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Background: Approximately 7% of the males exhibit reduced fertility; however, the regulatory genes and pathways involved remain largely unknown. TBC1 domain family member 21 (TBC1D21) contains a conserved RabGAP catalytic domain that induces GDP/GTP exchange to inactivate Rabs by interacting with microtubules. We previously reported that Tbc1d21-null mice exhibit severe sperm tail defects with a disrupted axoneme, and that TBC1D21 interacts with RAB10. However, the pathological mechanisms underlying the Tbc1d21 loss-induced sperm tail defects remain unknown., Results: Murine sperm from wild-type and Tbc1d21-null mice were comparatively analyzed using proteomic assays. Over 1600 proteins were identified, of which 15 were significantly up-regulated in Tbc1d21-null sperm. Notably, several tektin (TEKT) family proteins, belonging to a type of intermediate filament critical for stabilizing the microtubular structure of cilia and flagella, were significantly up-regulated in Tbc1d21 -/- sperm. We also found that TBC1D21 interacts with TEKT1. In addition, TEKT1 co-localized with RAB10 during sperm tail formation. Finally, we found Tbc1d21-null sperm exhibited abnormal accumulation of TEKT1 in the midpiece region, accompanied by disrupted axonemal structures., Conclusions: These results reveal that TBC1D21 modulates TEKTs protein localization in the axonemal transport system during sperm tail formation., (© 2024 American Association for Anatomy.)

The aims of our study were to examine whether initial or subsequent adiposity status had a greater effect on hypertension. We collected data in 1992 and again in 2007 from the same group of 597 individuals in the middle age. The subjects were classified into four groups: individuals with a normal body mass index (BMI) in 1992 and 2007 were in Group I; those with a normal BMI in 1992, but became overweight or obese in 2007 were in Group II; those who were overweight or obese in 1992, but had a normal BMI in 2007 were in Group III; and those who were overweight or obese in 1992 and 2007 were in Group IV. Their demographic data were recorded. The relationship between adiposity status and hypertension was analyzed using logistic regression model. The cumulative incidence of hypertension was 35.5%, 56.3%, 50.0%, and 65.1% for Group I to IV, respectively. Compared with Group I, after adjusted factors, the hazard ratio (HR) was 1.80 for Group II (P = .001), 1.40 for Group III (P = .150), and 2.31 for Group IV (P < .001). Adiposity status in 2007 could predict hypertension (OR = 2.5, P < .001), as opposed to the initial adiposity status (P = .148). Subsequently adiposity status could have major effects on hypertension. Our society is very short of public health resources, particularly in developing countries, we should pay more attention to current adiposity status and encourage middle-aged people to lose weight., (© 2024 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

The therapeutic efficacy of peptide-based drugs is commonly hampered by the intrinsic propensity to aggregation. A notable example is human calcitonin (hCT), a peptide hormone comprising 32 amino acids, which is synthesized and secreted by thyroid gland parafollicular cells (C cells). This hormone plays a vital role in regulating blood calcium levels and upholding bone integrity. Despite its physiological importance, utilizing hCT as a drug is hampered by its inclination to form amyloid. To address this limitation, an alternative is provided by salmon calcitonin (sCT), which possesses a lower aggregation propensity. Although sharing the same disulfide bond at the N terminus as hCT, sCT differs from hCT at a total of 16 amino acid positions. However, due to the dissimilarity in sequences, using sCT as a clinical replacement occasionally results in adverse side effects in patients. Earlier investigations have highlighted the significant roles of Tyr-12 and Asn-17 in inducing the formation of amyloid fibrils. By introducing double mutations at these sites, the ability to hinder aggregation can be significantly augmented. This study delves into the oligomerization and helical structure formation of the hCT double mutant (Y12LN17H hCT, noted as DM hCT), as well as two single mutants (Y12L and N17H), aiming to elucidate the mechanism behind hCT fibrillization. In addition, computational prediction tools were employed again to identify potential substitutes. Although the results yielded were not entirely satisfactory, a comparison between the newly examined and previously found hCT double mutants provides insights into the reduced aggregation propensity of the latter. This research endeavor holds the promise of informing the design of more effective therapeutic peptide drugs in the future., (© 2024 The Protein Society.)

Objective: Irritability in children with autism spectrum disorder (ASD) is prominent and often leads to distress to both autistic children and their families. However, the nature of irritability in autism and the difference from nonautistic children have rarely been examined. This study aimed to investigate the clinical characteristics of irritability in autism, and to compare the symptom profiles with those of disruptive mood dysregulation disorder (DMDD) in nonautistic children. Methods: Fifty-six children aged 7-17 years (mean age 10.36 ± 3.05) were recruited into this study (21 with DMDD, 21 with high-functioning autism [hfASD], and 14 healthy volunteers [HV]). Their parents completed the Aberrant Behavior Checklist-Irritability (ABC-I) subscale and the Strengths and Difficulties Questionnaire (SDQ) parent report form. The ABC-I subscale was analyzed as a whole and broken into subsets (ABC-I-Irritability, ABC-I-Agitation, and ABC-I-Crying). The symptom profiles of irritability and the association with psychosocial difficulties were compared between groups. Results: The ABC-I-Irritability scores of children with hfASD closely matched to those of children with DMDD. In addition, both DMDD and hfASD groups could be differentiated from HV group in five of the six items except "depressed mood." However, in the ABC-I-Agitation scale, children with DMDD, but not hfASD, had higher scores in "Aggressive to other patients and staff" and "Stamps feet while banging objects or slamming doors" than HV. Regarding psychosocial outcomes, irritability in children with DMDD and hfASD were associated with emotional problems as measured by the SDQ. Moreover, irritability in DMDD was associated with conduct problems, and the hfASD group exhibited the similar trend. Conclusions: Symptom profiles of irritability and the associated emotional and conduct problems in children with hfASD were similar to those of DMDD in the nonautistic population. Future studies are warranted to explore the underlying neurophysiological mechanisms of irritability between autistic and nonautistic children for further insight into the nature of irritability in autism.

The development of nanomedicines that combine photothermal therapy (PTT) with photodynamic therapy (PDT) is considered promising for cancer treatment, but still faces the challenge of enhancing tumoricidal efficiency. Fortunately, apart from the well-acknowledged effect on direct tumor cell-killing, nitric oxide (NO) is also considered to be effective for the enhancement of both PTT and PDT. However, both the low loading efficiency of NO precursor and the short half-life time and diffusion distance of NO hamper the synergistic therapeutic efficacy of NO. Taking the aforementioned factors into account, a mitochondria-targeted nitric oxide nanogenerator, EArgFe@Ce6, is constructed to achieve high loading of the NO donor l-Arginine (l-Arg) for synergistic photodynamic/gas/photothermal therapy upon single 660 nm light irradiation. The coordination of epigallocatechin gallate (EGCG) and ferric ions (Fe 3+ ) provides EArgFe@Ce6 supreme photothermal capability to perform low-temperature PTT (mPTT). EGCG endows EArgFe@Ce6 with mitochondria-targeting capability and meanwhile favors hypoxia alleviation for enhanced PDT. The PDT-produced massive reactive oxygen species (ROS) further catalyzes l-Arg to generate a considerable amount of NO to perform gas therapy and sensitize both mPTT and PDT. In vitro and in vivo studies demonstrate that the synergistic photodynamic/gas/photothermal therapy triggered by single 660 nm light irradiation is highly effective for tumor treatments., (© 2023 Wiley-VCH GmbH.)

Natural living materials serving as biotherapeutics exhibit great potential for treating various diseases owing to their immunoactivity, tissue targeting, and other biological activities. In this review, the recent developments in engineered living materials, including mammalian cells, bacteria, viruses, fungi, microalgae, plants, and their active derivatives that are used for treating various diseases are summarized. Further, the future perspectives and challenges of such engineered living material-based biotherapeutics are discussed to provide considerations for future advances in biomedical applications., (© 2023 Wiley-VCH GmbH.)

To overcome the limitations of doxorubicin (DOX) chemotherapy, nanomedicines that integrate additional photothermal therapy (PTT) and chemodynamic therapy (CDT) strategies are highlighted as promising alternatives for the treatment of malignant tumors. However, time-consuming preparation processes, biosafety concerns, and the bottlenecks of individual therapeutic modalities often limit the practical applications of this strategy. To address these issues, this work designs an oxygen economizer that additionally serves as a Fenton reaction amplifier through the simple assembly of epigallocatechin gallate (EGCG), pluronic F-127 (PF127), iron (III) ions, and doxorubicin (DOX) for the enhancement of synergistic PTT/CDT/chemotherapy. The resulting nanoformulation, EFPD, can target mitochondria and inhibit cell respiration to reduce O 2 consumption, thus boosting DOX-mediated H 2 O 2 generation for enhanced CDT and simultaneously improving hypoxia-limited DOX chemotherapy efficacy. Moreover, the coordination between EGCG and Fe 3+ provides EFPD with excellent photothermal conversion efficiencies (η = 34.7%) for PTT and photothermal-accelerated drug release. Experimental results indicate that EFPD-mediated synergistic enhancement of PTT/CDT/chemotherapy can achieve excellent therapeutic outcomes, including enhanced ablation of solid tumors, reduced metastasis and cardiotoxicity, and extended life spans., (© 2023 Wiley-VCH GmbH.)

Background: The novel coronavirus disease 2019 (COVID-19) has affected a large number of countries. Informing the public and decision makers of the COVID-19's economic burdens is essential for understanding the real pandemic impact., Methods: COVID-19 premature mortality and disability impact in Taiwan was analyzed using the Taiwan National Infectious Disease Statistics System (TNIDSS) by estimating the sex/age-specific years of life lost through death (YLLs), the number of years lived with disability (YLDs), and the disability-adjusted life years (DALYs) from January 2020 to November 2021., Results: Taiwan recorded 1004.13 DALYs (95% CI: 1002.75-1005.61) per 100,000 population for COVID-19, with YLLs accounting for 99.5% (95% CI: 99.3%99.6%) of all DALYs, with males suffering more from the disease than females. For population aged ≥ 70 years, the disease burdens of YLDs and YLLs were 0.1% and 99.9%, respectively. Furthermore, we found that duration of disease in critical state contributed 63.9% of the variance in DALY estimations., Conclusions: The nationwide estimation of DALYs in Taiwan provides insights into the demographic distributions and key epidemiological parameter for DALYs. The essentiality of enforcing protective precautions when needed is also implicated. The higher YLLs percentage in DALYs also revealed the fact of high confirmed death rates in Taiwan. To reduce infection risks and disease, it is crucial to maintain moderate social distancing, border control, hygiene measures, and increase vaccine coverage levels., Competing Interests: Declaration of Competing Interest The authors have declared that no competing interest exists., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Autism spectrum condition and attention-deficit/hyperactivity disorder (ADHD) are associated with a range of physical health conditions. The aim of this study was to examine the etiological components contributing to co-occurring physical health conditions in autism and ADHD., Methods: In this nationwide Child and Adolescent Twin Study in Sweden, we analyzed data from 10,347 twin pairs aged 9 and 12. Clinical diagnoses of autism, ADHD, and physical health conditions were identified through the Swedish National Patient Register. Subclinical phenotypes of autism and ADHD were defined by symptom thresholds on a standardized parent-interview, the Autism-Tics, ADHD, and Other Comorbidities inventory. Associations between physical health conditions and autism/ADHD phenotypes were examined using generalized estimating equations. Bivariate twin models were applied to estimate the extent to which genetic and environmental risk factors accounted for physical health comorbidities., Results: Similar patterns of association with physical health conditions were found in clinical and subclinical autism/ADHD, with odds ratios ranging from 1.31 for asthma in subclinical ADHD to 8.03 for epilepsy in clinical autism. The estimated genetic correlation (r a ) with epilepsy was 0.50 for clinical autism and 0.35 for subclinical autism. In addition, a modest genetic correlation was estimated between clinical autism and constipation (r a  = 0.31), functional diarrhea (r a  = 0.27) as well as mixed gastrointestinal disorders (r a  = 0.30). Genetic effects contributed 0.86 for mixed gastrointestinal disorders in clinical ADHD (r a  = 0.21). Finally, subclinical ADHD shared genetic risk factors with epilepsy, constipation, and mixed gastrointestinal disorders (r a  = 0.30, 0.17, and 0.17, respectively)., Limitations: Importantly, since medical records from primary care were not included in the registry data used, we probably identified only more severe rather than the full range of physical health conditions. Furthermore, it needs to be considered that the higher prevalence of physical health conditions among autistic children and children with ADHD could be associated with the increased number of medical visits., Conclusions: Shared genetic effects contribute significantly to autism and ADHD phenotypes with the co-occurring physical health conditions across different organ systems, including epilepsy and gastrointestinal disorders. The shared genetic liability with co-occurring physical health conditions was present across different levels of autism and ADHD symptom severity., (© 2023. The Author(s).)

Due to the complexity and heterogeneity in the tumor microenvironment, the efficacy of breast cancer treatment has been significantly impeded. Here, we established a living system using an engineered M13 bacteriophage through chemical cross-linking and biomineralization to remodel the tumor microenvironment. Chemically cross-linking of the engineered bacteriophage gel (M13 Gel) could in situ synthesize photothermal palladium nanoparticles (PdNPs) on the pVIII capsid protein to obtain M13@Pd Gel. In addition, NLG919 was further loaded into a gel to form (M13@Pd/NLG gel) for down-regulating the expression of tryptophan metabolic enzyme indoleamine 2,3-dioxygenase 1 (IDO1). Both in vitro and in vivo studies showed that the M13 bacteriophage served not only as a cargo-loaded device but also as a self-immune adjuvant, which induced the immunogenic death of tumor cells effectively and down-regulated IDO1 expression. Such a bioactive gel system constructed by natural living materials could reverse immunosuppression and significantly improve the anti-breast cancer response.

Ligand-targeting drug delivery systems have made significant strides for disease treatments with numerous clinical approvals in this era of precision medicine. Herein, we report a class of small molecule-based immune checkpoint-targeting maytansinoid conjugates. From the ligand targeting ability, pharmacokinetics profiling, in vivo anti-pancreatic cancer, triple-negative breast cancer, and sorafenib-resistant liver cancer efficacies with quantitative mRNA analysis of treated-tumor tissues, we demonstrated that conjugate 40a not only induced lasting regression of tumor growth, but it also rejuvenated the once immunosuppressive tumor microenvironment to an "inflamed hot tumor" with significant elevation of gene expressions that were not accessible in the vehicle-treated tumor. In turn, the immune checkpoint-targeting small molecule drug conjugate from this work represents a new pharmacodelivery strategy that can be expanded with combination therapy with existing immune-oncology treatment options.

Although cancer vaccines exhibit great advances in the field of immunotherapy, developing an efficient vaccine platform for personalized tumor immunotherapy is still a major challenge. Here we demonstrate that a bioactive vaccine platform (HMP@Ag) fabricated with hybrid M13 phage and personal tumor antigens can facilitate delivery of antigens into lymph nodes and activate antigen-presenting cells (APCs) through the Toll-like receptor 9 (TLR9) signaling pathway, which boosts both innate and adaptive immune response. As an adjuvant platform, hybrid M13 phages can deliver various tumor-specific antigens through simple adsorption to support the current development of personalized vaccines for cancers. Notably, the HMP@Ag vaccine not only prevented the tumors, but also delayed the tumor growth in established (subcutaneous and orthotopic) and metastatic tumor-bearing models while synergy with immune checkpoint blockade (ICB) therapy. Moreover, HMP@Ag triggered a robust neoantigen-based specific immune response in tumor-specific mutation models. In a clinically relevant surgery model, using autologous cell membrane from primary tumors-based HMP@Ag cooperation with ICB dramatically inhibited the post-operation recurrence, and elicited a long-term immune memory effect simultaneously. These findings imply that the M13 phage represents a powerful tool to develop a bio-activated hybrid platform for personalized therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Radiotherapy is adopted to obliterate multiple malignant tumors clinically, which might also induce antitumor immune response. However, traditional radiotherapy is not enough to ablate tumors and activate long-term immunological response. Here, we developed a hybrid nanoplatform (MGTe) composed of GTe (glutathione (GSH) decorated Te nanoparticles) and fusing tumor cell membranes (TM) and bacterial outer membranes (BM). In this nanoplatform, GTe was designed for radiotherapy sensitization, concurrently the fusion of TM and BM was expected for amplifying antitumor immune. With a high-Z element, MGTe could enhance radiosensitivity by reactive oxygen species (ROS) production and cancer cell immunogenic death (ICD) under X-ray irradiation, which would also trigger antitumor immune. At meanwhile, TM and BM would further enlarge the immunological effects through antigen presenting cells (APCs) maturation and cytotoxic T lymphocytes (CTLs) stimulation. In this synergistic strategy, the combination of MGTe and X-ray showed significant tumor inhibition by radiation-driven immunotherapy, which will find great potential as an attractive clinical alternative to fight against tumor with reduced side effects., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objectives: The myeloid-derived suppressor cells (MDSCs) frequently have a high expansion in cancer patients. This research explored whether administration of β-glucan could increase anti-tumor immunity in oral squamous cell carcinoma (OSCC) patients., Materials and Methods: This study evaluated the MDSC level of circulating blood as CD33 + /CD11b + /HLA-DR -/low by flow cytometry in 30 healthy donors (HDs, group I), in 48 oral squamous cell carcinoma (OSCC) patients before and after 14-day preoperative administration of β-glucan (group II), and in 52 OSCC patients without taking β-glucan (group III)., Results: A significantly higher mean MDSC level was observed in 100 OSCC patients than in 30 HDs (p < .001). There was a significant reduction of the mean MDSC level in group II patients after taking β-glucan (p < .001). Moreover, we discovered a significantly higher recurrence-free survival (RFS) in group II than in group III patients (p = .026). Finally, the multivariate Cox regression further identified the MDSC level ≤1% and administration of β-glucan as more favorable prognostic factors for OSCC patients., Conclusion: Preoperative administration of β-glucan can augment anti-tumor immunity and increase RFS rate via subversion of suppressive function of MDSC in OSCC patients., (© 2021 Wiley Periodicals LLC.)

We report the design, synthesis and evaluation of a class of phosphatidylserine-targeting zinc (II) dipicolylamine drug conjugates and show that conjugate 16b elicits immune cell infiltration and remodels the "cold" hepatic tumor microenvironment to the inflamed "hot" tumor. Structure-property relationship study via linker modifications and subsequent pharmacokinetics profiling were carried out to improve the solubility and stability of the conjugates in vivo. In a spontaneous hepatocellular carcinoma mouse model, we showed that conjugate 16b exhibited better antitumor efficacy than sorafenib. In particular, significant increase of CD8 + T cell infiltration and granzyme B level was observed, providing insights in sensitizing tumors from intrinsic immune suppressive microenvironment. Evaluation of tumor inflammation-related mRNA expression profile revealed that conjugate 16b, through inductions of key gene expressions including STAT1, CXCL9, CCL5, and PD-L1, rejuvenated tumor microenvironment with enhancement in T cell-, macrophage-, NK cell-, chemokines and cytokines'- functions. Our study establishes that an apoptosis-targeting theranostic enables enrichment of multifaceted immune cells into the tumor mass, which provides potential therapeutic strategies in the combination with immune checkpoint blockade treatment., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

miR-30b, which is encoded by the gene located on chromosome 8q24.22, plays an important role in a variety of diseases. In most types of tumors, miR-30b significantly inhibits the proliferation, migration, and invasion of cancer cells through the regulation of target genes. Moreover, miR-30b can inhibit the PI3K/AKT signaling pathway through the regulation of EGFR, AKT, Derlin-1, GNA13, SIX1, and other target genes, thus inhibiting the EMT process of tumor cells and promoting apoptosis. In addition, miR-30 plays a significant role in alleviating drug resistance in tumor cells. Although the use of miR-30b as a clinical diagnostic indicator or anticancer drug is still facing great difficulties in the short term, with the deepening of research, the potential application of miR-30b is emerging., Competing Interests: Conflict of interest: Authors state no conflict of interest., (© 2022 Zhen-Jie Fu et al., published by De Gruyter.)

Although highly heritable, environment also contributes to the etiology of autism spectrum disorder (ASD), with several specific environmental factors previously suggested. A registry-linked population-based twin cohort of 15,701 pairs (586 individuals with an ASD diagnosis), was established within the Child and Adolescent Twin Study in Sweden. Participants were evaluated for autistic symptoms at age 9 using the Autism-Tics, ADHD and other Comorbidities parental interview. A series of binary cut-offs indicated whether participants scored over various ASD symptom percentiles. Three early medical factors previously associated with ASD, beyond familial confounding (low birth weight, congenital malformations and perinatal hypoxia), were summed up creating an individual cumulative exposure load. A series of unconditional logistic regressions between all individuals and conditional regressions within twin pairs were performed for each outcome and exposure level. Between all individuals increasing cumulative early exposure loads were associated with increasing risk of ASD diagnosis (OR 3.33 (95%CI 1.79-6.20) for three exposures) and autistic symptoms (ranging from OR 2.12 (1.57-2.86) for three exposures at the 55th symptom percentile cut-off to OR 3.39 (2.2-5.24) at the 95th). Within twin pairs, the association between three exposures and an ASD diagnosis remained similar, but not statistically significant (OR 2.39 (0.62-9.24)). Having a higher load of early cumulative exposure was consistently associated with autistic symptoms after adjusting for familial confounding and sex (OR 3.45 (1.66-7.15) to OR 7.36 (1.99-27.18)). This study gives support to the cumulative stress hypothesis of ASD, and the dimensional model regarding environmental exposures, after adjustment for familial confounding., (© 2022. The Author(s).)

Radiotherapy is widely applied for multiple malignant tumors ablation in the clinic. However, redundant doses of X-rays might destroy normal tissue in the periphery of tumor sites. Here, we developed an integrated nanosystem (Bac@BNP) composed of engineered bacteria (Bac) and Bi 2 S 3 nanoparticles (BNPs) for sensitizing radiotherapy. Bac could target and colonize in tumor sites alternatively, which overexpressed cytolysin A (ClyA) protein to regulate the cell cycle from a radioresistant phase to a radiosensitive phase. Simultaneously, peptide-modified BNPs, as a radiosensitizer with a high-Z element, was released from the surface of Bac owing to the matrix metalloproteinase-2 (MMP-2) response in the tumor microenvironment. Under X-ray irradiation, BNPs could enhance the radiotherapy sensitivity by triggering the intracellular generation of reactive oxygen species (ROS), coupled with DNA damage. In this constructed nanosystem, the combination of Bac@BNP and X-ray irradiation led to significant suppression of breast carcinoma in murine models with reduced side effects.

Taking inspiration from percutaneous ethanol injection (PEI) for tumor ablation, an acetaldehyde generator (SC@ZIF@ADH) is constructed for tumor treatment by modifying a metal-organic framework nanocarrier (ZIF), which is loaded with alcohol dehydrogenase (ADH), onto the surface of Saccharomyces cerevisiae (SC). Oral administration of SC@ZIF@ADH can target tumor via mannose-mediated targeting to tumor associated macrophages (TAMs) and generate ethanol at the hypoxic tumor areas. Ethanol is subsequently catalyzed to toxic acetaldehyde by ADH, inducing tumor cells apoptosis and polarizing TAMs toward the anti-tumor phenotype. In vivo animal results show that this acetaldehyde generator can cause a temulence-like reaction in the tumor, significantly inhibiting tumor progression, and might provide an intelligent and nonsurgical substitute for PEI therapy., (© 2021 Wiley-VCH GmbH.)

There is mixed evidence on the association between headache and attention-deficit/hyperactivity disorder (ADHD), as well as headache and ADHD medications. This systematic review and meta-analysis investigated the co-occurrence of headache in children with ADHD, and the effects of ADHD medications on headache. Embase, Medline and PsycInfo were searched for population-based and clinical studies comparing the prevalence of headache in ADHD and controls through January 26, 2021. In addition, we updated the search of a previous systematic review and network meta-analysis of double-blind randomized controlled trials (RCTs) on ADHD medications on June 16, 2020. Trials of amphetamines, atomoxetine, bupropion, clonidine, guanfacine, methylphenidate, and modafinil with a placebo arm and reporting data on headache as an adverse event, were included. Thirteen epidemiological studies and 58 clinical trials were eligible for inclusion. In epidemiological studies, a significant association between headache and ADHD was found [odds ratio (OR) = 2.01, 95% confidence interval (CI) = 1.63-2.46], which remained significant when limited to studies reporting ORs adjusted for possible confounders. The pooled prevalence of headaches in children with ADHD was 26.6%. In RCTs, three ADHD medications were associated with increased headache during treatment periods, compared to placebo: atomoxetine (OR = 1.29, 95% CI = 1.06-1.56), guanfacine (OR = 1.43, 95% CI = 1.12-1.82), and methylphenidate (OR = 1.33, 95% CI = 1.09-1.63). The summarized evidence suggests that headache is common in children with ADHD, both as part of the clinical presentation as such and as a side effect of some standard medications. Monitoring and clinical management strategies of headache in ADHD, in general, and during pharmacological treatment are recommended.

Tyrosine kinase inhibitors of epidermal growth factor receptor (EGFR-TKIs) are currently used therapy for non-small cell lung cancer (NSCLC) patients; however, drug resistance during cancer treatment is a critical problem. Survivin is an anti-apoptosis protein, which promotes cell proliferation and tumor growth that highly expressed in various human cancers. Here, we show a novel synthetic compound derived from gefitinib, do-decyl-4-(4-(3-(4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)propyl) piper-azin-1-yl)-4-oxobutanoate, which is named as SP101 that inhibits survivin expression and tumor growth in both the EGFR-wild type and -T790M of NSCLC. SP101 blocked EGFR kinase activity and induced apoptosis in the A549 (EGFR-wild type) and H1975 (EGFR-T790M) lung cancer cells. SP101 reduced survivin proteins and increased active caspase 3 for inducing apoptosis. Ectopic expression of survivin by a survivin-expressed vector attenuated the SP101-induced cell death in lung cancer cells. Moreover, SP101 inhibited the gefitinib-resistant tumor growth in the xenograft human H1975 lung tumors of nude mice. SP101 substantially reduced survivin proteins but conversely elicited active caspase 3 proteins in tumor tissues. Besides, SP101 exerted anticancer abilities in the gefitinib resistant cancer cells separated from pleural effusion of a clinical lung cancer patient. Consistently, SP101 decreased the survivin proteins and the patient-derived xenografted lung tumor growth in nude mice. Anti-tumor ability of SP101 was also confirmed in the murine lung cancer model harboring EGFR T790M-L858R. Together, SP101 is a new EGFR inhibitor with inhibiting survivin that can be developed for treating EGFR wild-type and EGFR-mutational gefitinib-resistance in human lung cancers., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Our previous study proved that Shen Qi Li Xin formula (SQLXF) improved the heart function of chronic heart failure (CHF) patients, while the action mechanism remains unclear., Methods: H&E staining and TUNEL staining were performed to measure myocardial damages. Western blot was used to examine the expression of proteins. Moreover, CCK-8 assay and flow cytometry were used to measure cell viability and cell apoptosis, respectively. Concentrations of ATP and ROS in cells, and mitochondrial membrane potential (MMP) were detected to estimate oxidative stress., Results: In vivo, we found that SQLXF improved cardiac hemodynamic parameters, reduced LDH, CK-MB and BNP production, and attenuated myocardial damages in CHF rats. Besides, SQLXF promoted mitochondrial fusion-related proteins expression and inhibited fission-related proteins expression in CHF rats and oxygen glucose deprivation/reoxygenation (OGD/R)-induced cardiac myocytes (CMs). In vitro, our data show that certain dose of SQLXF inhibited OGD/R-induced CMs apoptosis, cell viability decreasing and oxidative stress., Conclusion: Overall, certain dose of SQLXF could effectively improve the cardiac function of CHF rats through inhibition of CMs apoptosis via balancing mitochondrial fission and fusion. Our data proved a novel action mechanism of SQLXF in CHF improvement, and provided a reference for clinical., (© 2021. The Author(s).)

Nitro-fatty acids are a class of endogenous electrophilic lipid mediators with anti-inflammatory and cytoprotective effects in a wide range of inflammatory and fibrotic disease models. While these beneficial biological effects of nitro-fatty acids are mainly attributed to their ability to form covalent adducts with proteins, only a small number of proteins are known to be nitro-alkylated and the scope of protein nitro-alkylation remains undetermined. Here we describe the synthesis and application of a clickable nitro-fatty acid probe for the detection and first global identification of mammalian proteins that are susceptible to nitro-alkylation. 184 high confidence nitro-alkylated proteins were identified in THP1 macrophages, majority of which are novel targets of nitro-fatty acids, including extended synaptotagmin 2 (ESYT2), signal transducer and activator of transcription 3 (STAT3), toll-like receptor 2 (TLR2), retinoid X receptor alpha (RXRα) and glucocorticoid receptor (NR3C1). In particular, we showed that 9-nitro-oleate covalently modified and inhibited dexamethasone binding to NR3C1. Bioinformatic analyses revealed that nitro-alkylated proteins are highly enriched in endoplasmic reticulum and transmembrane proteins, and are overrepresented in lipid metabolism and transport pathways. This study significantly expands the scope of protein substrates targeted by nitro-fatty acids in living cells and provides a useful resource towards understanding the pleiotropic biological roles of nitro-fatty acids as signaling molecules or as multi-target therapeutic agents., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Multiple biological barriers in solid tumors severely restrict the penetration of nanomedicines, which is a main cause for therapeutic failure in traditional tumor treatment. Here, a tumor-specific nanogenerator of peroxynitrite (ONOO - ), prepared by loading cisplatin and sodium nitroprusside into poly(d,l-lactide- co -glycolide) polymersomes, was designed to improve drug delivery and enhance tumor chemotherapy. After a cascade of nicotinamide adenine dinucleotide phosphate oxidases catalysis and glutathione reduction, the nanogenerator, namely, PMCS, could selectively induce the generation of ONOO - in tumor. The generated ONOO - could not only strengthen vascular permeability significantly but also improve the accumulation and penetration of PMCS in tumor by activating matrix metalloproteinases-mediated degradation of extracellular matrix. Along with endocytosis, PMCS released cisplatin to induce tumor cell apoptosis. Moreover, free cisplatin liberated from dead cells infected neighboring tumor cells quickly via ONOO - -mediated up-regulated copper transporter 1, further amplifying chemotherapeutic efficacy. This study advances ONOO - as a potent modality to address the main issues of therapeutic delivery, including but not limited to chemotherapy.

Background: Non-shared environment (NSE) effects account for around one-third of the etiology of autism spectrum disorder (ASD). However, the knowledge of mechanisms and phenotypic profiles associated with NSE in ASD is scarce., Methods: A systematic search was conducted using Embase, MEDLINE, and PsycINFO for studies published in English between 1990 and August 2020 using co-twin control design to compare behavioral and biological phenotypes among monozygotic (MZ) twin pairs concordant/discordant for ASD, clinical autism symptoms, or autistic traits. Risk of bias was assessed through a modified Newcastle-Ottawa Scale., Results: Twenty six articles were included. Differential DNA methylation and gene expression were found among ASD discordant twins; however, genetic results were inconsistent. Neurological disorders and early medical events were associated with ASD and autistic traits, while no within pair differences were found for minor physical anomalies or head circumference. Structural and functional brain imaging studies and research on social and other cognitive/behavioral functions were inconclusive. Risk of bias assessment found that all studies used the same exposure (or outcome) measures to collect data for participants and most used either secure health-related records or structured interviews for ascertainment of exposure; however, only a handful of studies representative of the population from which they were drawn. Formal assessment of risk of publication bias (i.e., funnel plot) was not possible., Conclusions: Our results suggest that NSE in ASD could be associated with heterogeneous postzygotic genetic mechanisms and manifest as a range of biological and behavioral phenotypes. Extant findings were limited by relatively few studies, small sample sizes, and methodological diversity. More research is needed on co-occurring biological and behavioral phenotypes using a consistent format for designing, analyzing, and reporting MZ ASD discordant twin studies in order to further examine the role of NSE in the etiology of ASD., Competing Interests: All authors declare no direct conflict of interest related to this review; however Lynnea Myers, Pei‐Yin Pan, Karl Lundin Remnélius, Janina Neufeld, and Sven Bölte are authors of some of the included studies. Sven Bölte discloses that he has in the last three years acted as an author, consultant, or lecturer for Medice and Roche. He receives royalties for textbooks and diagnostic tools from Hogrefe, Kohlhammer, and UTB.Since this systematic review did not directly involve human subjects, no ethical permission was needed., (© 2021 The Authors. JCPP Advances published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

Immunotherapy has provided a promising strategy for the treatment of cancers. However, even in tumors with high antigen burdens, the systemic inhibition of the antigen presentation still greatly restricts the application of immunotherapy. Here, we construct a tumor protein-engineering system based on the functional tripeptide, Asp-Phe-Tyr (DFY), which can automatically collect and deliver immunogenetic tumor proteins from targeted cells to immune cells. Through a tyrosinase-catalyzed polymerization, the DFY tripeptide selectively accumulates in tyrosinase high-expressed melanoma cells. Then quinone-rich intermediates are covalently linked with tumor-specific proteins by Michael addition and form tumor protein-carried microfibers that could be engulfed by antigen-presenting cells and exhibited tumor antigenic properties for boosting immune effect. In melanoma cells with deficient antigen presentation, this system can successfully enrich and transport tumor antigen-containing proteins to immune cells. Furthermore, in the in vivo study on murine melanoma, the transdermal delivery of the DFY tripeptide suppressed the tumor growth and the postsurgery recurrence. Our findings provide an avenue for the regulation of the immune system on an organism by taking advantage of certain polymerization reactions by virtue of chemical biology.

Lay Abstract: Neurological disorders, such as epilepsy and cerebral palsy, have been reported to occur among individuals with autism beyond chance and may have an impact on daily living across the lifespan. Although there has been research investigating neurological disorders in autism, the findings are not always conclusive. Previous summaries of existing studies have not evaluated the full range of neurological disorders. This study aimed to comprehensively explore the neurological problems appearing in autism to provide updated information that is needed for better healthcare and support in this population. We looked at already published studies focusing on risk or frequency of neurological disorders in autism. Our results suggest that individuals with autism are more likely than the general population to have a range of neurological disorders, including epilepsy, macrocephaly, hydrocephalus, cerebral palsy, migraine/headache, and inborn abnormalities of the nervous system. In order to provide individualized healthcare and support of high quality to individuals diagnosed with autism, health care professionals and other support providers need to be attentive to neurological complications. To further improve our understanding about the link between autism and neurological disorders, future research should follow the neurological health of children who are diagnosed with or are at increased likelihood of autism.

Attention-deficit/hyperactivity disorder (ADHD) has been associated with increased risk for physical comorbidity. This study used a twin cohort to investigate the association between physical diseases and phenotypic variations of ADHD. A twin cohort enriched for ADHD and other neurodevelopmental conditions were analysed. The Attention Problems subscale of the Child Behavior Checklist/Adult Behavior Checklist (CBCL/ABCL-AP) was used to measure the participants' severity of ADHD symptoms. Physical health issues were obtained with a validated questionnaire and were tested in relation to ADHD symptom severity in a co-twin control model. Neurological problems were significantly associated with a diagnosis of ADHD. A conditional model for the analysis of within-twin pair effects revealed an inverse association between digestive problems and the severity of ADHD symptoms, after adjusting for co-existing autism spectrum disorder and ADHD medications. Our findings suggest that individuals with ADHD are susceptible to neurological problems, why a thorough neurological check-up is indicated in clinical practice for this population. In addition, health conditions of digestive system could be considered as a non-shared environmental factor for behavioral phenotypes in ADHD. It supports the possible role of gut-brain axis in the underpinnings of ADHD symptoms, at least for a subgroup of individuals with certain genetic predisposition.

Global alterations in the metabolic network provide substances and energy to support tumor progression. To fuel these metabolic processes, extracellular matrix (ECM) plays a dominant role in supporting the mass transport and providing essential nutrients. Here, we report a fibrinogen and thrombin based coagulation system to construct an artificial ECM (aECM) for selectively cutting-off the tumor metabolic flux. Once a micro-wound is induced, a cascaded gelation of aECM can be triggered to besiege the tumor. Studies on cell behaviors and metabolomics reveal that aECM cuts off the mass transport and leads to a tumor specific starvation to inhibit tumor growth. In orthotopic and spontaneous murine tumor models, this physical barrier also hinders cancer cells from distant metastasis. The in vivo gelation provides an efficient approach to selectively alter the tumor mass transport. This strategy results in a 77% suppression of tumor growth. Most importantly, the gelation of aECM can be induced by clinical operations such as ultrasonic treatment, surgery or radiotherapy, implying this strategy is potential to be translated into a clinical combination regimen.

Patients with kidney failure commonly require dialysis to remove nitrogenous wastes and to reduce burden to the kidney. Here, we show that a bacterial cocktail orally delivered in animals with kidney injury can metabolize blood nitrogenous waste products before they diffuse through the intestinal mucosal barrier. The microbial cocktail consists of three strains of bacteria isolated from faecal microbiota that metabolize urea and creatinine into amino acids, and is encapsulated in calcium alginate microspheres coated with a polydopamine layer that is selectively permeable to small-molecule nitrogenous wastes. In murine models of acute kidney injury and chronic kidney failure, and in porcine kidney failure models, the encapsulated microbial cocktail significantly reduced urea and creatinine concentrations in blood, and did not lead to any adverse effects.

This study used a twin cohort to investigate the association of autism spectrum disorder (ASD) and autistic traits with somatic health. A total of 344 twins (172 pairs; mean age 15.56 ± 5.62 years) enriched for ASD and other neurodevelopmental conditions were examined. Medical history and current physical problems were collected with a validated questionnaire to determine twin's somatic health. The Social Responsiveness Scale (SRS-2) was used to measure the participant's severity of autistic traits. Identified somatic health issues with significant within-twin pair differences were tested in relation to both ASD diagnosis and autistic traits in a co-twin control model. Twins with ASD exhibited more neurological and immunological health problems compared to those without ASD (p = 0.005 and p = 0.004, respectively). The intra-pair differences of neurological conditions and SRS-2 score were significantly correlated in monozygotic twins differing for autism traits (r = 0.40, p = 0.001), while the correlation was not found for immunological problems. In addition, a conditional model for analysis of within-twin pair effects revealed an association between neurological problems and clinical ASD diagnosis (Odds ratio per neurological problem 3.15, p = 0.02), as well as autistic traits (β = 10.44, p = 0.006), after adjusting for possible effects of co-existing attention deficit hyperactivity disorder and general intellectual abilities. Our findings suggest that neurological problems are associated with autism, and that non-shared environmental factors contribute to the overlap for both clinical ASD and autistic traits. Further population-based twin studies are warranted to validate our results and examine in detailed the shared genetic and environmental contributions of neurological problems and ASD.

Nanotheranostic agents (NTAs) that integrate diagnostic capabilities and therapeutic functions have great potential for personalized medicine, yet poor tumor specificity severely restricts further clinical applications of NTAs. Here, a pro-NTA (precursor of nanotheranostic agent) activation strategy is reported for in situ NTA synthesis at tumor tissues to enhance the specificity of tumor therapy. This pro-NTA, also called PBAM, is composed of an MIL-100 (Fe)-coated Prussian blue (PB) analogue (K 2 Mn[Fe(CN) 6 ]) with negligible absorption in the near-infrared region and spatial confinement of Mn 2+ ions. In a mildly acidic tumor microenvironment (TME), PBAM can be specifically activated to synthesize the photothermal agent PB nanoparticles, with release of free Mn 2+ ions due to the internal fast ion exchange, resulting in the "ON" state of both T 1 -weighted magnetic resonance imaging and photoacoustic signals. In addition, the combined Mn 2+ -mediated chemodynamic therapy in the TME and PB-mediated photothermal therapy guarantee a more efficient therapeutic performance compared to monotherapy. In vivo data further show that the pro-NTA activation strategy could selectively brighten solid tumors and detect invisible lymph node metastases with high specificity., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Mounting evidence suggests that the gut microbiota contribute to colorectal cancer (CRC) tumorigenesis, in which the symbiotic Fusobacterium nucleatum ( Fn ) selectively increases immunosuppressive myeloid-derived suppressor cells (MDSCs) to hamper the host's anticancer immune response. Here, a specifically Fn -binding M13 phage was screened by phage display technology. Then, silver nanoparticles (AgNP) were assembled electrostatically on its surface capsid protein (M13@Ag) to achieve specific clearance of Fn and remodel the tumor-immune microenvironment. Both in vitro and in vivo studies showed that of M13@Ag treatment could scavenge Fn in gut and lead to reduction in MDSC amplification in the tumor site. In addition, antigen-presenting cells (APCs) were activated by M13 phages to further awaken the host immune system for CRC suppression. M13@Ag combined with immune checkpoint inhibitors (α-PD1) or chemotherapeutics (FOLFIRI) significantly prolonged overall mouse survival in the orthotopic CRC model., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Traditional phototherapies face the issue that the insufficient penetration of light means it is difficult to reach deep lesions, which greatly reduces the feasibility of cancer therapy. Here, an implantable nitric oxide (NO)-release device is developed to achieve long-term, long-distance, remote-controllable gas therapy for cancer. The device consists of a wirelessly powered light-emitting diode (wLED) and S-nitrosoglutathione encapsulated with poly(dimethylsiloxane) (PDMS), obtaining the NO-release wLED (NO-wLED). It is found that NO release from the NO-wLED can be triggered by wireless charging and the concentration of produced NO reaches 0.43 × 10 -6 m min -1 , which can achieve a killing effect on cancer cells. In vivo anticancer experiments exhibit obvious inhibitory effect on the growth of orthotopic cancer when the implanted NO-wLED is irradiated by wireless charging. In addition, recurrence of cancer can be prevented by NO produced from the NO-wLED after surgery. By illumination in the body, this strategy overcomes the poor penetration and long-wavelength dependence of traditional phototherapies, which also provides a promising approach for in vivo gas therapy remote-controlled by wireless charging., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Nucleophosmin/nucleoplasmin family 1 (NPM1) has broad physiological functions, such as DNA replication, transcription, ribosome biogenesis, and centrosome replication. This study explored the clinicopathological importance of NPM1 as a prognostic marker for oral squamous cell carcinoma (OSCC)., Methods: We collected specimens from 96 OSCC, 45 oral epithelial dysplasia (OED), and 29 normal oral mucosa (NOM). NPM1 expression was analyzed via immunohistochemistry. Correlations between NPM1and clinical parameters were analyzed using Student t test, chi-squared test, and Kaplan-Meier product-limit method., Results: The NPM1 labeling indices (LIs) were significantly higher in OSCCs than in NOM and oral OED. Higher NPM1 expression was significantly correlated with larger tumor size, nodal metastasis, and advanced clinical stage. Multivariate analysis revealed that higher NPM1 LIs were an unfavorable independent factor for survival., Conclusions: Upregulated NPM1 is an independent biomarker of poor prognosis and NPM1 inhibitors may be promising in molecular targeted therapy against OSCC., (© 2019 Wiley Periodicals, Inc.)

Multitudinous industrial products in daily life put human health at risk of heavy metal exposure, and natural bacteria have displayed superior performance in bioadsorption and biodegradation of heavy metal. In this study, a bacteria-based bioreactor is developed to precisely bioadsorb lead (Pb) ions, eliminate concomitant reactive oxygen species (ROS), and remit the injury of acute/chronic Pb poisoning. A nonpathogenic bacteria Escherichia coli MG1655 (Bac) is decorated with antioxidative cerium oxide nanoparticles (Ceria) on the surface through a bio-orthogonal reaction, and the complex bioreactor could spontaneously aggregate in organs with high concentration of Pb. Furthermore, the excess Pb is bioadsorbed by bacteria and the concomitant ROS is eliminated by Ceria nanoparticles. In vitro and in vivo studies demonstrate that this integral biotic/abiotic hybrid bioreactor successfully realizes detoxication of Pb and reparation of injury, also accompanied with inappreciable side effects., Competing Interests: The authors declare no conflict of interest., (© 2019 The Authors. Published by WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim.)

The microbiota in the human gut is strongly correlated with the progression of colorectal cancer (CRC) and with therapeutic responses to CRC. Here, by leveraging the higher concentration of the pro-tumoural Fusobacterium nucleatum and the absence of antineoplastic butyrate-producing bacteria in the faecal microbiota of patients with CRC, we show that-in mice with orthotopic colorectal tumours or with spontaneously formed colorectal tumours-oral or intravenous administration of irinotecan-loaded dextran nanoparticles covalently linked to azide-modified phages that inhibit the growth of F. nucleatum significantly augments the efficiency of first-line chemotherapy treatments of CRC. We also show that oral administration of the phage-guided irinotecan-loaded nanoparticles in piglets led to negligible changes in haemocyte counts, immunoglobulin and histamine levels, and liver and renal functions. Phage-guided nanotechnology for the modulation of the gut microbiota might inspire new approaches for the treatment of CRC.

Objectives: Methylphenidate (MPH) is highly effective in controlling the symptoms of attention-deficit/hyperactivity disorder (ADHD), but some children with ADHD either do not respond to, or do not tolerate, treatment. Dextromethorphan (DM) is a neuroprotective agent which has been used in the treatment of neuropsychiatric disorders. This clinical trial had examined the effect of DM on the use of MPH in the children with ADHD. Methods: This randomized double-blind clinical trial had evaluated 44 male outpatients, aged between 6 and 12 years, with a diagnosis of ADHD. The study subjects were randomly assigned into one of the two groups: receiving MPH alone (15-60 mg per day) or MPH plus DM (30-60 mg per day) for 8 weeks. Assessments, comprising the Chinese version of the Child Behavior Checklist (CBCL-C) scale and the Swanson, Nolan and Pelham Questionnaire (SNAP)-IV rating tests conducted by parents and the serum cytokines measured by microarray and enzyme-linked immunosorband assay (ELISA), were compared between groups at baseline and at 8 weeks after the medication was started. Results: There were a significant decrease at the mean scores of both CBCL-C and SNAP-IV scales after 8 weeks of treatment, but no significant differences between MPH and MPH+DM groups. Compared with the MPH-only group, the mean scores of some psychometric parameters reported on the CBCL-C and SNAP-IV scales regarding time effects as well as the attention problems on the CBCL-C scale regarding group effect were significantly higher in the DM+MPH group. Although there were no significant differences in the levels of various serum cytokines between groups, the subjects in the DM-MPH group had relatively fewer and lower levels of adverse effects. Significant interactions were found between the withdrawn/depression item reported on the CBCL-C scale and tumor necrosis factor α (ခTNF-α) ( p = 0.027), as well as between thought problems item on the CBCL-C and TNF-α ( p = 0.028) in subjects who had received DM+MPH treatment. Conclusion: Following the trial, DM+MPH was not superior to MPH alone for the treatment of children with ADHD, yet DM may potentially have negative effects on ADHD symptoms when combined with MPH. Clinical Trial Registration: Clinicaltrials.gov, trial number: NCT01787136.

Objectives: Irritability is among the most bothersome emotional symptoms in children. It often leads to mental health services referral, significant impairment, and distress to their families. Although there is increasing scientific evidence supporting the existence of extreme irritability in the Diagnostic and Statistical Manual of Mental Disorders, 5th ed. (DSM-5) diagnosis of disruptive mood dysregulation disorder, few studies have investigated the measurement of irritability in children. This pilot study aimed to examine the psychometric properties of the Chinese version of the Affective Reactivity Index (ARI) and the Aberrant Behavior Checklist (ABC)-irritability subscale. In addition, we investigated adaptive difficulties among children with irritability., Methods: A total of 97 children and adolescents 6 to 17 years of age (M = 10.20, SD = 2.70) were recruited from the psychiatric outpatient department of a university hospital in Taipei. The participants completed the Chinese version of the ARI self-report form and the Social Adjustment Inventory for Children and Adolescents (SAICA). Their parents completed the ARI parent report form, the Chinese version of the ABC-irritability subscale, and the Child Behavior Checklist. Diagnostic interviews were administered based on diagnostic criteria of DSM-5 to confirm the participants' psychiatric diagnoses., Results: The Chinese ABC-irritability subscale and the parent and self-report scales of the Chinese ARI showed good test-retest reliability, internal consistency, and concurrent validity. Scores from the ABC-irritability subscale and two forms of the ARI were all significantly correlated with aggressive behaviors, anxious/depressed symptoms, and social problems. In addition, irritability among children was significantly associated with maladjustment in school, with peer problems, and with problems at home., Conclusions: Our findings suggest that irritability may be associated with impaired social adaptive functioning among children and adolescents. The Chinese version of the ARI and the ABC-irritability subscale are useful for measuring irritability in both clinical and research settings in the Chinese population.

Adenosine triphosphate (ATP) is the most important immediate energy source for driving intracellular biochemical reactions in nearly all life forms. Controllable generation of ATP in life is still an unrealized goal. Here, thylakoid fragments are recombined with lipid molecules to synthesize a synthetic/biological hybrid proteoliposome, named highly efficient life-support intracellular opto-driven system (HELIOS) for the generation of ATP. With red light irradiation, HELIOS can improve the intracellular ATP concentration to 1.38-2.45 times in various cell lines. Moreover, it is noticed that HELIOS-mediated ATP generation can comprehensively promote cell functions such as protein synthesis and insulin secretion. At organ and individual levels, it is also proved that HELIOS can rescue a mouse heart from myocardial infarction and sustain life of fasting zebrafish Danio rerio models. The photo-powered artificial organelle can deepen our understanding of metabolism and enable the development of optical therapy that targets intracellular energy supply., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objectives: Disruptive mood dysregulation disorder (DMDD) is characterized by nonepisodic irritability and has a high rate of comorbidity with attention-deficit/hyperactivity disorder (ADHD). This is the first study to explore the effects of aripiprazole combined with methylphenidate on clinical symptoms and cognitive functions in patients with DMDD and ADHD., Methods: Patients with DMDD and ADHD (the DMDD-ADHD Group, n = 24; aged 7-17 years) completed a 6-week, open-label trial of aripiprazole and methylphenidate. The pre- and posttreatment outcome measures included the parent-rated Swanson, Nolan, and Pelham Scale-version IV, Child Behavior Checklist, and self-reported Beck Youth Inventories-II, as well as a neuropsychological battery composed of the Children's Color Trail Test and Conner's Continuous Performance Test. The comparison group consisting of patients with ADHD (the ADHD Group, n = 27) was recruited to investigate the differences in clinical and neuropsychological profiles between the two groups at baseline., Results: The DMDD-ADHD Group showed worse irritability, disruptive behaviors, anxious/depressed symptoms, and social problems relative to the ADHD Group at baseline assessments. The combination treatment significantly improved irritability, externalizing symptoms, depression, anxiety, attention, social problems, and reaction time variability. The effect sizes of reductions in parent-rated irritability, oppositional defiant symptoms, and inattention were comparable (Cohen's d = 1.26, 1.11, and 1.40, respectively)., Conclusions: This pilot study showed the tolerability of the aripiprazole/methylphenidate combination by patients with DMDD and ADHD and its efficaciousness for treating clinical symptoms and for improving cognitive function. Further randomized, controlled, cross-over studies are needed.

Cytotherapy has received considerable attention in the field of cancer therapy, and various chemical or genetic methods have been applied to remold natural cells for improved therapeutic outcome of cytotherapy. A simple method to modify lymphocytes for cancer treatment by using a clinically used molecule, δ-aminolevulinic acid (δ-ALA), is reported here. After incubation with this molecule, tumor-targeted lymphocytes spontaneously synthesize anti-neoplastic drug protoporphyrin X (PpIX), and specifically accumulate in cancer tissue. Under periodic 630 nm laser irradiation, lymphocytes generate vesicle-like apoptotic body (Ab) containing the above-produced PpIX, and the facilitated delivery of PpIX from Ab makes an excellent therapeutic effect for Ras-mutated cancer cells under a second irradiation. Importantly, a microfluidic device is further fabricated to simplify cell sorting and drug synthesis with a one-step operation, which could promote generalization of this strategy. In vitro and in vivo studies confirm the success of such an easy-operated and global-regulated strategy for cancer therapy., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objective: To explore the role of Internet addiction in the development of self-harm/suicidal behavior among adolescents after 1-year of follow-up., Study Design: We conducted this 1-year, prospective cohort study of 1861 adolescents (mean age 15.93 years) attending a senior high school in Taiwan; 1735 respondents (93.2%) were classified as having no history of self-harm/suicidal attempts in the initial assessment and were referred to as the "noncase" cohort. The Chen Internet Addiction Scale was used to identify individuals with Internet addiction. The participants were evaluated for self-harm/suicidal behavior again 1 year later and the "noncase" cohort was selected for statistical analysis. To examine the relationship between Internet addiction and self-harm/suicidal behavior, multivariate logistic regression analysis was performed using Internet addiction at baseline as the predictor for newly developed self-harm/suicidal behavior in the next year, after adjustment for potential confounding variables., Results: The prevalence rate of Internet addiction at baseline was 23.0%. There were 59 students (3.9%) who were identified as having developed new self-harm/suicidal behaviors on follow-up assessments. After controlling for the effects of potential confounders, the relative risk of newly emerging self-harm/suicidal behavior for participants who were classified as Internet addicted was 2.41 (95% CI 1.16-4.99, P = .018) when compared with those without Internet addiction., Conclusions: Our findings indicate that Internet addiction is prospectively associated with the incidence of self-harm/suicidal behavior in adolescents., (Copyright © 2018 Elsevier Inc. All rights reserved.)

A reprogrammable transgenic mouse strain, called Col1a1 4F2A-Oct4-GFP, was bred for the present study. Because the somatic cells of this mouse strain contain only two copies of each Yamanaka factor, these animals are inefficient at producing induced pluripotent stem cells (iPSCs; approx. 0.005%) under traditional culture conditions. With an optimized culture condition, the iPSC production rate of mouse embryonic fibroblasts (MEFs) of Col1a1 4F2A-Oct4-GFP mice (MEF C ol1a1 4F2A-Oct4- GFP ) was increased to approximately 8%. Further, promotion of cell proliferation by serum supplementation did not enhance iPSC production. Inhibition of transforming growth factor β (TGF-β) in the serum by SB431542 neither affected the growth rate of MEF C ol1a1 4F2A-Oct4- GFP nor promoted iPSC production. However, the use of the gamma-irradiated STO-NEO-LIF (γSNL) cells to serve as feeders for iPSC production resulted in a 5-fold higher rate of iPSC production than the use of γMEF ICR feeders. Interestingly, the use of SB431542 with the γMEF ICR -adopted system could eliminate this difference. RT-PCR-based comparative analysis further demonstrated that TGF-β expression was 10-fold higher in γMEF ICR than in γSNL cells. Consistent with previous reports, mesenchymal to epithelial transition was found to participate in the initial steps of reprogramming in the specific context of MEF C ol1a1 4F2A-Oct4- GFP . Moreover, we found that the initial seeding density is one of the pivotal factors for determining a high efficiency of iPSC generation. The iPSCs efficiently generated from our MEF C ol1a1 4F2A-Oct4- GFP resembled mouse embryonic stem cells (mESCs) in aspects of teratoma formation and germline transmission. Depending on the culture conditions, our Col1a1 4F2A-Oct4-GFP mouse system can generate bona fide iPSCs with variable efficiencies, which can serve as a tool for interrogating the route taken by cells during somatic reprogramming., (© 2018 Federation of European Biochemical Societies.)