bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical and bi-genomic DNA findings of patients suspected to have mitochondrial diseases
Authors: Gedikbasi Asuman , Toksoy Guven , Karaca Meryem , Gulec Cagri , Balci Mehmet Cihan , Gunes Dilek , Gunes Seda , Aslanger Ayca Dilruba , Unverengil Gokcen , Karaman Birsen , Basaran Seher , Demirkol Mubeccel , Gokcay Gulden Fatma , Uyguner Zehra Oya 
Published: June 2023

Background: Mitochondrial diseases are the most common group of inherited metabolic disorders, causing difficulties in definite diagnosis due to clinical and genetic heterogeneity. Clinical components are predominantly associated with pathogenic variants shown in nuclear or mitochondrial genomes that affect vital respiratory chain function. The development of high-throughput sequencing technologies has accelerated the elucidation of the genetic etiology of many genetic diseases that previously remained undiagnosed.Methods: Thirty affected patients from 24 unrelated families with clinical, radiological, biochemical, and histopathological evaluations considered for mitochondrial diseases were investigated. DNA isolated from the peripheral blood samples of probands was sequenced for nuclear exome and mitochondrial DNA (mtDNA) analyses. MtDNA sequencing was also performed from the muscle biopsy material in one patient. For segregation, Sanger sequencing is performed for pathogenic alterations in five other affected family members and healthy parents.Results: Exome sequencing revealed 14 different pathogenic variants in nine genes encoding mitochondrial function peptides (AARS2, EARS2, ECHS1, FBXL4, MICOS13, NDUFAF6, OXCT1, POLG, and TK2) in 12 patients from nine families and four variants in genes encoding important for muscle structure (CAPN3, DYSF, and TCAP) in six patients from four families. Three probands carried pathogenic mtDNA variations in two genes (MT-ATP6 and MT-TL1). Nine variants in five genes are reported for the first time with disease association: (AARS2: c.277C&gt;T/p.(R93*), c.845C&gt;G/p.(S282C); EARS2: c.319C&gt;T/p.(R107C), c.1283delC/p.(P428Lfs*); ECHS1: c.161G&gt;A/p.(R54His); c.202G&gt;A/p.(E68Lys); NDUFAF6: c.479delA/p.(N162Ifs*27); and OXCT1: c.1370C&gt;T/p.(T457I), c.1173-139G&gt;T/p.(?).Conclusion: Bi-genomic DNA sequencing clarified genetic etiology in 67% (16/24) of the families. Diagnostic utility by mtDNA sequencing in 13% (3/24) and exome sequencing in 54% (13/24) of the families prioritized searching for nuclear genome pathologies for the first-tier test. Weakness and muscle wasting observed in 17% (4/24) of the families underlined that limb-girdle muscular dystrophy, similar to mitochondrial myopathy, is an essential point for differential diagnosis. The correct diagnosis is crucial for comprehensive genetic counseling of families. Also, it contributes to making treatment-helpful referrals, such as ensuring early access to medication for patients with mutations in the TK2 gene.
Modification of Pacific water in the northern Canadian Arctic
Authors: Dmitrenko Igor A. , Kirillov Sergei A. , Rudels Bert , Geilfus Nicolas-Xavier , Ehn Jens , Babb David G. , Lilien David A. , Dahl-Jensen Dorthe 
Published: June 2023

The oceanography of the northern Canadian Arctic Archipelago (CAA) remains poorly studied. Here we present a unique set of conductivity–temperature–depth (CTD) and nitrate profiles collected in a fjord system around Axel Heiberg Island in the northern CAA during April–May 2022. The profiles are examined within the context of upstream observations in the Arctic Ocean and downstream observations in the central CAA, and reveal the origin of water masses and their interactions with ambient water from the continental slope and the nearby tidewater glacier outlet. The subsurface water (~25–180 m depth) is associated with the Pacific water outflow from the Arctic Ocean. The underlying halocline separates Pacific water from a deeper layer of polar water that has interacted with the warm (&gt;0°C) Atlantic water observed below 240 m depth. Pacific water is significantly modified compared to the adjoining Arctic Ocean, as evidenced by the following details. Cold water intrusions from the tidewater glacier create deviations of ~0.25°C in the temperature profile through the subsurface water down to a depth of 140 m. Profiles show no thermal signature of Pacific summer water. Compared to the adjacent Arctic Ocean, the deeper fraction of Pacific-derived water and the Atlantic-modified polar water are warmer, while the underlying Atlantic water is colder. Overall, our results suggest that Pacific and Atlantic water in this area of the northern CAA are modified due to enhanced vertical mixing in a narrow band over the continental slope and shelf off the CAA, and are further modified by interactions with outlet glaciers in the area. This implies that tracing the initial thermohaline signature of the Pacific and Atlantic water flow through the CAA seems to be hardly possible without the use of additional tracers. We also find evidence of geothermal heating near the seafloor, which is not surprising given the observed presence of terrestrial geothermal vents around Axel Heiberg Island, and speculate this heat flux limits ice growth near the glacier terminus.
EZH1/2 dual inhibitors suppress HTLV-1-infected cell proliferation and hyperimmune response in HTLV-1-associated myelopathy
Authors: Koseki Akihito , Araya Natsumi , Yamagishi Makoto , Yamauchi Junji , Yagishita Naoko , Takao Naoki , Takahashi Katsunori , Kunitomo Yasuo , Honma Daisuke , Araki Kazushi , Uchimaru Kaoru , Sato Tomoo , Yamano Yoshihisa 
Published: June 2023

BackgroundHuman T-cell leukemia virus type 1 (HTLV-1) causes HTLV-1-associated myelopathy (HAM), adult T-cell leukemia/lymphoma (ATL), HTLV-1-associated uveitis, and pulmonary diseases. Although both HAM and ATL show proliferation of infected cells, their pathogeneses are quite different. In particular, the pathogenesis of HAM is characterized by hyperimmune responses to HTLV-1-infected cells. Recently, we demonstrated the overexpression of histone methyltransferase EZH2 in ATL cells and the cytotoxic effects of EZH2 inhibitors and EZH1/2 dual inhibitors on these cells. However, these phenomena have never been studied in HAM. Furthermore, what effect these agents have on the hyperimmune response seen in HAM is completely unknown.MethodsIn this study, we investigated histone methyltransferase expression levels in infected cell populations (CD4+ and CD4+CCR4+ cells) from patients with HAM using microarray and RT-qPCR analyses. Next, using an assay system that utilizes the spontaneous proliferation characteristic of peripheral blood mononuclear cells derived from patients with HAM (HAM-PBMCs), we investigated the effects of EZH2 selective inhibitors (GSK126 and tazemetostat) and EZH1/2 dual inhibitors (OR-S1 and valemetostat, also known as DS-3201), particularly on cell proliferation rate, cytokine production, and HTLV-1 proviral load. We also examined the effect of EZH1/2 inhibitors on the proliferation of HTLV-1-infected cell lines (HCT-4 and HCT-5) derived from patients with HAM.ResultsWe found elevated expression of EZH2 in CD4+ and CD4+CCR4+ cells from patients with HAM. EZH2 selective inhibitors and EZH1/2 inhibitors significantly inhibited spontaneous proliferation of HAM-PBMC in a concentration-dependent manner. The effect was greater with EZH1/2 inhibitors. EZH1/2 inhibitors also reduced the frequencies of Ki67+ CD4+ T cells and Ki67+ CD8+ T cells. Furthermore, they reduced HTLV-1 proviral loads and increased IL-10 levels in culture supernatants but did not alter IFN-γ and TNF-α levels. These agents also caused a concentration-dependent inhibition of the proliferation of HTLV-1-infected cell lines derived from patients with HAM and increased annexin-V(+)7-aminoactinomycin D(−) early apoptotic cells.ConclusionThis study showed that EZH1/2 inhibitors suppress HTLV-1-infected cell proliferation through apoptosis and the hyperimmune response in HAM. This indicates that EZH1/2 inhibitors may be effective in treating HAM.
Reliability and validity of the electronic version of the Hopkins verbal learning test-revised in middle-aged and elderly Chinese people
Authors: Jiang Lichen , Xu Ming , Xia Shunyao , Zhu Jiahui , Zhou Qi , Xu Luoyi , Shi Chuan , Wu Daxing 
Published: June 2023

BackgroundThe aging population is increasing, making it essential to have a standardized, convenient, and valid electronic memory test that can be accessed online for older people and caregivers. The electronic version of the Hopkins Verbal Learning Test-Revised (HVLT-R) as a test with these advantages and its reliability and validity has not yet been tested. Thus, this study examined the reliability and validity of the electronic version of the HVLT-R in middle-aged and elderly Chinese people to provide a scientific basis for its future dissemination and use.MethodsWe included 1,925 healthy participants aged over 40, among whom 38 were retested after 3–6 months. In addition, 65 participants completed both the pad and paper-and-pencil versions of the HVLT-R (PAP-HVLT-R). We also recruited 42 Alzheimer’s disease (AD) patients, and 45 amnestic mild cognitive impairment (aMCI) patients. All participants completed the Pad-HVLT-R, the Hong Kong Brief Cognitive Test (HKBC), the Brief Visual Memory Test-Revised (BVMT-R), and the Logical Memory Test (LM).Results(1) Reliability: the Cronbach’s α value was 0.94, the split-half reliability was 0.96. The test–retest correlation coefficients were moderate, ranging from 0.38 to 0.65 for direct variables and 0.16 to 0.52 for derived variables; (2) Concurrent validity: the Pad-HVLT-R showed a moderate correlation with the HKBC and BVMT-R, with correlation coefficients between total recall of 0.41 and 0.54, and between long-delayed recall of 0.42 and 0.59, respectively. It also showed a high correlation with the LM, with correlation coefficients of 0.72 for total recall and 0.62 for long-delayed recall; (3) Convergent validity: the Pad-HVLT-R was moderately correlated with the PAP version, with correlation coefficients ranging from 0.29 to 0.53 for direct variables and 0.15 to 0.43 for derived variables; (4) Discriminant capacity: the Pad-HVLT-R was effective in differentiating AD patients, as demonstrated by the ROC analysis with AUC values of 0.834 and 0.934 for total recall and long-delayed recall, respectively.Conclusion(1) The electronic version of HVLT-R has good reliability and validity in middle-aged and elderly Chinese people; (2) The electronic version of HVLT-R can be used as an effective tool to distinguish AD patients from healthy people.
Predicting DWI-FLAIR mismatch on NCCT: the role of artificial intelligence in hyperacute decision making
Authors: Kim Beom Joon , Zhu Kairan , Qiu Wu , Singh Nishita , McDonough Rosalie , Cimflova Petra , Bala Fouzi , Kim Jongwook , Kim Yong Soo , Bae Hee-Joon , Menon Bijoy K. 
Published: June 2023

BackgroundThe presence of diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) mismatch was used to determine eligibility for intravenous thrombolysis in clinical trials. However, due to the restricted availability of MRI and the ambiguity of image assessment, it is not widely implemented in clinical practice.MethodsA total of 222 acute ischemic stroke patients underwent non-contrast computed tomography (NCCT), DWI, and FLAIR within 1 h of one another. Human experts manually segmented ischemic lesions on DWI and FLAIR images and independently graded the presence of DWI-FLAIR mismatch. Deep learning (DL) models based on the nnU-net architecture were developed to predict ischemic lesions visible on DWI and FLAIR images using NCCT images. Inexperienced neurologists evaluated the DWI-FLAIR mismatch on NCCT images without and with the model’s results.ResultsThe mean age of included subjects was 71.8 ± 12.8  years, 123 (55%) were male, and the baseline NIHSS score was a median of 11 [IQR, 6–18]. All images were taken in the following order: NCCT – DWI – FLAIR, starting after a median of 139 [81–326] min after the time of the last known well. Intravenous thrombolysis was administered in 120 patients (54%) after NCCT. The DL model’s prediction on NCCT images revealed a Dice coefficient and volume correlation of 39.1% and 0.76 for DWI lesions and 18.9% and 0.61 for FLAIR lesions. In the subgroup with 15  mL or greater lesion volume, the evaluation of DWI-FLAIR mismatch from NCCT by inexperienced neurologists improved in accuracy (from 0.537 to 0.610) and AUC-ROC (from 0.493 to 0.613).ConclusionThe DWI-FLAIR mismatch may be reckoned using NCCT images through advanced artificial intelligence techniques.
OPRM1 A118G polymorphism modulating motor pathway for pain adaptability in women with primary dysmenorrhea
Authors: Hsu Pei-Shan , Cheng Chou-Ming , Chao Hsiang-Tai , Lin Ming-Wei , Li Wei-Chi , Lee Lin-Chien , Liu Ching-Hsiung , Chen Li-Fen , Hsieh Jen-Chuen 
Published: June 2023

IntroductionPrimary dysmenorrhea (PDM) is a common condition among women of reproductive age, characterized by menstrual pain in the absence of any organic causes. Previous research has established a link between the A118G polymorphism in the mu-opioid receptor (OPRM1) gene and pain experience in PDM. Specifically, carriers of the G allele have been found to exhibit maladaptive functional connectivity between the descending pain modulatory system and the motor system in young women with PDM. This study aims to explore the potential relationship between the OPRM1 A118G polymorphism and changes in white matter in young women with PDM.MethodsThe study enrolled 43 individuals with PDM, including 13 AA homozygotes and 30 G allele carriers. Diffusion tensor imaging (DTI) scans were performed during both the menstrual and peri-ovulatory phases, and tract-based spatial statistics (TBSS) and probabilistic tractography were used to explore variations in white matter microstructure related to the OPRM1 A118G polymorphism. The short-form McGill Pain Questionnaire (MPQ) was used to access participants’ pain experience during the MEN phase.ResultsTwo-way ANOVA on TBSS analysis revealed a significant main effect of genotype, with no phase effect or phase-gene interaction detected. Planned contrast analysis showed that during the menstrual phase, G allele carriers had higher fractional anisotropy (FA) and lower radial diffusivity in the corpus callosum and the left corona radiata compared to AA homozygotes. Tractographic analysis indicated the involvement of the left internal capsule, left corticospinal tract, and bilateral medial motor cortex. Additionally, the mean FA of the corpus callosum and the corona radiata was negatively correlated with MPQ scales in AA homozygotes, but this correlation was not observed in G allele carriers. No significant genotype difference was found during the pain-free peri-ovulary phase.DiscussionOPRM1 A118G polymorphism may influence the connection between structural integrity and dysmenorrheic pain, where the G allele could impede the pain-regulating effects of the A allele. These novel findings shed light on the underlying mechanisms of both adaptive and maladaptive structural neuroplasticity in PDM, depending on the specific OPRM1 polymorphism.
Early life growth and developmental trajectory in children with biliary atresia undergoing primary liver transplantation
Authors: Fang Heping , Li Zehao , Xian Ruoling , Yin Yu , Wang Juan , Guo Hongling , Dai Xiaoke , Zhang Mingman , Hu Yan , Li Yingcun 
Published: June 2023

ObjectiveTo clarify the early growth and developmental characteristics of children with biliary atresia (BA) undergoing primary liver transplantation (pLT).MethodsA prospective cohort study, which specifically focused on BA-pLT children, was conducted after the diagnosis of BA by following the children at the time of pLT and 1, 3, 5, 7 months and 1 year after pLT for growth and developmental monitoring. The growth parameters were calculated according to the WHO standard, and the developmental status was assessed using Denver Developmental Screening Tests.ResultsA total of 48 BA children who received pLT at the age of 5.00 ± 0.94 months were analyzed. The weight-for-ageZ-value (ZW) and length-for-ageZ-value (ZL) were higher than the head circumference-for-ageZ-value (ZHC) at pLT (P = 0.002 and 0.02), but they were all lower than the WHO growth standard (Z = 0) (P &lt; 0.001). TheZWandZHCdecreased first and then returned to the population level at 1 year after pLT, while theZLonly returned to the preoperative status and was lower than theZWandZHC(P &lt; 0.001). Developmental screening showed that 35% (17/48) of the children were defined as suspicious and 15% (7/48) were abnormal at 1–4 months after pLT, the most likely time to be suspected of developmental delay. At 1 year after pLT, gross motor skill delay still existed (12/45, 27%), and language skill delay began to appear (4/45, 9%).ConclusionsBA-pLT children suffer from growth and developmental problems. LowZHCis the main growth problem before pLT, while lowZLis the problem after pLT. Developmental delays are significant after pLT, especially in motor and language skills. The current study suggested that further studies are warranted to clarify the long-term growth and developmental outcomes of BA-pLT children, to compare them with children undergoing the Kasai procedure and to explore their influencing factors and possible mechanisms.
Bifunctional antibiotic hybrids: A review of clinical candidates
Authors: Koh Augustine Jing Jie , Thombare Varsha , Hussein Maytham , Rao Gauri G. , Li Jian , Velkov Tony 
Published: June 2023

Antibiotic resistance is a top threat to human health and a priority across the globe. This problematic issue is accompanied by the decline of new antibiotics in the pipeline over the past 30 years. In this context, an urgent need to develop new strategies to combat antimicrobial resistance is in great demand. Lately, among the possible approaches used to deal with antimicrobial resistance is the covalent ligation of two antibiotic pharmacophores that target the bacterial cells through a dissimilar mode of action into a single hybrid molecule, namely hybrid antibiotics. This strategy exhibits several advantages, including better antibacterial activity, overcoming the existing resistance towards individual antibiotics, and may ultimately delay the onset of bacterial resistance. This review sheds light on the latest development of the dual antibiotic hybrids pipeline, their potential mechanisms of action, and challenges in their use.
Height and subjective body image are associated with suicide ideation among Korean adolescents
Authors: Song Kyungchul , Lee Junghan , Lee San , Jeon Soyoung , Lee Hye Sun , Kim Ho-Seong , Chae Hyun Wook 
Published: June 2023

IntroductionSuicide is the leading cause of death among Korean adolescents. Suicide has been found to be associated with body mass index (BMI), height, and subjective body image among adults, but investigations of these associations among adolescents are limited. Thus, we aimed to examine to what extent suicide ideation is associated with height, BMI, and subjective body image among Korean adolescents.MethodsThis study examined the data of 6,261 adolescents, selected from a nationally representative survey. The participants were divided into subgroups by sex, suicide ideation, and subjective body image. Logistic regression analyses were performed to examine the association of suicide ideation with height, BMI, and subjective body image.ResultsThe proportion of perceived obesity was high in the total sample; the height Z-score was lower for the group with suicide ideation than the group without suicide ideation; the height Z-scores were also lower for female participants with suicide ideation than those female participants without suicide ideation. The proportions of depressed mood, suicide ideation, and suicide attempts were higher among the total sample and female participants with perceived obesity than among those with a normal body image. On logistic regression, perceived obesity was positively associated with suicide ideation even after adjusting for age, height Z-score, weight Z-score, and depressed mood, whereas height Z-score was negatively associated with suicide ideation. These relationships were more prominent among female participants than among male participants.ConclusionLow height and perceived obesity, not real obesity, are associated with suicide ideation among Korean adolescents. These findings indicate that the need for an integrated approach to growth, body image, and suicide in adolescents is warranted.
Robust segregation of donor and recipient cells from single-cell RNA-sequencing of transplant samples
Authors: Wilson Gavin W. , Duong Allen , Moshkelgosha Sajad , Bader Gary , Keshavjee Shaf , Martinu Tereza , Juvet Stephen C. , Yeung Jonathan C. 
Published: June 2023

BackgroundSingle-cell RNA-sequencing (scRNA-seq) technology has revealed novel cell populations in organs, uncovered regulatory relationships between genes, and allowed for tracking of cell lineage trajectory during development. It demonstrates promise as a method to better understand transplant biology; however, fundamental bioinformatic tools for its use in the context of transplantation have not been developed. One major need has been a robust method to identify cells as being either donor or recipient genotype origin, and ideally without the need to separately sequence the donor and recipient.MethodsWe implemented a novel two-stage genotype discovery method (scTx) optimized for transplant samples by being robust to disparities in cell number and cell type. Using both in silico and real-world scRNA-seq transplant data, we benchmarked our method against existing demultiplexing methods to profile their limitations in terms of sequencing depth, donor and recipient cell imbalance, and single nucleotide variant input selection.ResultsUsing in silico data, scTx could more accurately separate donor from recipient cells and at much lower genotype ratios than existing methods. This was further validated using solid-organ scRNA-seq data where scTx could more reliably identify when a second genotype was present and at lower numbers of cells from a second genotype.ConclusionscTx introduces the capability to accurately segregate donor and recipient gene expression at the single-cell level from scRNA-seq data without the need to separately genotype the donor and recipient. This will facilitate the use of scRNA-seq in the context of transplantation.