Delivery of circATF7IP siRNA via Lipid Nanoparticles Alleviates LPS-induced Depressive-Like Behaviors.

Major depressive disorder (MDD) is a prevalent mental disorder that significantly impacts social and psychological function, but no effective medication is currently available. Circular RNAs (circRNAs) have been reported to participate in the pathogenesis of MDD which are envisioned as promising therapeutic targets. However, nonviral-based delivery strategies targeting circRNA against MDD are not thoroughly investigated. Here, it is identified that circATF7IP is significantly upregulated in plasma samples and positively correlated with 24-Hamilton Depression Scale (HAMD-24) scores of MDD patients. Synergistic amine lipid nanoparticles (SALNPs) are designed to deliver siRNA targeting circATF7IP (si-circATF7IP) into the hippocampus brain region by intranasal administration. Intranasal delivery of SALNP-si-circATF7IP successfully alleviated the depressive-like behaviors in the LPS-induced mouse depression model via decreasing CD11b+CD45dim microglia population and pro-inflammatory cytokine productions (TNF-α and IL-6). These results indicate that the level of circATF7IP positively correlates with MDD pathogenesis, and SALNP delivery of si-circATF7IP via intranasal administration is an effective strategy to ameliorate LPS-induced depressive-like behaviors.

Direct Implantation of Patient Brain Tumor Cells into Matching Locations in Mouse Brains for Patient-Derived Orthotopic Xenograft Model Development.

Background: Despite multimodality therapies, the prognosis of patients with malignant brain tumors remains extremely poor. One of the major obstacles that hinders development of effective therapies is the limited availability of clinically relevant and biologically accurate (CRBA) mouse models. Methods: We have developed a freehand surgical technique that allows for rapid and safe injection of fresh human brain tumor specimens directly into the matching locations (cerebrum, cerebellum, or brainstem) in the brains of SCID mice. Results: Using this technique, we successfully developed 188 PDOX models from 408 brain tumor patient samples (both high-and low-grade) with a success rate of 72.3% in high-grade glioma, 64.2% in medulloblastoma, 50% in ATRT, 33.8% in ependymoma, and 11.6% in low-grade gliomas. Detailed characterization confirmed their replication of the histopathological and genetic abnormalities of the original patient tumors. Conclusions: The protocol is easy to follow, without a sterotactic frame, in order to generate large cohorts of tumor-bearing mice to meet the needs of biological studies and preclinical drug testing.