Miracle-dz/UniFAR-FTUs huggingface dataset:
Association of BRCA Mutations and Anti-müllerian Hormone Level in Young Breast Cancer Patients

Background: Several preclinical and clinical studies have suggested that BRCA-mutation carriers may have decreased ovarian reserve. However, data in this area are limited and inconsistent, especially in young breast cancer patients. Objective: This study evaluated the association between BRCA mutation status and serum anti-Müllerian hormone (AMH) level in young, reproductive-aged patients with breast cancer. Materials and Methods: Patients ≤ 40 years of age with breast cancer and who had known BRCA status and baseline serum AMH level at Samsung Medical Center, Seoul, Korea, were considered for inclusion. A total of 52 BRCA mutation carriers (27 BRCA1 and 25 BRCA2) and 264 non-carriers were selected for analyses. The serum level of AMH was compared according to presence of a BRCA mutation, and linear and logistic regression analyses were performed to evaluate the association between BRCA mutation and serum AMH level. Results: No difference was found in clinical characteristics between BRCA-mutation carriers and non-carriers. Subjects with any BRCA mutation had a significantly lower median AMH than those without a mutation (2.60 vs. 3.85 ng/mL, 32% reduction, P = 0.004). Linear regression analysis showed a significant negative association between BRCA mutation and AMH level. In addition, logistic regression demonstrated non-significantly increased odds of mutation carriers having AMH < 1.2 ng/mL. However, no difference was found between BRCA1/2 mutations. Conclusions: Breast cancer patients with BRCA mutation have significantly lower serum AMH level. Fertility preservation should be considered more aggressively in young breast cancer patients with BRCA mutation.
Microbiota of the Gut-Lymph Node Axis: Depletion of Mucosa-Associated Segmented Filamentous Bacteria and Enrichment of Methanobrevibacter by Colistin Sulfate and Linco-Spectin in Pigs

Microorganisms are translocated from the gut to lymphatic tissues via immune cells, thereby challenging and training the mammalian immune system. Antibiotics alter the gut microbiome and consecutively might also affect the corresponding translocation processes, resulting in an imbalanced state between the intestinal microbiota and the host. Hence, understanding the variant effects of antibiotics on the microbiome of gut-associated tissues is of vital importance for maintaining metabolic homeostasis and animal health. In the present study, we analyzed the microbiome of (i) pig feces, ileum, and ileocecal lymph nodes under the influence of antibiotics (Linco-Spectin and Colistin sulfate) using 16S rRNA gene sequencing for high-resolution community profiling and (ii) ileocecal lymph nodes in more detail with two additional methodological approaches, i.e., cultivation of ileocecal lymph node samples and (iii) metatranscriptome sequencing of a single lymph node sample. Supplementation of medicated feed showed a local effect on feces and ileal mucosa-associated microbiomes. Pigs that received antibiotics harbored significantly reduced amounts of segmented filamentous bacteria (SFB) along the ileal mucosa (p = 0.048; 199.17-fold change) and increased amounts of Methanobrevibacter, a methanogenic Euryarchaeote in fecal samples (p = 0.005; 20.17-fold change) compared to the control group. Analysis of the porcine ileocecal lymph node microbiome exposed large differences between the viable and the dead fraction of microorganisms and the microbiome was altered to a lesser extent by antibiotics compared with feces and ileum. The core microbiome of lymph nodes was constituted mainly of Proteobacteria. RNA-sequencing of a single lymph node sample unveiled transcripts responsible for amino acid and carbohydrate metabolism as well as protein turnover, DNA replication and signal transduction. The study presented here is the first comparative study of microbial communities in feces, ileum, and its associated ileocecal lymph nodes. In each analyzed site, we identified specific phylotypes susceptible to antibiotic treatment that can have profound impacts on the host physiological and immunological state, or even on global biogeochemical cycles. Our results indicate that pathogenic bacteria, e.g., enteropathogenic Escherichia coli, could escape antibiotic treatment by translocating to lymph nodes. In general ileocecal lymph nodes harbor a more diverse and active community of microorganisms than previously assumed.
Collectivism Is Associated With Greater Neurocognitive Fluency in Older Adults

Neuropsychological research has been limited in the representation of cultural diversity due to various issues, raising questions regarding the applicability of findings to diverse populations. Nonetheless, culture-dependent differences in fundamental psychological processes have been demonstrated. One of the most basic of these, self-construal (individualism, collectivism), is central to how many other differences are interpreted. Self-construals may have possible consequences on social interactions, emotions, motivation, and cognition. This study aimed to evaluate the impact of self-construal on neurocognitive functions in older adults. A total of 86 community-dwelling older adults 60 years and older were assessed with three common self-report measures of self-construal along individualism and collectivism (IC). A cognitive battery was administered to assess verbal and non-verbal fluency abilities. Latent profile analysis (LPA) was used to categorize individuals according to IC, and one-way analyses of covariance (ANCOVA), including relevant covariates (e.g., ethnicity, gender, linguistic abilities), were used to compare neurocognitive functions between individualists and collectivists. Collectivists outperformed individualists on left frontally-mediated measures of verbal fluency (action, phonemic) after controlling for relevant covariates, F(1,77) = 6.942, p = 0.010, η2 = 0.061. Groups did not differ on semantic fluency, non-verbal fluency, or attention/working memory (all ps > 0.05). These findings suggest a cognitive advantage in collectivists for verbal processing speed with an additional contribution of left frontal processes involved in lexicosemantic retrieval. Self-construal may provide a meaningful descriptor for diverse samples in neuropsychological research and may help explain other cross-cultural differences.
Next-Generation Cancer Immunotherapy Targeting Glypican-3

Glypican-3 (GPC3), a 65 kD protein consisting of 580 amino acids, is a heparan sulfate proteoglycan bound to the cell membrane by glycosylphosphatidylinositol. This protein is expressed in the liver and the kidney of healthy fetuses but is hardly expressed in adults, except in the placenta. Contrarily, GPC3 is specifically expressed in hepatocellular carcinoma (HCC), ovarian clear cell carcinoma, melanoma, squamous cell carcinoma of the lung, hepatoblastoma, nephroblastoma (Wilms tumor), yolk sac tumor, and some pediatric cancers. Although the precise function of GPC3 remains unclear, it has been strongly suggested that it is related to the malignant transformation of HCC. We identified GPC3 as a promising target for cancer immunotherapy and have been working on the development of cancer immunotherapeutic agents targeting it through clinical trials. In some trials, it was revealed that the GPC3 peptide vaccines we developed using human leukocyte antigen-A24- and A2-restricted GPC3-derived peptides could induce GPC3-specific cytotoxic T cells in most vaccinated patients and thereby improve their prognosis. To further improve the clinical efficacy of cancer immunotherapy targeting GPC3, we are also developing next-generation therapeutic strategies using T cells engineered to express antigen-specific T-cell receptor or chimeric antigen receptor. In addition, we have successfully monitored the levels of serum full-length GPC3 protein, which is somehow secreted in the blood. The utility of GPC3 as a biomarker for predicting tumor recurrence and treatment efficacy is now being considered. In this review article, we summarize the results of clinical trials carried out by our team and describe the novel agent targeting the cancer-specific shared antigen, GPC3.
Small molecule targeting of RNA structures in neurological disorders

Aberrant RNA structure and function operate in neurological disease progression and severity. As RNA contributes to disease pathology in a complex fashion, that is, via various mechanisms, it has become an attractive therapeutic target for small molecules and oligonucleotides. In this review, we discuss the identification of RNA structures that cause or contribute to neurological diseases as well as recent progress toward the development of small molecules that target them, including small molecule modulators of pre‐mRNA splicing and RNA repeat expansions that cause microsatellite disorders such as Huntington's disease and amyotrophic lateral sclerosis. The use of oligonucleotide‐based modalities is also discussed. There are key differences between small molecule and oligonucleotide targeting of RNA. The former targets RNA structure, while the latter prefers unstructured regions. Thus, some targets will be preferentially targeted by oligonucleotides and others by small molecules.
Vitrification and storage of oral mucosa epithelial cell sheets

Shipping time and shipping delays might affect the quality of the stem cells based engineered “organs. ” In our laboratory, we have developed a limbal stem cell deficient (LSCD) rabbit model. To reverse the LSCD, we cultured oral mucosal epithelial cells for 2–3 weeks and engineered cultured autologous oral mucosa epithelial cell sheets (CAOMECS), which were grafted on the LSCD cornea. The purpose of this study was to vitrify CAOMECS and to store it until the CAOMECS can be grafted onto patients. CAOMECS were vitrified in LN2 for up to 204 days. We tested two different methods of vitrification with different solutions; however, CAOMECS were only viable when they were not stored in a vitrification solution; results were only reported from this CAOMECS. On the basis of hematoxylin and eosin staining, we showed that the CAOMECS morphology was well preserved after long‐term storage in LN2. Most of the preservation solutions maintained the CAOMECS phenotype (Ki67, proliferating cell nuclear antigen (PCNA), Beta‐Catenin, ZO‐1, E‐Cadherin, CK3, CK4, CK13). The exception was the solution composed with ethylene glycol and Dimethyl sulfoxide (DMSO): this resulted in loss of DeltaN‐p63 expression. DeltaN‐p63 is an important marker for cell proliferation. The expression of proteins involved in cell–cell connection and the differentiation markers were maintained. Apoptosis was not detected in the thawed CAOMECS. We demonstrated that CAOMECS can be stored long‐term in LN2 without affecting their morphology and phenotype.
LurR is a regulator of the central lactate oxidation pathway in sulfate-reducing Desulfovibrio species

The central carbon/lactate utilization pathway in the model sulfate-reducing bacterium, Desulfovibrio vulgaris Hildenborough, is encoded by the highly conserved operon DVU3025-3033. Our earlier in vitro genome-wide study had suggested a network of four two-component system regulators that target this large operon; however, how these four regulators control this operon was not known. Here, we probe the regulation of the lactate utilization operon with mutant strains and DNA-protein binding assays. We show that the LurR response regulator is required for optimal growth and complete lactate utilization, and that it activates the DVU3025-3033 lactate oxidation operon as well as DVU2451, a lactate permease gene, in the presence of lactate. We show by electrophoretic mobility shift assays that LurR binds to three sites in the upstream region of DVU3025, the first gene of the operon. NrfR, a response regulator that is activated under nitrite stress, and LurR share similar binding site motifs and bind the same sites upstream of DVU3025. The DVU3025 promoter also has a binding site motif (Pho box) that is bound by PhoB, a two-component response regulator activated under phosphate limitation. The lactate utilization operon, the regulator LurR, and LurR binding sites are conserved across the order Desulfovibrionales whereas possible modulation of the lactate utilization genes by additional regulators such as NrfR and PhoB appears to be limited to D. vulgaris.
Automatic acoustic identification of individuals in multiple species: improving identification across recording conditions

Many animals emit vocal sounds which, independently from the sounds’ function, contain some individually distinctive signature. Thus the automatic recognition of individuals by sound is a potentially powerful tool for zoology and ecology research and practical monitoring. Here, we present a general automatic identification method that can work across multiple animal species with various levels of complexity in their communication systems. We further introduce new analysis techniques based on dataset manipulations that can evaluate the robustness and generality of a classifier. By using these techniques, we confirmed the presence of experimental confounds in situations resembling those from past studies. We introduce data manipulations that can reduce the impact of these confounds, compatible with any classifier. We suggest that assessment of confounds should become a standard part of future studies to ensure they do not report over-optimistic results. We provide annotated recordings used for analyses along with this study and we call for dataset sharing to be a common practice to enhance the development of methods and comparisons of results.
Brain Death Enhances Activation of the Innate Immune System and Leads to Reduced Renal Metabolic Gene Expression.

BACKGROUND Brain-death associated inflammation has been implicated in decreased kidney allograft function and survival, but the underlying mechanisms have not been well distinguished from the conditions of critical care itself. We have developed a clinically translatable model to separate and investigate strategies to improve donor management and critical care. METHODS Brain-dead (n=12) and sham (n=5) rhesus macaques were maintained for 20 hours under ICU-level conditions. Samples were collected for immunophenotyping, analysis of plasma proteins, coagulation studies, and gene analysis for changes in immune and metabolic profile with comparison to naive samples (n=10). RESULTS We observed an increase in circulating leukocytes and cytokines, activation of complement and coagulation pathways, and upregulation of genes associated with inflammation in both brain-dead and sham subjects relative to naïve controls. Sham demonstrated an intermediate phenotype of inflammation compared to brain-death. Analysis of gene expression in kidneys from brain-death kidneys revealed a similar upregulation of inflammatory profile in both BD and sham subjects, but BD presented a distinct reduction in metabolic and respiratory processes compared to sham and naïve kidneys. CONCLUSION Brain death is associated with activation of specific pathways of the innate immune system and changes to metabolic gene expression in renal tissue itself, however sham donors presented an intermediate inflammatory response attributable to the critical care environment. The early onset and penetrating impact of this inflammatory response underscores the need for early intervention to prevent peri operative tissue injury to transplantable organs.
Alternative oxidase is an important player in the regulation of nitric oxide levels under normoxic and hypoxic conditions in plants.

Plant mitochondria possess two different pathways for electron transport from ubiquinol: the cytochrome pathway and the alternative oxidase (AOX) pathway. The AOX pathway plays an important role in stress tolerance and is induced by various metabolites and signals. Previously, several lines of evidence suggested that the AOX pathway prevents overproduction of superoxide and other reactive oxygen species. More recent evidence suggests that AOX also plays a role in regulation of nitric oxide (NO) production and signalling. The AOX pathway is induced under low phosphate, hypoxia, pathogen infections and elicitor treatments. The induction of AOX under aerobic conditions in response to various stresses can reduce electron transfer through complexes III and IV and thus prevents the leakage of electrons to nitrite and the subsequent accumulation of NO. Excess of NO under various stresses can inhibit complex IV, thus the AOX pathway minimizes nitrite-dependent NO synthesis that would arise from enhanced electron leakage in the cytochrome pathway. By preventing NO generation, AOX can reduce peroxynitrite formation and tyrosine nitration. In contrast to its function under normoxia, AOX has a specific role under hypoxia, where AOX can facilitate nitrite-dependent NO production. This reaction drives the phytoglobin-NO cycle to increase energy efficiency under hypoxia.
The Effects of High Cushioned Versus Minimal Cushioned Shoes on Dynamic Postural Stability of Older Adults During Obstacle Crossing

Footwear can affect postural stability in individuals, particularly in elderly people. Agingrelated decline in postural stability, particularly in the mediolateral (ML) direction, is a risk factor for falls and fall-related injuries among older adults. This study aimed to investigate the effects of high cushioned and minimal shoes on dynamic postural stability in ML during obstacle crossing in defined older and younger adults. Six healthy older adults (50–60 years old, body weight: 74.8 kg, body height: 168.0 cm) and six healthy younger adults (18–32 years old, body weight: 73.8 kg, body height: 174.8 cm) participated in the study. A Vicon motion analysis system with 10 optical cameras was used to capture the obstacle (20 cm height) crossing motion of the participants at 200 Hz, and ground reaction forces of obstacle crossing were collected at 1000 Hz. Motion data of obstacle crossing were collected at three shoe conditions, namely, minimal shoe, high cushioned shoe and barefoot (control). Data from five trials of obstacle crossing for each shoe condition were processed using Vicon Nexus software 2.11. 0 and Matlab R2013b. Displacement and velocity of centre of mass (COM) in the ML direction, COM–centre of pressure (COP) ML separation, step length, step velocity, toe clearance, pre-horizontal distance, hip flexion angle and hip abduction angle during obstacle crossing were examined. One-way ANOVA with pairwise analysis showed that toe clearance was significantly larger in the high cushioned shoe conditions than in the minimal shoe and barefoot conditions in older adults (high cushioned shoes vs. barefoot: p = 0.019; cushioned shoes vs. minimal shoes: p = 0.031) and younger adults (high cushioned shoes vs. barefoot: p = 0.016; high cushioned shoes vs. minimal shoes: p = 0.000). No significant difference in the measures was found between the minimal shoe and barefoot conditions in each group. Compared with older adults, younger adults showed significantly larger step length in barefoot condition (p = 0.000) and minimal shoe (p = 0.016). Independent t-test for examination
Im Spannungsfeld zwischen hochdeutscher Norm und niederdeutscher Sprachkompetenz

This article contains an edition of a 17th-century Low German letter addressed to the German congregation in Stockholm. Seen against the shift of writing language from Low to High German, this letter is analyzed in respect to code-mixing, which is shown to fulfill a communicative function. Furthermore the author here suggests that the code-mixing observed in the letter can be described as congruent lexicalization, where Low German syntactic structures are filled with both Low and High German lexical material.
Processing of prompt gamma-ray timing data for proton range measurements at a clinical beam delivery

In proton therapy, patients benefit from the precise deposition of the dose in the tumor volume due to the interaction of charged particles with matter. Currently, the determination of the beam range in the patient’s body during the treatment is not a clinical standard. This lack causes broad safety margins around the tumor, which limits the potential of proton therapy. To overcome this obstacle, different methods are under investigation aiming at the verification of the proton range in real time during the irradiation. One approach is the prompt gamma-ray timing (PGT) method, where the range of the primary protons is derived from time-resolved profiles (PGT spectra) of promptly emitted gamma rays, which are produced along the particle track in tissue. After verifying this novel technique in an experimental environment but far away from treatment conditions, the translation of PGT into clinical practice is intended. Therefore, new hardware was extensively tested and characterized using short irradiation times of 70 ms and clinical beam currents of 2 nA. Experiments were carried out in the treatment room of the University Proton Therapy Dresden. A pencil beam scanning plan was delivered to a target without and with cylindrical air cavities of down to 5 mm thickness. The range shifts of the proton beam induced due to the material variation could be identified from the corresponding PGT spectra, comprising events collected during the delivery of a whole energy layer. Additionally, an assignment of the PGT data to the individual pencil beam spots allowed a spot-wise analysis of the variation of the PGT distribution mean and width, corresponding to range shifts produced by the different air cavities. Furthermore, the paper presents a comprehensive software framework which standardizes future PGT analysis methods and correction algorithms for technical limitations that have been encountered in the presented experiments.
Quantitative Predictive Imaging Biomarkers of Lumbar Intervertebral Disc Degeneration

Study Design Observational comparative study. Purpose To compare fractional anisotropy (FA) maps with T2 values of the nucleus pulposus (NP) and annulus fibrosus (AF) of intervertebral discs in healthy volunteers and patients to develop a predictive disc health scale. Overview of Literature T2-weighted magnetic resonance imaging (MRI) is not sensitive to early morphological changes and provides no quantitative biomarker profile for early degeneration. Methods We examined 59 healthy controls and 59 patients with back pain by MRI using T2 relaxometry and diffusion tensor imaging (DTI). Each group was divided into three age subgroups: A (<30 years, n=12); B (30–50 years, n=26); and C (>50 years, n=21). We obtained FA values for AF and NP and T2 values for NP for each intervertebral disc. Furthermore, we calculated the FA (AF/NP) ratios. Results We categorized 590 intervertebral discs from 118 participants, 566 of which were analyzed with T2 relaxometry and DTI. The T2 values were as follows: subgroup A, 55.8±4.4 ms; B, 48.5±6.9 ms; C, 45.8±8.7 ms (p<0.050). The T2 values for the healthy controls of the subgroups A, B, and C were >120 ms, 90–100 ms, and 70 ms, respectively (p<0.001). Control subgroup A had higher T2 values and AF/NP ratios than subgroups B and C; the AF values were not significantly different. Control subgroup B had higher T2 values and AF/NP ratios than subgroup C but lower FA (NP). Conclusions FA maps of the AF/NP ratio and T2 values of NP are potential microstructure biomarkers of normal and degenerating discs and can help detect early degeneration using a predictive disc health score on a continuous scale.