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Purpose: People of Culturally and Linguistically Diverse (CALD) backgrounds face disparities in cancer care. This scoping review aims to identify the breadth of international literature focused on cancer survivorship programs/interventions specific to CALD populations, and barriers and facilitators to program participation., Methods: Scoping review included studies focused on interventions for CALD cancer survivors after curative-intent treatment. Electronic databases: Medline, Embase, CINAHL, PsycInfo and Scopus were searched, for original research articles from database inception to April 2022., Results: 710 references were screened with 26 included: 14 randomized (54%), 6 mixed-method (23%), 4 non-randomized experimental (15%), 2 qualitative studies (8%). Most were United States-based (85%), in breast cancer survivors (88%; Table 1), of Hispanic/Latinx (54%) and Chinese (27%) backgrounds. Patient-reported outcome measures were frequently incorporated as primary endpoints (65%), or secondary endpoints (15%). 81% used multi-modal interventions with most encompassing domains of managing psychosocial (85%) or physical (77%) effects from cancer, and most were developed through community-based participatory methods (46%) or informed by earlier work by the same research groups (35%). Interventions were usually delivered by bilingual staff (88%). 17 studies (77%) met their primary endpoints, such as meeting feasibility targets or improvements in quality of life or psychological outcomes. Barriers and facilitators included cultural sensitivity, health literacy, socioeconomic status, acculturation, and access., Conclusions: Positive outcomes were associated with cancer survivorship programs/interventions for CALD populations. As we identified only 26 studies over the last 14 years in this field, gaps surrounding provision of cancer survivorship care in CALD populations remain., Implications for Cancer Survivors: Ensuring culturally sensitive and specific delivery of cancer survivorship programs and interventions is paramount in providing optimal care for survivors from CALD backgrounds., (© 2023. The Author(s).)

Objectives: The relationships among positional obstructive sleep apnea (POSA), obstructive sleep apnea (OSA), and periodic limb movements during sleep (PLMS) remain unclear. We investigated these relationships with respect to the severity of OSA and explored the underlying mechanisms., Methods: We retrospectively reviewed 6,140 eligible participants who underwent full-night diagnostic polysomnography at four clinical centers over a 5-year period, utilizing event-synchronized analysis. We evaluated the periodic limb movement index (PLMI) and the periodic limb movement with arousal index (PLMAI). The impacts of POSA on the PLMI, PLMAI, and PLMS were analyzed in relation to the severity of OSA., Results: The mean PLMI, the mean PLMAI, and the prevalence of PLMS were significantly lower in participants with severe OSA compared to the mild and moderate OSA groups. The mean PLMI among those with mild OSA exceeded that of control participants. Furthermore, the mean PLMI (4.8±12.7 vs. 2.6±9.8 events/hr, P<0.001), the mean PLMAI (0.9±3.7 vs. 0.5±3.3 events/hr, P<0.001), and the prevalence of PLMS (11% vs. 5.3%, P<0.001) were higher in patients with POSA than in those with non-positional OSA. This PLMS finding was particularly pronounced among those with severe OSA (odds ratio [OR], 1.554; 95% confidence interval [CI], 1.065-2.267) and was less evident in the mild (OR, 0.559; 95% CI, 0.303-1.030) and moderate (OR, 1.822; 95% CI, 0.995-3.339) groups., Conclusion: Patients with POSA, especially those with severe OSA, exhibit a comparatively high prevalence of PLMS. In cases involving prominent PLMS, the diagnosis and treatment of POSA and OSA should be considered.

Aberrant cholesterol metabolism causes neurological disease and neurodegeneration, and mitochondria have been linked to perturbed cholesterol homeostasis via the study of pathological mutations in the ATAD3 gene cluster. However, whether the cholesterol changes were compensatory or contributory to the disorder was unclear, and the effects on cell membranes and the wider cell were also unknown. Using patient-derived cells, we show that cholesterol perturbation is a conserved feature of pathological ATAD3 variants that is accompanied by an expanded lysosome population containing membrane whorls characteristic of lysosomal storage diseases. Lysosomes are also more numerous in Drosophila neural progenitor cells expressing mutant Atad3, which exhibit abundant membrane-bound cholesterol aggregates, many of which co-localize with lysosomes. By subjecting the Drosophila Atad3 mutant to nutrient restriction and cholesterol supplementation, we show that the mutant displays heightened cholesterol dependence. Collectively, these findings suggest that elevated cholesterol enhances tolerance to pathological ATAD3 variants; however, this comes at the cost of inducing cholesterol aggregation in membranes, which lysosomal clearance only partly mitigates., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Introduction: Korean autistic persons who have endured an integrated secondary education system have been exposed to school bullying, causing trauma and stigma to them. It also blocks them from entering a tertiary education system and a decent work, resulting in a lower quality of life. However, research on how it affects autistic persons has not yet been conducted in Korea., Methods: Fourteen adult autistic persons in the Republic of Korea participated in the semi-structured focused group interviews. Their conversations were analyzed through qualitative coding., Results: The interview results show the rare voice of Korean autistic people. Although interviewees experienced physical, verbal, and sexual violence against them during the secondary education period, they could not get substantial assistance from schools and society. Interviewees agreed that bullying is inherent in the secondary education system of Korea, even in Korean culture. They experienced the cause of bullying being attributed to them as victims rather than perpetrators, and impunity is given to the bullying assailants. Early analyses of this article confirm that such experiences are combined with the sociocultural climate of elitism, meritocracy, and authoritarianism in the Republic of Korea., Conclusion: The study confirmed that the autistic person's bullying experience does not come from the social inability of autistic people but the "profound" competition and discriminative atmosphere of the society. The result urges further studies on the bullying experience of East Asian autistic persons and the construction of Korean intervention strategies to prevent school violence against Koreans with disabilities, especially autistic pupils., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Yoon, Seo and Je.)

Aim: Investigate TKI sitravatinib plus anti-PD-1 antibody tislelizumab in patients with unresectable/advanced/metastatic melanoma with disease progression on/after prior first-line anti-PD-(L)1 monotherapy. Methods: Open-label, multicenter, multicohort study (NCT03666143). Patients in the melanoma cohort (N = 25) received sitravatinib once daily plus tislelizumab every 3 weeks. The primary end point was safety and tolerability. Results: Treatment-emergent adverse events (TEAEs) occurred in all patients, with ≥grade 3 TEAEs in 52.0%. Most TEAEs were mild-or-moderate in severity, none were fatal, and few patients discontinued treatment owing to TEAEs (12.0%). Objective response rate was 36.0% (95% CI: 18.0-57.5). Median progression-free survival was 6.7 months (95% CI: 4.1-not estimable). Conclusion: Sitravatinib plus tislelizumab had manageable safety/tolerability in patients with anti-PD-(L)1 refractory/resistant unresectable/advanced/metastatic melanoma, with promising antitumor activity. Clinical Trial Registration : NCT03666143 (ClinicalTrials.gov).

Small molecule inhibitors of Bruton's tyrosine kinase (BTK) have been approved for the treatment of multiple B-cell malignancies and are being evaluated for autoimmune and inflammatory diseases. Various BTK inhibitors (BTKi) have distinct potencies, selectivity profiles, and binding modes within the ATP-binding site. On the basis of the latter feature, BTKis can be classified into those that occupy the back-pocket, H3 pocket, and the hinge region only. Hypothesizing that differing binding modes may have differential impact on the B-cell receptor (BCR) signaling pathway, we evaluated the activities of multiple BTKis in B-cell lymphoma models in vitro and in vivo. We demonstrated that, although all three types of BTKis potently inhibited BTK-Y223 autophosphorylation and phospholipase C gamma 2 (PLCγ2)-Y1217 transphosphorylation, hinge-only binders were defective in inhibiting BTK-mediated calcium mobilization upon BCR activation. In addition, PLCγ2 activation was effectively blocked by back-pocket and H3 pocket binders but not by hinge-only binders. Further investigation using TMD8 cells deficient in Rac family small GTPase 2 (RAC2) revealed that RAC2 functioned as a bypass mechanism, allowing for residual BCR signaling and PLCγ2 activation when BTK kinase activity was fully inhibited by the hinge-only binders. These data reveal a kinase activity-independent function of BTK, involving RAC2 in transducing BCR signaling events, and provide mechanistic rationale for the selection of clinical candidates for B-cell lymphoma indications., (©2023 The Authors; Published by the American Association for Cancer Research.)

Relaxor ferroelectrics (RFEs) are being actively investigated for energy-storage applications due to their large electric-field-induced polarization with slim hysteresis and fast energy charging-discharging capability. Here, a novel nanograin engineering approach based upon high kinetic energy deposition is reported, for mechanically inducing the RFE behavior in a normal ferroelectric Pb(Zr 0.52 Ti 0.48 )O 3 (PZT), which results in simultaneous enhancement in the dielectric breakdown strength (E DBS ) and polarization. Mechanically transformed relaxor thick films with 4 µm thickness exhibit an exceptional E DBS of 540 MV m -1 and reduced hysteresis with large unsaturated polarization (103.6 µC cm -2 ), resulting in a record high energy-storage density of 124.1 J cm -3 and a power density of 64.5 MW cm -3 . This fundamental advancement is correlated with the generalized nanostructure design that comprises nanocrystalline phases embedded within the amorphous matrix. Microstructure-tailored ferroelectric behavior overcomes the limitations imposed by traditional compositional design methods and provides a feasible pathway for realization of high-performance energy-storage materials., (© 2023 Wiley-VCH GmbH.)

Epithelial ovarian cancer (EOC) is the most lethal gynaecological malignancy, and despite advancements in therapeutics, most women unfortunately still succumb to their disease. Immunotherapies, in particular immune checkpoint inhibitors (ICI), have been therapeutically transformative in many tumour types, including gynaecological malignancies such as cervical and endometrial cancer. Unfortunately, these therapeutic successes have not been mirrored in ovarian cancer clinical studies. This review provides an overview of the ovarian tumour microenvironment (TME), particularly factors associated with survival, and explores current research into immunotherapeutic strategies in EOC, with an exploratory focus on novel therapeutics in navigating drug resistance., Competing Interests: ADeF declares receiving grant funding from AstraZeneca. All other authors declared that there are no conflicts of interest., (© The Author(s) 2023.)

The CRISPR-Cas9 system has enabled researchers to precisely modify/edit the sequence of a genome. A typical editing experiment consists of two steps: (1) editing cultured cells; (2) cell cloning and selection of clones with and without intended edit, presumed to be isogenic. The application of CRISPR-Cas9 system may result in off-target edits, whereas cloning will reveal culture-acquired mutations. We analyzed the extent of the former and the latter by whole genome sequencing in three experiments involving separate genomic loci and conducted by three independent laboratories. In all experiments we hardly found any off-target edits, whereas detecting hundreds to thousands of single nucleotide mutations unique to each clone after relatively short culture of 10-20 passages. Notably, clones also differed in copy number alterations (CNAs) that were several kb to several mb in size and represented the largest source of genomic divergence among clones. We suggest that screening of clones for mutations and CNAs acquired in culture is a necessary step to allow correct interpretation of DNA editing experiments. Furthermore, since culture associated mutations are inevitable, we propose that experiments involving derivation of clonal lines should compare a mix of multiple unedited lines and a mix of multiple edited lines.

Purpose: This study aimed to establish the genetic cause of a novel autosomal recessive neurodevelopmental disorder characterized by global developmental delay, movement disorder, and metabolic abnormalities., Methods: We performed a detailed clinical characterization of 4 unrelated individuals from consanguineous families with a neurodevelopmental disorder. We used exome sequencing or targeted-exome sequencing, cosegregation, in silico protein modeling, and functional analyses of variants in HEK293 cells and Drosophila melanogaster, as well as in proband-derived fibroblast cells., Results: In the 4 individuals, we identified 3 novel homozygous variants in oxoglutarate dehydrogenase (OGDH) (NM&#95;002541.3), which encodes a subunit of the tricarboxylic acid cycle enzyme α-ketoglutarate dehydrogenase. In silico homology modeling predicts that c.566C>T:p.(Pro189Leu) and c.890C>A:p.(Ser297Tyr) variants interfere with the structure and function of OGDH. Fibroblasts from individual 1 showed that the p.(Ser297Tyr) variant led to a higher degradation rate of the OGDH protein. OGDH protein with p.(Pro189Leu) or p.(Ser297Tyr) variants in HEK293 cells showed significantly lower levels than the wild-type protein. Furthermore, we showed that expression of Drosophila Ogdh (dOgdh) carrying variants homologous to p.(Pro189Leu) or p.(Ser297Tyr), failed to rescue developmental lethality caused by loss of dOgdh. SpliceAI, a variant splice predictor, predicted that the c.935G>A:p.(Arg312Lys)/p.(Phe264&#95;Arg312del) variant impacts splicing, which was confirmed through a mini-gene assay in HEK293 cells., Conclusion: We established that biallelic variants in OGDH cause a neurodevelopmental disorder with metabolic and movement abnormalities., Competing Interests: Conflict of Interest H.Z.E. and H.Y. are employees of GeneDx, LLC. R.D.G. is a consultant for Minovia Therapeutics. All other authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

We herein report a facile molten-salt synthetic strategy to prepare transparent and uniform Li, Ba-doped (K,Na)NbO 3 (KNN) single-crystal microcuboids (∼80 μm). By controlling the degree of supersaturation, different growth modes were found and the single-crystal microcuboids were synthesized via island-like oriented attachment of KNN particles onto the growing surface. The distinct relaxor ferroelectric (RFE) properties were achieved in the single-crystal microcuboids, which were different from the normal ferroelectric (FE) properties found in their KNN ceramic counterparts prepared through a solid-state reaction using the same initial precursors. The RFE properties were realized by dislocation-induced nanodomain formation during oriented attachment growth of single-crystal microcuboids, which is different from the current strategies to derive the nanodomains by the local compositional inhomogeneity or the application of an electric field. The dislocations served as nucleation sites for ferroelectric domain walls and block the growth of domains. The KNN single-crystal microcuboids exhibited a higher effective piezoelectric coefficient (∼459 pm/V) compared to that of the bulk KNN ceramic counterpart (∼90 pm/V) and showed the broad diffuse maxima in the temperature dependence dielectric permittivity. The high maximum polarization (69.6 μC/cm 2 ) at a relatively low electric field (30 kV/cm) was beneficial for energy storage applications. Furthermore, the KNN-based transparent, flexible pressure sensor directly monitored the mechanical motion of human activity without any external electric power. This study provides insights and synthetic strategies of single-crystal RFE microcuboids for other different perovskites, in which nanodomain structures are primarily imposed by their chemical composition.

In this protocol, we take CRISPR/Cas9 and Gal4/UAS approaches to achieve tissue-specific knockout in parallel with rescue of the knockout by cDNA expression in Drosophila . We demonstrate that guide RNAs targeting the exon-intron junction of target genes cleave the genomic locus of the genes, but not UAS-cDNA transgenes, in a tissue where Gal4 drives Cas9 expression. The efficiency of this approach enables the determination of pathogenicity of disease-associated variants in human genes in a tissue-specific manner in Drosophila . For complete details on the use and execution of this protocol, please refer to Yap et al. (2021)., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)

The 2-oxoglutarate dehydrogenase-like (OGDHL) protein is a rate-limiting enzyme in the Krebs cycle that plays a pivotal role in mitochondrial metabolism. OGDHL expression is restricted mainly to the brain in humans. Here, we report nine individuals from eight unrelated families carrying bi-allelic variants in OGDHL with a range of neurological and neurodevelopmental phenotypes including epilepsy, hearing loss, visual impairment, gait ataxia, microcephaly, and hypoplastic corpus callosum. The variants include three homozygous missense variants (p.Pro852Ala, p.Arg244Trp, and p.Arg299Gly), three compound heterozygous single-nucleotide variants (p.Arg673Gln/p.Val488Val, p.Phe734Ser/p.Ala327Val, and p.Trp220Cys/p.Asp491Val), one homozygous frameshift variant (p.Cys553Leufs ∗ 16), and one homozygous stop-gain variant (p.Arg440Ter). To support the pathogenicity of the variants, we developed a novel CRISPR-Cas9-mediated tissue-specific knockout with cDNA rescue system for dOgdh, the Drosophila ortholog of human OGDHL. Pan-neuronal knockout of dOgdh led to developmental lethality as well as defects in Krebs cycle metabolism, which was fully rescued by expression of wild-type dOgdh. Studies using the Drosophila system indicate that p.Arg673Gln, p.Phe734Ser, and p.Arg299Gly are severe loss-of-function alleles, leading to developmental lethality, whereas p.Pro852Ala, p.Ala327Val, p.Trp220Cys, p.Asp491Val, and p.Arg244Trp are hypomorphic alleles, causing behavioral defects. Transcript analysis from fibroblasts obtained from the individual carrying the synonymous variant (c.1464T>C [p.Val488Val]) in family 2 showed that the synonymous variant affects splicing of exon 11 in OGDHL. Human neuronal cells with OGDHL knockout exhibited defects in mitochondrial respiration, indicating the essential role of OGDHL in mitochondrial metabolism in humans. Together, our data establish that the bi-allelic variants in OGDHL are pathogenic, leading to a Mendelian neurodevelopmental disease in humans., Competing Interests: Declaration of interests I.H. serves on the Scientific Advisory Board of Biogen. A.R. is an employee of GeneDx. The remaining authors declare no competing interests., (Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Coronavirus disease 2019 (COVID-19) has negatively affected the lives of people with disabilities; therefore, they need fast vaccination allocation. However, many countries, especially the Republic of Korea, have hesitated to vaccinate people with disabilities. This opinion article will explain why vaccine allocation priority is required for autistic people and people with disabilities in the COVID-19 pandemic crisis, including reporting on self-quarantine's stresses and psychological burdens., Competing Interests: The author has no potential conflicts of interest to disclose., (© 2021 The Korean Academy of Medical Sciences.)

Purpose: Many immune checkpoint inhibitors (ICIs) have been approved on the basis of tumor response end points in nonrandomized trials, including objective response rate (ORR) and duration and depth of response. We aimed to assess the validity of these end points as surrogate end points for overall survival (OS) in patients with advanced solid tumors treated with ICIs at trial and treatment arm levels., Methods: ICI trials in advanced solid cancers published between January 1, 2000, and March 31, 2020, were included. Correlations between ORR, durable response (DR) of ≥ 6 months, complete response (CR), and OS were assessed for treatment comparisons (trial-level) and for patients receiving ICI (arm-level), using weighted linear regression., Results: Sixty-three trials were eligible, including 58 randomized controlled trials and 20 nonrandomized controlled trials (78 ICI arms and 30,815 patients). The majority were phase III (63%), and OS was the most common primary end point (40%). In relative treatment comparisons, correlations between ORR risk ratio and OS hazard ratio (HR), 6-month DR ratio and OS HR, and CR ratio and OS HR were r = 0.58, r = 0.62, and r = 0.42, respectively. Exploratory studies in melanoma, non-small-cell lung cancer, and other tumors showed similar results, although 6-month DR ratio was strongly correlated with OS HR ( r = 0.89). Within ICI arms only, correlations between ORR and 12-month OS, 6-month DR and 12-month OS, and CR and 12-month OS were r = 0.76, r = 0.84, and r = 0.50, respectively, in all eligible trials., Conclusion: Relative measures of tumor response (ORR, 6-month DR, and CR) are poor surrogate end points for OS in ICI studies. However, ORR and 6-month DR are prognostic of 12-month OS in ICI studies supporting their use for screening activity of novel agents in early-phase nonrandomized trials., Competing Interests: Peey-Sei Kok Research Funding: AstraZeneca Travel, Accommodations, Expenses: Pfizer Other Relationship: Roche, AstraZeneca Ian Marschner Consulting or Advisory Role: AbbVie Research Funding: Janssen Michael Friedlander Honoraria: AstraZeneca, MSD, Lilly, Takeda, Novartis, GlaxoSmithKline Consulting or Advisory Role: AstraZeneca, MSD, AbbVie, Lilly, Takeda, Novartis, GlaxoSmithKline Speakers' Bureau: AstraZeneca, ACT Genomics Research Funding: BeiGene, AstraZeneca, Novartis Travel, Accommodations, Expenses: AstraZeneca Chee Khoon Lee Honoraria: AstraZeneca, Pfizer, Amgen, Takeda, Yuhan, Boehringer Ingelheim Consulting or Advisory Role: Novartis, Boehringer Ingelheim, Takeda, AstraZeneca, Yuhan, Amgen Research Funding: AstraZeneca, Roche, Merck KGaA No other potential conflicts of interest were reported.Peey-Sei Kok Research Funding: AstraZeneca Travel, Accommodations, Expenses: Pfizer Other Relationship: Roche, AstraZeneca Ian Marschner Consulting or Advisory Role: AbbVie Research Funding: Janssen Michael Friedlander Honoraria: AstraZeneca, MSD, Lilly, Takeda, Novartis, GlaxoSmithKline Consulting or Advisory Role: AstraZeneca, MSD, AbbVie, Lilly, Takeda, Novartis, GlaxoSmithKline Speakers' Bureau: AstraZeneca, ACT Genomics Research Funding: BeiGene, AstraZeneca, Novartis Travel, Accommodations, Expenses: AstraZeneca Chee Khoon Lee Honoraria: AstraZeneca, Pfizer, Amgen, Takeda, Yuhan, Boehringer Ingelheim Consulting or Advisory Role: Novartis, Boehringer Ingelheim, Takeda, AstraZeneca, Yuhan, Amgen Research Funding: AstraZeneca, Roche, Merck KGaA No other potential conflicts of interest were reported., (© 2021 by American Society of Clinical Oncology.)

Various supraparticles have been extensively studied owing to their excellent catalytic properties that are attributed to their inherent porous structure; however, their mechanical properties have not garnered attention owing to their less dense structure. We demonstrate a rational approach for fabricating assembled supraparticles and, subsequently, highly dense microspheres. In addition, 3 mol % yttria-stabilized zirconia (3YSZ) and alumina particles were selected as building blocks and assembled into higher-order architectures using a droplet-based template method (spray drying) for validation with proof-of-concept. Moreover, structural features such as density, size, sphericity, and morphology of supraparticles were controlled by adjusting the competing kinetics occurring between the assembly of building blocks and evaporation of the solvent in the droplets. The preparatory aqueous suspension and process parameters were optimized as well. A detailed understanding of the formation mechanism facilitated the yield of tailor-made supraparticles and, thereafter, highly dense microspheres (approximate relative density = 99%) with excellent sphericity (>98%) via heat treatment. The microspheres displayed highest hardness (26.77 GPa) and superior elastic modulus (210.19 GPa) compared with the mechanical properties of the 3YSZ samples reported to date. Ultimately, the proposed supraparticle engineering provided insight for controlling the structural features and resultant micromechanical properties, which widely extends the applicability of supraparticle-based functional materials for practical purposes that require materials with high density and excellent mechanical properties.

In this paper, we demonstrated a multiscale micro- and nano-structured magneto-mechano-triboelectric nanogenerator (MMTENG) enabled by a salt particle imprinting process to power an internet of thing (IoT) sensor. The fine salt particles were utilized to form a multiscale structure on a triboelectric polymer film by mechanical pressure via an eco-friendly, low-cost, and simple process, thereby reinforcing the contact triboelectrification and electrostatic induction. The surface modified MMTENG can generate an open-circuit peak-to-peak voltage of 851 V, a short-circuit current of 155 μA, and a maximum peak power of 10.3 mW under an AC magnetic field of 8 Oe. The energy device also presented output stability over 124 million operating cycles. Finally, the electricity of the surface enhanced MMTENG device was directly utilized to power an IoT temperature sensor with integration of an energy harvester, energy conversion circuit, and storage capacitor.

Background: ATPase family AAA-domain containing protein 3A (ATAD3A) is a nuclear-encoded mitochondrial membrane-anchored protein involved in diverse processes including mitochondrial dynamics, mitochondrial DNA organization, and cholesterol metabolism. Biallelic deletions (null), recessive missense variants (hypomorph), and heterozygous missense variants or duplications (antimorph) in ATAD3A lead to neurological syndromes in humans., Methods: To expand the mutational spectrum of ATAD3A variants and to provide functional interpretation of missense alleles in trans to deletion alleles, we performed exome sequencing for identification of single nucleotide variants (SNVs) and copy number variants (CNVs) in ATAD3A in individuals with neurological and mitochondrial phenotypes. A Drosophila Atad3a Gal4 knockin-null allele was generated using CRISPR-Cas9 genome editing technology to aid the interpretation of variants., Results: We report 13 individuals from 8 unrelated families with biallelic ATAD3A variants. The variants included four missense variants inherited in trans to loss-of-function alleles (p.(Leu77Val), p.(Phe50Leu), p.(Arg170Trp), p.(Gly236Val)), a homozygous missense variant p.(Arg327Pro), and a heterozygous non-frameshift indel p.(Lys568del). Affected individuals exhibited findings previously associated with ATAD3A pathogenic variation, including developmental delay, hypotonia, congenital cataracts, hypertrophic cardiomyopathy, and cerebellar atrophy. Drosophila studies indicated that Phe50Leu, Gly236Val, Arg327Pro, and Lys568del are severe loss-of-function alleles leading to early developmental lethality. Further, we showed that Phe50Leu, Gly236Val, and Arg327Pro cause neurogenesis defects. On the contrary, Leu77Val and Arg170Trp are partial loss-of-function alleles that cause progressive locomotion defects and whose expression leads to an increase in autophagy and mitophagy in adult muscles., Conclusion: Our findings expand the allelic spectrum of ATAD3A variants and exemplify the use of a functional assay in Drosophila to aid variant interpretation.

2-Oxoglutarate dehydrogenase (OGDH) is a rate-limiting enzyme in the mitochondrial TCA cycle, encoded by the OGDH gene. α-Ketoglutarate dehydrogenase (OGDH) deficiency was previously reported in association with developmental delay, hypotonia, and movement disorders and metabolic decompensation, with no genetic data provided. Using whole exome sequencing, we identified two individuals carrying a homozygous missense variant c.959A>G (p.N320S) in the OGDH gene. These individuals presented with global developmental delay, elevated lactate, ataxia and seizure. Fibroblast analysis and modeling of the mutation in Drosophila were used to evaluate pathogenicity of the variant. Skin fibroblasts from subject # 2 showed a decrease in both OGDH protein and enzyme activity. Transfection of human OGDH cDNA in HEK293 cells carrying p.N320S also produced significantly lower protein levels compared to those with wild-type cDNA. Loss of Drosophila Ogdh (dOgdh) caused early developmental lethality, rescued by expressing wild-type dOgdh (dOgdh WT ) or human OGDH (OGDH WT ) cDNA. In contrast, expression to the mutant OGDH (OGDH N320S ) or dOgdh carrying homologous mutations to human OGDH p.N320S variant (dOgdh N324S ) failed to rescue lethality of dOgdh null mutants. Knockdown of dOgdh in the nervous system resulted in locomotion defects which were rescued by dOgdh WT expression but not by dOgdh N324S expression. Collectively, the results indicate that c.959A>G variant in OGDH leads to an amino acid change (p.N320S) causing a severe loss of OGDH protein function. Our study establishes in the first time a genetic link between an OGDH gene mutation and OGDH deficiency., (© 2020 SSIEM.)

Current organoid models are limited by their inability to mimic mature organ architecture and associated tissue microenvironments 1,2 . Here we create multilayer bladder 'assembloids' by reconstituting tissue stem cells with stromal components to represent an organized architecture with an epithelium surrounding stroma and an outer muscle layer. These assembloids exhibit characteristics of mature adult bladders in cell composition and gene expression at the single-cell transcriptome level, and recapitulate in vivo tissue dynamics of regenerative responses to injury. We also develop malignant counterpart tumour assembloids to recapitulate the in vivo pathophysiological features of urothelial carcinoma. Using the genetically manipulated tumour-assembloid platform, we identify tumoural FOXA1, induced by stromal bone morphogenetic protein (BMP), as a master pioneer factor that drives enhancer reprogramming for the determination of tumour phenotype, suggesting the importance of the FOXA1-BMP-hedgehog signalling feedback axis between tumour and stroma in the control of tumour plasticity.

Importance: Progression-free survival (PFS) rate at 6 months has been proposed as a potential surrogate for overall survival (OS) rate at 12 months for immune checkpoint inhibitor (ICI) trials but requires further assessment for validation., Objective: To validate 6-month PFS and objective response rate (ORR) as estimators of 12-month OS in the ICI arms of randomized clinical trials (RCTs)., Data Sources: Electronic databases (Medline, EMBASE, and the Cochrane Central Register of Controlled Trials) were searched for ICI RCTs published between January 2000 and June 2019., Study Selection: Eligible studies were phase 2 and phase 3 ICI RCTs in advanced solid cancers that reported ORR, PFS, and OS. A total of 99 articles (from 60 studies) of 2502 articles were selected by consensus., Data Extraction and Synthesis: Data were screened and extracted independently. Estimation models for 12-month OS and to assess correlation coefficient between end points were developed using linear regression. Data were extracted in July 2019, and analyses were conducted in September 2019. This study is reported following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline., Main Outcomes and Measures: Validation of previously reported 6-month PFS and ORR estimation models for 12-month OS using contemporary RCTs. Calibration of 6-month PFS and ORR model-estimated vs observed 12-month OS in ICI arms were assessed by correlation coefficient (r) and weighted Brier scores. Secondary analyses were performed for subgroups (ie, ICI-only, ICI-combination, line of therapy, programmed cell death 1 ligand 1 selected, and unselected)., Results: Data from 60 RCTs with 74 experimental ICI arms were used. The development data set included 25 arms from studies published January 2000 to January 2017. The estimation model for 12-month OS using 6-month PFS was: (1.06 × PFS6) + 0.16 + (0.04 × melanoma) - (0.03 × NSCLC) + (0 × other tumors), in which PFS6 indicates 6-month PFS and NSCLC indicates non-small cell lung cancer. The estimation model for 12-month OS using ORR was (0.15 × ORR) + 0.52 + (0 × melanoma) - (0.02 × NSCLC) - (0.01 × other tumors). A total of 49 arms from studies published after January 2017 to June 2019 formed the validation data set. When the models were applied on the validation data set, calibration between the 6-month PFS model estimated vs observed 12-month OS was good (r = 0.89; Brier score, 0.008), but poor for the ORR model (r = 0.47; Brier score, 0.03). Findings were similar across all subgroups., Conclusions and Relevance: The findings of this study suggest that the estimation model using 6-month PFS could reliably estimate 12-month OS in ICI trials. This study could assist in better selection and prioritization of ICI agents for testing in RCTs based on phase 2 single-arm RCT results.

Mutations in the nuclear matrix protein Matrin 3 (MATR3) have been identified in amyotrophic lateral sclerosis and myopathy. To investigate the mechanisms underlying MATR3 mutations in neuromuscular diseases and efficiently screen for modifiers of MATR3 toxicity, we generated transgenic MATR3 flies. Our findings indicate that expression of wild-type or mutant MATR3 in motor neurons reduces climbing ability and lifespan of flies, while their expression in indirect flight muscles (IFM) results in abnormal wing positioning and muscle degeneration. In both motor neurons and IFM, mutant MATR3 expression results in more severe phenotypes than wild-type MATR3, demonstrating that the disease-linked mutations confer pathogenicity. We conducted a targeted candidate screen for modifiers of the MATR3 abnormal wing phenotype and identified multiple enhancers involved in axonal transport. Knockdown of these genes enhanced protein levels and insolubility of mutant MATR3. These results suggest that accumulation of mutant MATR3 contributes to toxicity and implicate axonal transport dysfunction in disease pathogenesis., (© 2020 The Authors. FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Quantification of intratumoral heterogeneity is essential for designing effective therapeutic strategies in the age of personalized medicine. In this study, we used a piezoelectric inkjet printer to enable analysis of intratumoral heterogeneity in a bladder cancer for the first time. Patient-derived tumor organoids were dissociated into single cell suspension and used as a bioink. The individual cells were precisely allocated into a microwell plate by drop-on-demand inkjet printing without any additive or treatment, followed by culturing into organoids for further analysis. The sizes and morphologies of the organoids were observed, so as the expression of proliferation and apoptotic markers. The tumor organoids also showed heterogeneous responses against chemotherapeutic agent. Further, we quantified mRNA expression levels of representative luminal and basal genes in both type of tumor organoids. These results verify the heterogeneous expression of various genes among individual organoids. This study demonstrates that the fully automated inkjet printing technique can be used as an effective tool to sort cells for evaluating intratumoral heterogeneity.

As one of the perovskite families, potassium sodium niobates (K 1- x Na x )NbO 3 (KNN) have been gaining tremendous attention due to their various functional properties which can be largely determined by their crystallographic phase and composition. However, a selective evolution of different phases for KNN with controlled composition can be difficult to achieve, especially in solution chemical synthesis because of its strong tendency to stabilize into orthorhombic phase at conventional synthetic temperature. We herein developed a facile solution approach to control the phase and composition of dopant-free KNN particles selectively through the modification of reaction parameters. A conventional hydrothermal synthesis method yielded orthorhombic KNN particles, while the monoclinic phase, which has never been observed in a bulk counterpart, was kinetically generated by the compositional modification of an intermediate phase under a high-intensity ultrasound irradiation. Cubic KNN particles were stabilized when ethylene glycol was used as a co-solvent together with deionized water through bonding between ethylene glycol molecules and the surface of the KNN. Composite-structured piezoelectric harvesters were fabricated using each phase of KNN particles and the β-phase poly(vinylidene fluoride- co -trifluoroethylene) polymer. Maximum output power was found for the harvester containing orthorhombic KNN particles. This facile synthetic methodology could pave a new pathway for fabricating numerous phase-controlled materials.

Recent studies have identified both recessive and dominant forms of mitochondrial disease that result from ATAD3A variants. The recessive form includes subjects with biallelic deletions mediated by non-allelic homologous recombination. We report five unrelated neonates with a lethal metabolic disorder characterized by cardiomyopathy, corneal opacities, encephalopathy, hypotonia, and seizures in whom a monoallelic reciprocal duplication at the ATAD3 locus was identified. Analysis of the breakpoint junction fragment indicated that these 67 kb heterozygous duplications were likely mediated by non-allelic homologous recombination at regions of high sequence identity in ATAD3A exon 11 and ATAD3C exon 7. At the recombinant junction, the duplication allele produces a fusion gene derived from ATAD3A and ATAD3C, the protein product of which lacks key functional residues. Analysis of fibroblasts derived from two affected individuals shows that the fusion gene product is expressed and stable. These cells display perturbed cholesterol and mitochondrial DNA organization similar to that observed for individuals with severe ATAD3A deficiency. We hypothesize that the fusion protein acts through a dominant-negative mechanism to cause this fatal mitochondrial disorder. Our data delineate a molecular diagnosis for this disorder, extend the clinical spectrum associated with structural variation at the ATAD3 locus, and identify a third mutational mechanism for ATAD3 gene cluster variants. These results further affirm structural variant mutagenesis mechanisms in sporadic disease traits, emphasize the importance of copy number analysis in molecular genomic diagnosis, and highlight some of the challenges of detecting and interpreting clinically relevant rare gene rearrangements from next-generation sequencing data., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

The algal cell immobilization is a commonly used technique for treatment of waste water, production of useful metabolites and management of stock culture. However, control over the size of immobilized droplets, the population of microbes, and production rate in current techniques need to be improved. Here, we use drop-on-demand inkjet printing to immobilize spores of the alga Ecklonia cava within alginate microparticles for the first time. Microparticles with immobilized spores were generated by printing alginate-spore suspensions into a calcium chloride solution. We demonstrate that the inkjet technique can control the number of spores in an ejected droplet in the range of 0.23 to 1.87 by varying spore densities in bioink. After the printing-based spore encapsulation, we observe initial sprouting and continuous growth of thallus until 45 days of culture. Our study suggest that inkjet printing has a great potential to immobilize algae, and that the ability to control the number of encapsulated spores and their microenvironments can facilitate research into microscopic interactions of encapsulated spores.

Designing a piezoelectric energy harvester (PEH) with high power density and high fatigue resistance is essential for the successful replacement of the currently using batteries in structural health monitoring (SHM) systems. Among the various designs, the PEH comprising of a cantilever structure as a passive layer and piezoelectric single crystal-based fiber composites (SFC) as an active layer showed excellent performance due to its high electromechanical properties and dynamic flexibilities that are suitable for low frequency vibrations. In the present study, an effort was made to investigate the reliable performance of hard and soft SFC based PEHs. The base acceleration of both PEHs is held at 7 m/s 2 and the frequency of excitation is tuned to their resonant frequency ( f r ) and then the output power ( P rms ) is monitored for 10 7 fatigue cycles. The effect of fatigue cycles on the output voltage, vibration displacement, dielectric, and ferroelectric properties of PEHs was analyzed. It was noticed that fatigue-induced performance degradation is more prominent in soft SFC-based PEH (SS-PEH) than in hard SFC-based PEH (HS-PEH). The HS-PEH showed a slight degradation in the output power due to a shift in f r , however, no degradation in the maximum power was noticed, in fact, dielectric and ferroelectric properties were improved even after 10 7 vibration cycles. In this context, the present study provides a pathway to consider the fatigue life of piezoelectric material for the designing of PEH to be used at resonant conditions for long-term operation.

Background: Tamarind seed polysaccharide (TSP) is used as a texturizing agent and a thickener in food and pharmaceutical products. There are no publications describing the addition of TSP to intra-articular injection formulations for arthritis., Objective: The purpose of this study was to investigate the rheology and efficacy of the formulation of TSP with hyaluronic acid (HA) as a new material for injection for arthritis., Methods: We investigated the viscoelastic properties of formulations of HA and TSP as potential lubricants for arthritis, and tested the improvement of right/left paw weight distribution in monosodium iodoacetate-induced arthritis in the rat., Results: HA formulations with 3% and 4% TSP showed improved rheological characteristics and were protected against changes induced by heat sterilization. Addition of TSP also reduced pain in the arthritis model, as evidenced by normalization of the distribution of paw weight., Conclusions: TSP is a potential material as a substitute for HA or in combination with HA for intra-articular injection for arthritis.

We report the effect of epoxy adhesion layers with different mechanical or physical property on a magnetoelectric (ME) composite laminate composed of FeBSi alloy (Metglas)/single-crystal Pb(Mg 1/3 Nb 2/3 )O 3 -Pb(Zr,Ti)O 3 /Metglas to achieve an improved ME conversion performance. Through theoretical simulation, it was revealed that the Young's modulus and the thickness of interfacial adhesives were major parameters that influence the conversion efficiency in ME composites. In the experimental evaluation, we utilized three epoxy materials with a distinct Young's modulus and adjusted the average thickness of the adhesion layers to optimize the ME conversion. The experimental results show that a thin epoxy layer with a high Young's modulus provided the best performance in the inorganic-based ME conversion process. By tailoring the interfacial adhesion property, the ME laminate generated a high conversion coefficient of 328.8 V/(cm Oe), with a mechanical quality factor of 132.0 at the resonance mode. Moreover, we demonstrated a highly sensitive alternating current magnetic field sensor that had a detection resolution below 10 pT. The optimization of the epoxy layers in the ME laminate composite provided significant enhancement of the ME response in a simple manner.

Here, a new bioprinting process by combining drop-on-demand inkjet printing with a spray-coating technique, which enables the high-resolution, high-speed, and freeform fabrication of large-scale cell-laden hydrogel structures is reported. Hydrogel structures with various shapes and composed of different materials, including alginate, cellulose nanofiber, and fibrinogen, are fabricated using the inkjet-spray printing. To manufacture cell-friendly hydrogel structures with controllable stiffness, gelatine methacryloyl is saponified to stabilize jet formation and is subsequently mixed with sodium alginate to prepare blend inks. The hydrogels crosslinked from the blend inks are characterized by assessing physical properties including the microstructure and mechanical stiffness and cellular responses including the cell viability, metabolic activity, and functionality of human dermal fibroblasts within the hydrogel. Cell-laden hydrogel structures are generated on a large scale and collagen type I secretion and spreading of cells within the hydrogels are assessed. The results demonstrate that the inkjet-spray printing system will ensure the formation of a cell-laden hydrogel structure with high shape fidelity in a rapid and reliable manner. Ultimately, the proposed printing technique and the blend bioink to be used to fabricate 3D laminated large-scale tissue equivalents that potentially mimic the function of native tissues is expected., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

ATP synthase, H + transporting, mitochondrial F1 complex, δ subunit (ATP5F1D; formerly ATP5D) is a subunit of mitochondrial ATP synthase and plays an important role in coupling proton translocation and ATP production. Here, we describe two individuals, each with homozygous missense variants in ATP5F1D, who presented with episodic lethargy, metabolic acidosis, 3-methylglutaconic aciduria, and hyperammonemia. Subject 1, homozygous for c.245C>T (p.Pro82Leu), presented with recurrent metabolic decompensation starting in the neonatal period, and subject 2, homozygous for c.317T>G (p.Val106Gly), presented with acute encephalopathy in childhood. Cultured skin fibroblasts from these individuals exhibited impaired assembly of F 1 F O ATP synthase and subsequent reduced complex V activity. Cells from subject 1 also exhibited a significant decrease in mitochondrial cristae. Knockdown of Drosophila ATPsynδ, the ATP5F1D homolog, in developing eyes and brains caused a near complete loss of the fly head, a phenotype that was fully rescued by wild-type human ATP5F1D. In contrast, expression of the ATP5F1D c.245C>T and c.317T>G variants rescued the head-size phenotype but recapitulated the eye and antennae defects seen in other genetic models of mitochondrial oxidative phosphorylation deficiency. Our data establish c.245C>T (p.Pro82Leu) and c.317T>G (p.Val106Gly) in ATP5F1D as pathogenic variants leading to a Mendelian mitochondrial disease featuring episodic metabolic decompensation., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

The discovery of a novel, selective and fully efficacious CB 2 agonist with satisfactory pharmacokinetic and pharmaceutical properties is described. Compound 6 was efficacious in a rat model of osteoarthritis pain following oral administration and, in contrast to morphine, maintained its analgesic effect throughout a 5-day subchronic treatment paradigm. These data were consistent with our hypothesis that full agonist efficacy is required for efficient internalization and recycling of the CB 2 receptor to avoid tachyphylaxis. Based on its overall favorable preclinical profile, 6 (APD371) was selected for further development for the treatment of pain., Competing Interests: The authors declare no competing financial interest.

Objective: To compare the effectiveness of extracorporeal shock wave therapy (ESWT) and trigger point injection (TPI) for the treatment of myofascial pain syndrome in the quadratus lumborum., Methods: In a retrospective study at our institute, 30 patients with myofascial pain syndrome in the quadratus lumborum were assigned to ESWT or TPI groups. We assessed ESWT and TPI treatment according to their affects on pain relief and disability improvement. The outcome measures for the pain assessment were a visual analogue scale score and pain pressure threshold. The outcome measures for the disability assessment were Oswestry Disability Index, Roles and Maudsley, and Quebec Back Pain Disability Scale scores., Results: Both groups demonstrated statistically significant improvements in pain and disability measures after treatment. However, in comparing the treatments, we found ESWT to be more effective than TPI for pain relief. There were no statistically significant differences between the groups with respect to disability., Conclusion: Compared to TPI, ESWT showed superior results for pain relief. Thus, we consider ESWT as an effective treatment for myofascial pain syndrome in the quadratus lumborum., Competing Interests: CONFLICT OF INTEREST: No potential conflict of interest relevant to this article was reported.

A ceramic substrate must not only have an excellent thermal performance but also be thin, since the electronic devices have to become thin and small in the electronics industry of the next generation. In this manuscript, a thin ceramic substrate (thickness: 30-70 µm) is reported for the next generation ceramic substrate. It is fabricated by a new process [granule spray in vacuum (GSV)] which is a room temperature process. For the thin ceramic substrates, AlN GSV films are deposited on Al substrates and their electric/thermal properties are compared to those of the commercial ceramic substrates. The thermal resistance is significantly reduced by using AlN GSV films instead of AlN bulk-ceramics in thermal management systems. It is due to the removal of a thermal interface material which has low thermal conductivity. In particular, the dielectric strengths of AlN GSV films are much higher than those of AlN bulk-ceramics which are commercialized, approximately 5 times. Therefore, it can be expected that this GSV film is a next generation substrate in thermal management systems for the high power application.

We previously identified mutations in Nardilysin (dNrd1) in a forward genetic screen designed to isolate genes whose loss causes neurodegeneration in Drosophila photoreceptor neurons. Here we show that NRD1 is localized to mitochondria, where it recruits mitochondrial chaperones and assists in the folding of α-ketoglutarate dehydrogenase (OGDH), a rate-limiting enzyme in the Krebs cycle. Loss of Nrd1 or Ogdh leads to an increase in α-ketoglutarate, a substrate for OGDH, which in turn leads to mTORC1 activation and a subsequent reduction in autophagy. Inhibition of mTOR activity by rapamycin or partially restoring autophagy delays neurodegeneration in dNrd1 mutant flies. In summary, this study reveals a novel role for NRD1 as a mitochondrial co-chaperone for OGDH and provides a mechanistic link between mitochondrial metabolic dysfunction, mTORC1 signaling, and impaired autophagy in neurodegeneration., (Copyright © 2017 Elsevier Inc. All rights reserved.)

We present drop-on-demand inkjet-based mammalian cell printing with a 30- μ m nozzle diameter for cell-level accuracy. High-speed imaging techniques have been used to analyze the go-and-stop movement of cells inside the nozzle under a pulsed pressure generated by a piezo-actuator and the jet formation after ejection. Patterning of an array of 20 × 20 dots on a glass substrate reveals that each printed drop contains 1.30 cells on average at the cell concentration of 5.0 × 10 6 cells ml -1 for the very small nozzle, whereas larger nozzles with the diameter of 50 and 80  μ m deliver 2.57 and 2.88 cells per drop, respectively. The effects of the size and concentration of printed cells on the number of cells have also been investigated. Furthermore, the effect of the nozzle diameter on printed cells has been evaluated through an examination of viability, proliferation, and morphology of cells by using a live/dead assay kit, CCK-8 assay, and cellular morphology imaging, respectively. We believe that the 30- μ m inkjet nozzle can be used for precise cell deposition without any damages to the printed mammalian cells.

Four mutations in the VAMP/synaptobrevin-associated protein B (VAPB) gene have been linked to amyotrophic lateral sclerosis (ALS) type 8. The mechanism by which VAPB mutations cause motor neuron disease is unclear, but studies of the most common P56S variant suggest both loss of function and dominant-negative sequestration of wild-type protein. Diminished levels of VAPB and its proteolytic cleavage fragment have also been reported in sporadic ALS cases, suggesting that VAPB loss of function may be a common mechanism of disease. Here, we tested whether neuronal overexpression of wild-type human VAPB would attenuate disease in a mouse model of familial ALS1. We used neonatal intraventricular viral injections to express VAPB or YFP throughout the brain and spinal cord of superoxide dismutase (SOD1) G93A transgenic mice. Lifelong elevation of neuronal VAPB slowed the decline of neurological impairment, delayed denervation of hindlimb muscles, and prolonged survival of spinal motor neurons. Collectively, these changes produced a slight but significant extension in lifespan, even in this highly aggressive model of disease. Our findings lend support for a protective role of VAPB in neuromuscular health.

ATPase family AAA-domain containing protein 3A (ATAD3A) is a nuclear-encoded mitochondrial membrane protein implicated in mitochondrial dynamics, nucleoid organization, protein translation, cell growth, and cholesterol metabolism. We identified a recurrent de novo ATAD3A c.1582C>T (p.Arg528Trp) variant by whole-exome sequencing (WES) in five unrelated individuals with a core phenotype of global developmental delay, hypotonia, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy. We also describe two families with biallelic variants in ATAD3A, including a homozygous variant in two siblings, and biallelic ATAD3A deletions mediated by nonallelic homologous recombination (NAHR) between ATAD3A and gene family members ATAD3B and ATAD3C. Tissue-specific overexpression of bor R534W , the Drosophila mutation homologous to the human c.1582C>T (p.Arg528Trp) variant, resulted in a dramatic decrease in mitochondrial content, aberrant mitochondrial morphology, and increased autophagy. Homozygous null bor larvae showed a significant decrease of mitochondria, while overexpression of bor WT resulted in larger, elongated mitochondria. Finally, fibroblasts of an affected individual exhibited increased mitophagy. We conclude that the p.Arg528Trp variant functions through a dominant-negative mechanism that results in small mitochondria that trigger mitophagy, resulting in a reduction in mitochondrial content. ATAD3A variation represents an additional link between mitochondrial dynamics and recognizable neurological syndromes, as seen with MFN2, OPA1, DNM1L, and STAT2 mutations., (Copyright © 2016 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

In this manuscript, an interesting phenomenon is reported. That is the self-growth of single crystals in Pb-free piezoelectric ceramics. These crystals are several centimeters in size. They are grown without any seed addition through a normal sintering process in modified potassium sodium niobate ceramics. It has been achieved by the composition designed to compensate the Na(+) loss which occurs during the liquid phase sintering. The composition of the crystals is (K0.4925Na(0.4925-x)Ba(0.015+x/2))Nb(0.995+x)O3 [x is determined by the Na(+) loss, due to Na2O volatilization]. These crystals have high piezoelectric voltage coefficients (g33, 131 10(-3)Vm/N), indicating that they are good candidates for piezoelectric sensors and energy harvesting devices. We hope that this report can offer the opportunity for many researchers to have an interest in these crystals.

The design and optimization of a novel trans-1,4-dioxycyclohexane GPR119 agonist series is described. A lead compound 21 was found to be a potent and efficacious GPR119 agonist across species, and possessed overall favorable pharmaceutical properties. Compound 21 demonstrated robust acute and chronic regulatory effects on glycemic parameters in the diabetic or non-diabetic rodent models., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Purpose: Downstaging after chemoradiotherapy (CRT) for rectal cancer usually occurs. The present study aimed to evaluate pathologic y-stage (yp-stage) and its influence on local recurrence and systemic recurrence in rectal cancer patients treated with CRT followed by surgical resection., Methods: We retrospectively analyzed 261 patients underwent preoperative CRT and radical resection for rectal cancer between August 2004 and December 2010. Patients received preoperative CRT consisting of 5-fluorouracil and leucovorin delivered with concurrent pelvic radiation of 45.0-50.4 Gy, followed by radical surgery at 6-8 weeks after CRT., Results: Of the 261 patients, 24 (9.2%) had yp-stage 0, 83 (31.8%) had yp-stage I, 86 (32.9%) had yp-stage II, and 68 (26.1%) had yp-stage III. Patients with yp-stage III had a greater prevalence of preoperative CEA, poorly differentiated tumor, lymphovascular invasion (LVI) and perineural invasion (PNI) than patients with lower yp-stages. We found that yp-stage, preoperative CEA, LVI, PNI and tumor regression grade were significant prognostic factors for both local and systemic recurrence. In multivariate analysis, yp-stage, LVI and PNI were significant factors for local and systemic recurrence. During the median follow-up of 37.5 months, the five-year local recurrence-free survival rate was 100.0%, 95.0%, 89.3%, and 80.6% of yp-stage 0-III, respectively. The five-year systemic recurrence-free survival was 95.8%, 75.3%, 71.4%, and 48.8% of yp-stages 0-III, respectively., Conclusion: The yp-stage after preoperative CRT for rectal cancer is closely correlated with local and systemic recurrence-free survival. Therefore, yp-stage should be considered as a prognostic factor for rectal cancer patients having a course of preoperative CRT.

Presynaptic resting Ca(2+) influences synaptic vesicle (SV) release probability. Here, we report that a TRPV channel, Inactive (Iav), maintains presynaptic resting [Ca(2+)] by promoting Ca(2+) release from the endoplasmic reticulum in Drosophila motor neurons, and is required for both synapse development and neurotransmission. We find that Iav activates the Ca(2+)/calmodulin-dependent protein phosphatase calcineurin, which is essential for presynaptic microtubule stabilization at the neuromuscular junction. Thus, loss of Iav induces destabilization of presynaptic microtubules, resulting in diminished synaptic growth. Interestingly, expression of human TRPV1 in Iav-deficient motor neurons rescues these defects. We also show that the absence of Iav causes lower SV release probability and diminished synaptic transmission, whereas Iav overexpression elevates these synaptic parameters. Together, our findings indicate that Iav acts as a key regulator of synaptic development and function by influencing presynaptic resting [Ca(2+)]., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Thick polycrystalline pure PbTiO3 films with nano size grains were synthesized for the first time by aerosol deposition. Annealed 7 μm thick films exhibit well-saturated ferroelectric hysteresis loops with a remanent polarization and coercive field of 35 μC/cm(2) and 94 kV/cm, respectively. A large-signal effective d33,eff value of >60 pm/V is achieved at room temperature. The measured ferroelectric transition temperature (Tc) of the films ∼550 °C is >50 °C higher than the reported values (∼490 °C) for PbTiO3 ceramics. First-principles calculations combined with electron energy loss spectroscopy (EELS) and structural analysis indicate that the film is composed of nano size grains with slightly decreased tetragonality. There is no severe off-stoichiometry, but a high compressive in-plane residual stress was observed in the film along with a high transition temperature and piezoelectric response. The ferroelectric characteristics were sustained until 200 °C, providing significant advancement toward realizing high temperature piezoelectric materials.

Background: Combination therapy is key to improving cancer treatment efficacy. Phorbol 12-myristate 13-acetate (PMA), a well-known PKC activator, increases the cytotoxicity of several anticancer drugs. Apicularen A induces cytotoxicity in tumor cells through disrupting microtubule networks by tubulin down-regulation. In this study, we examined whether PMA increases apicularen A-induced cytotoxicity in HeLa cells., Methods: Cell viability was examined by thiazolyl blue tetrazolium (MTT) assays. To investigate apoptotic potential of apicularen A, DNA fragmentation assays were performed followed by extracting genomic DNA, and caspase-3 activity assays were performed by fluorescence assays using fluorogenic substrate. The cell cycle distribution induced by combination with PMA and apicularen A was examined by flow cytometry after staining with propidium iodide (PI). The expression levels of target proteins were measured by Western blotting analysis using specific antibodies, and α-tubulin mRNA levels were assessed by reverse transcription polymerase chain reaction (RT-PCR). To examine the effect of combination of PMA and apicularen A on the microtubule architecture, α-tubulin protein and nuclei were visualized by immunofluorescence staining using an anti-α-tubulin antibody and PI, respectively., Results: We found that apicularen A induced caspase-dependent apoptosis in HeLa cells. PMA synergistically increased cytotoxicity and apoptotic sub-G1 population induced by apicularen A. These effects were completely blocked by the PKC inhibitors Ro31-8220 and Go6983, while caspase inhibition by Z-VAD-fmk did not prevent cytotoxicity. RNA interference using siRNA against PKCα, but not PKCβ and PKCγ, inhibited cytotoxicity induced by combination PMA and apicularen A. PMA increased the apicularen A-induced disruption of microtubule networks by further decreasing α- and β-tubulin protein levels in a PKC-dependent manner., Conclusions: These results suggest that the synergy between PMA and apicularen A is involved by PKCα activation and microtubule disruption, and that may inform the development of novel approaches to treat cancer.

Parkinson's disease (PD) is a common neurodegenerative disease, yet the underlying causative molecular mechanisms are ill defined. Numerous observations based on drug studies and mutations in genes that cause PD point to a complex set of rather subtle mitochondrial defects that may be causative. Indeed, intensive investigation of these genes in model organisms has revealed roles in the electron transport chain, mitochondrial protein homeostasis, mitophagy, and the fusion and fission of mitochondria. Here, we attempt to synthesize results from experimental studies in diverse systems to define the precise function of these PD genes, as well as their interplay with other genes that affect mitochondrial function. We propose that subtle mitochondrial defects in combination with other insults trigger the onset and progression of disease, in both familial and idiopathic PD.

Apicularen A is a novel antitumor agent and strongly induces death in tumor cells. In this study, we synthesized apicularen A acetate, an acetyl derivative of apicularen A, and investigated its antitumor effect and mechanism in HM7 colon cancer cells. Apicularen A acetate induced apoptotic cell death and caspase-3 activation; however, the pan-caspase inhibitor Z-VAD-fmk could not prevent this cell death. Apicularen A acetate induced the loss of mitochondrial membrane potential and the translocation of apoptosis-inducing factor (AIF) from mitochondria. In addition, apicularen A acetate significantly decreased tubulin mRNA and protein levels and induced disruption of microtubule networks. Taken together, these results indicate that the mechanism of apicularen A acetate involves caspase-independent apoptotic cell death and disruption of microtubule architecture., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: We examined factors associated with positive consequences for family members who served as caregivers of terminal cancer patients., Methods: We conducted a nationwide cross-sectional survey of 501 bereaved family members who served as caregivers for terminal cancer patients. The main outcomes were measured by the previously developed Caregiving Consequences Inventory, which assesses perceived rewards and burdens of caregiving., Results: Bereaved family caregivers reported high levels of perceived rewards and burden. Among the characteristics of bereaved family members, older age, female gender, and having a religion were associated with some domains of perceived rewards, but being a spouse of a patient was negatively associated with some domains of perceived rewards. Caregiver depression or perceived burden did not affect positive consequences of caregiving. However, receiving bereavement care was significantly associated with positive outcome in all four perceived reward domains (sense of mastery [adjusted odds ratio {aOR} = 1.69; 95% CI, 1.05-2.70]; appreciation for others [aOR = 2.19; 95% CI, 1.27-3.76]; meaning in life [aOR = 1.80; 95% CI, 1.13-2.89]; and reprioritization about his/her life [aOR = 2.02; 95% CI, 1.27-3.19])., Conclusions: Family caregivers of terminal cancer patients experience burdens, but caregiving also has positive consequences. This study has important implications for the development of bereavement interventions that aim to encourage positive outcomes and reduce negative outcomes for caregivers., (Copyright © 2012 John Wiley & Sons, Ltd.)