Miracle-dz/UniFAR-FTUs huggingface dataset:
Precise genotyping of circular mobile elements from metagenomic data uncovers human-associated plasmids with recent common ancestors

Mobile genetic elements with circular genomes play a key role in the evolution of microbial communities. Their circular genomes correspond to circular walks in metagenome graphs, and yet, assemblies derived from natural microbial communities produce graphs riddled with spurious cycles, complicating the accurate reconstruction of circular genomes. We present DomCycle, an algorithm that reconstructs likely circular genomes based on the identification of so-called “dominant” graph cycles. In the implementation, we leverage paired reads to bridge assembly gaps and scrutinize cycles through a nucleotide-level analysis, making the approach robust to misassembly artifacts. We validated the approach using simulated and real sequencing data. Application of DomCycle to 32 publicly available DNA shotgun sequence data sets from diverse natural environments led to the reconstruction of hundreds of circular mobile genomes. Clustering revealed 20 highly prevalent and cryptic plasmids that have clonal population structures with recent common ancestors. This method facilitates the study of microbial communities that evolve through horizontal gene transfer.
Magnetic resonance imaging and diffusion tensor imaging reconstruction of connectomes in a macropod, the quokka (Setonix brachyurus)

The diversity of the diprotodontids provides an excellent opportunity to study how a basic marsupial cortical plan has been modified for the needs of the mammals living in different habitats. Very little is known about the connections of the cerebral cortex with the deep brain structures (basal ganglia and thalamus) in this evolutionarily significant group of mammals. In this study, we performed mapping of brain regions and connections in a diprotodontid marsupial from data obtained from an excised brain scanned in high‐field (9.4 T) microstructural magnetic resonance imaging (MRI) instrument. The analysis was based on two MRI methodologies. First, high‐resolution structural scans were used to map MRI visible brain regions from T1w and T2w images. Second, extensive diffusion tensor imaging (DTI) data were obtained to elucidate connectivity between brain areas using deterministic diffusion tracking of neuronal brain fibers. From the data, we were able to identify corticostriate connections between the frontal association and dorsomedial isocortex and the head of the caudate, and between the lateral somatosensory cortex and the putamen. We were also able to follow the olfactory and limbic connections by tracing fibers in the fornix, cingulum, intrabulbar part of the anterior commissure, and lateral olfactory tract. There was segregation of fibers in the anterior commissure such that olfactory connections passed through the rostroventral part and successively more dorsal cortical areas connected through more dorsal parts of the commissure. Our findings confirm a common pattern of cortical connectivity in therian mammals, even where brain expansion has occurred independently in diverse groups.
Scalability of the Positive and Negative Syndrome Scale in first‐episode schizophrenia assessed by Rasch models

Historically, assessment of the psychometric properties of the Positive and Negative Syndrome Scale (PANSS) has had several foci: (1) calculation of reliability indexes, (2) extraction of subdimensions from the scale, and (3) assessment of the validity of the total score. In this study, we aimed to examine the scalability and to assess the clinical performance of the 30‐item PANSS total score as well as the scalability of a shorter version (PANSS‐6) of the scale.
Monitoring and Diagnosis for Autonomic Systems: A Requirement Engineering Approach

Autonomic computing holds great promise for software systems of the future, but at the same time poses great challenges for Software Engineering. Autonomic computing research aims to design software systems that self-configure, self-repair, self-optimize and self-protect, so as to reduce software maintenance cost while improving performance. The aim of our research is to develop tool-supported methodologies for designing and operating autonomic systems. Like other researchers in this area, we assume that autonomic system architectures consist of monitoring, analysis/diagnosis, planning, and execution components that define a feedback loop and serve as the basis for system self-management. This thesis proposes an autonomic framework founded on models of requirements and design. This framework defines the normal operation of a software system in terms of models of its requirements (goal models) and/or operation (statechart models). These models determine what to monitor and how to interpret log data in order to diagnose failures. The monitoring component collects and manages log data. The diagnostic component analyzes log data, identifies failures, and pinpoints problematic components. We transform the diagnostic problem into a propositional satisfiability (SAT) problem solvable by off-the-shelf SAT solvers. Log data are preprocessed into a compact propositional encoding that scales well with growing problem size. For repair, our compensation component executes compensation actions to restore the system to an earlier consistent state. The framework repairs failures through reconfiguration when monitoring and diagnosis use requirements. The reconfiguration component selects a best system reconfiguration that contributes most positively to the system's non-functional requirements. It selects a reconfiguration that achieves this while reconfiguring the system minimally. The framework does not currently offer a repair mechanism when monitoring and diagnosis use statecharts. We illustrate our framework with two medium-sized, publicly-available case studies. We evaluate the framework's performance through a series of experiments on randomly generated and progressively larger specifications. The results demonstrate that our approach scales well with problem size, and can be applied to industrial sized software applications.
Incidence of myeloid malignancies by subtype in Hong Kong and comparisons with Asian and white men and women in the United States

Abstract Data on incidence rates of myeloid malignancies for subtypes based on the World Health Organization (WHO) classification are lacking in Asian populations. We compared age-adjusted incidence rates for 27 myeloid malignancy WHO-defined subtypes in Hong Kong (HK) (2014–2016) with those for Asian and white individuals living in the United States (U.S.) (2010–2016). Except for overall acute myeloid leukemia (AML) (2.23 cases per 100,000) and myeloproliferative neoplasms (MPNs) (2.10 cases per 100,000), rates of all subtypes were <1 case per 100,000 person-years in HK. Overall rates of AML, myelodysplastic syndrome (MDS), and MDS/MPN were lower in HK compared to white and Asian individuals in the U.S., but the patterns by specific subtype varied. For these three broad groupings of myeloid malignancies, rates in U.S. Asians were intermediate to those in HK and white individuals in the U.S. These results suggest the possibility of a multifactorial etiology for specific myeloid malignancy subtypes that should be evaluated in future epidemiological studies.
Can food parenting practices explain the association between parental education and children’s food intake? The Feel4Diabetes-study

Abstract Objective: This study aimed to investigate the mediating role of food parenting practices (FPP), including home availability of different types of foods and drinks, parental modelling of fruit intake, permissiveness and the use of food as a reward in the relationship between parental education and dietary intake in European children. Design: Single mediation analyses were conducted to explore whether FPP explain associations between parents’ educational level and children’s dietary intake measured by a parent-reported FFQ. Setting: Six European countries. Participants: Parent–child dyads (n 6705, 50·7 % girls, 88·8 % mothers) from the Feel4Diabetes-study. Results: Children aged 8·15 ± 0·96 years were included. Parental education was associated with children’s higher intake of water, fruits and vegetables and lower intake of sugar-rich foods and savoury snacks. All FPP explained the associations between parental education and dietary intake to a greater or lesser extent. Specifically, home availability of soft drinks explained 59·3 % of the association between parental education and sugar-rich food intake. Home availability of fruits and vegetables was the strongest mediators in the association between parental education and fruit and vegetable consumption (77·3 % and 51·5 %, respectively). Regarding savoury snacks, home availability of salty snacks and soft drinks was the strongest mediators (27·6 % and 20·8 %, respectively). Conclusions: FPP mediate the associations between parental education and children’s dietary intake. This study highlights the importance of addressing FPP in future interventions targeting low-educated populations.
A Phase 1b/2 Study of Sabizabulin, a Novel Oral Cytoskeleton Disruptor, in Men With Metastatic Castration-Resistant Prostate Cancer with Progression on an Androgen Receptor Targeting Agent.

PURPOSE Sabizabulin, an oral cytoskeleton disruptor was tested in a Phase 1b/2 clinical study in men with metastatic castration resistant prostate cancer (mCRPC). EXPERIMENTAL DESIGN The Phase 1b portion utilized a 3+3 design with escalating daily oral doses of 4.5 mg - 81 mg and increasing schedule in 39 mCRPC patients treated with one or more androgen receptor targeting agents. Prior taxane chemotherapy was allowed. The Phase 2 portion tested a daily dose of 63 mg in 41 patients with no prior chemotherapy. Efficacy was assessed using PCWG3 and RECIST 1.1 criteria. RESULTS The MTD was not defined in the Phase 1b and the recommended Phase 2 dose was set at 63 mg/day. The most common adverse events (>10% frequency) at the 63 mg oral daily dosing (combined Phase 1b/2 data) were predominantly Grade 1-2 events. Grade ³3 events included diarrhea (7.4%), fatigue (5.6%) and ALT/AST elevations (5.6% and 3.7%, respectively). Neurotoxicity and neutropenia were not observed. Preliminary efficacy data in patients treated with {greater than or equal to}1 continuous cycle of 63 mg or higher included objective response rate in 6/29 (20.7%) patients with measurable disease (1 complete, 5 partial) and 14/48 (29.2%) patients had PSA declines. The Kaplan-Meier median radiographic progression-free survival was estimated to be 11.4 months (n=55). Durable responses lasting >2.75 years were observed. CONCLUSIONS This clinical trial demonstrated that chronic oral daily dosing of sabizabulin has a favorable safety profile with preliminary antitumor activity. These data support the ongoing Phase 3 VERACITY trial of sabizabulin in men with mCRPC.
Early Renin Recovery After Adrenalectomy in Aldosterone-Producing Adenomas: A Prospective Study.

The aim of the study was to clarify the relationship and the time of aldosterone and renin recoveries at immediate and long-term follow-up in aldosterone-producing adenoma (APA) patients who underwent adrenalectomy. Prospective and longitudinal protocol in a cohort of APA patients was followed in a single center. Among 43 patients with primary aldosteronism (PA), thirteen APA patients were enrolled in this study. Blood was collected for aldosterone, renin, potassium, creatinine, cortisol, and ACTH before and 1, 3, 5, 7, 15, 30, 60, 90, 120, 180, 270, 360 days after adrenalectomy. At diagnosis, most patients (84%) had hypokalemia and high median aldosterone levels (54.8; 24.0-103 ng/dl) that decreased to undetectable (<2.2) or very low (<3.0) levels between fifth to seventh days after surgery; then, between 3-12 months, its levels gradually increased to the lower normal range. The suppressed renin (2.3; 2.3-2.3 mU/l) became detectable between the fifteen and thirty days after surgery, remaining normal throughout the study. The aldosterone took longer than renin to recover (60 vs.15 days; p<0.002) and patients with higher aldosterone had later recovery (p=0.03). The cortisol/ACTH levels remained normal despite the presence of a post-operative hypoaldosteronism. Blood pressure and antihypertensive requirement decreased after adrenalectomy. In conclusion, our prospective study shows the borderline persistent post-operative hypoaldosteronism in the presence of early renin recovery indicating incapability of the zona glomerulosa of the remaining adrenal gland to produce aldosterone. These findings contribute to the comprehension of differences in renin and aldosterone regulation in APA patients, although both are part of the same interconnected system.
Dimension of Sentang (Azadirachta excelsa Jack) and Production of Soybean (Glycine max (L) Merril) in Agroforestry System DIMENSI POHON SENTANG (Azadirachta excelsa Jack) DAN PRODUKSI KEDELAI (Glycine max (L) Merril) DI DALAM SISTEM AGROFORESTRI

System which integrating forestry and agriculture is known by agroforestry. Utilizing of unproductive land below the trees will be more optimum. Sentang (Azadirachta excelsa Jack) is one of the plants that can be used in agroforestry system. The aim of this research was to know the effect of agroforestry toward tree dimension and production of some soybean varieties. Research design that was used in this research is split plot design that consisted of 2 factors and three repetitions. Planting pattern as a main plot is a the first factor, consisted of planting pattern of agroforestry (S1) and monoculture (S0). The second factor that was a submain plot is some varieties of soybean which consisted of variety of Grobogan, Anjasmoro, Tanggamus, and Wilis.The results shows that accretion mean of tree height, stem and crown diameter of Sentang in agroforestry plot are bigger than in monocultural plot. Lateral root in monocultural plot is deeper than in agroforestry plot. The difference of plant growth in each planting pattern of agroforestry is affected by interaction among plant component. Utilizing of some soybean varieties in agroforestry of sentang one year old did not result significant production than in monoculture pattern. In this research, variety Tanggamus and Wilis on monoculturural plot has better growth and production than variety of Grobogan and Anjasmoro.Key words: agroforestry, tree dimension, sentang (Azadirachta excelsa Jack), soybean, varieties.
Somatization in Adolescents With Persistent Symptoms After Concussion: A Retrospective Chart Review.

OBJECTIVE After concussion, approximately 30% of adolescents experience symptoms that persist beyond 1 month postinjury. For some, these symptoms affect functioning, development, and quality of life. Somatization, where psychological distress contributes to physical symptoms, may contribute to persistent symptoms after concussion in some adolescents. Understanding how clinicians identify somatization in adolescents with persistent symptoms after concussion in practice is a critical next step in improving our understanding, identification, and subsequent treatment of somatization in this patient population. To address this, the investigators assessed and compared characteristics of adolescents with persistent symptoms after concussion with and without clinician-identified somatization. METHODS Participants were adolescents (N=94) referred for persistent symptoms after concussion to a specialty youth concussion clinic between January 2016 and May 2018. A retrospective chart review extracted demographic and injury characteristics, symptoms after concussion, school attendance, premorbid experiences, mental health, and medical service use. Participants with physician-identified somatization were compared with those without physician-identified somatization on these measures. RESULTS Adolescents with identified somatization had more severe and atypical neurological and psychiatric symptoms after concussion and more postinjury impairment in school attendance, were more likely to have a history of premorbid chronic pain or medically unexplained symptoms, and obtained more neuroimaging and health care after injury compared with those unaffected by somatization. They did not differ in mood or anxiety symptom self-reports. CONCLUSIONS This study identified characteristic differences and similarities in adolescents with and without clinician-identified somatization after a prolonged concussion recovery. These findings have the potential to improve clinical identification of somatization in youths following a concussion and may aid in treatment among this demographic group.
Validation of the Italian version of the pediatric CMT quality of life outcome measure

The pediatric Charcot‐Marie‐Tooth (CMT) specific quality of life (QOL) outcome measure (pCMT‐QOL) is a recently developed and validated patient‐reported measure of health QOL for children with CMT. The aim of this study was to provide and validate an Italian version of the pCMT‐QOL. The original English version was translated and adapted into Italian using standard procedures. pCMT‐QOL was administered to patients genetically diagnosed with CMT, aged 8 to 18 years. A retest was given 2 weeks later to assess reliability in all patients. A total of 22 patients (median age 14 years, DS 2.5; M:F 1:1) affected with CMT (19 CMT1A, 2 CMT2A, 1 CMT2K) were assessed as part of their clinical visit. The Italian‐pCMT‐QOL demonstrate a high test‐retest reliability. None of the patients experienced difficulty in completing the questionnaire, no further corrections were needed after administration in patients. The Italian‐pCMT‐QOL is a reliable, culturally adapted and comparable version of the original English pCMT‐QOL. This questionnaire is expected to be valuable in monitoring disease progression and useful for future clinical trials in Italian‐speaking children with CMT.
Significance of KRAS mutation testing in biliary brushing cytology specimens: A 10‐year retrospective review

Biliary strictures can be caused by benign and malignant conditions. A biliary duct brushing diagnosis can be challenging because of low cellularity and overlapping morphology among different entities, leading to a variable reported sensitivity. This study aimed to assess the value of KRAS mutation testing in adding cytological diagnosis of biliary duct brushings.
Advances in Head and Neck Cancer Pain

Head and neck cancer (HNC) affects over 890,000 people annually worldwide and has a mortality rate of 50%. Aside from poor survival, HNC pain impairs eating, drinking, and talking in patients, severely reducing quality of life. Different pain phenotype in patients (allodynia, hyperalgesia, and spontaneous pain) results from a combination of anatomical, histopathological, and molecular differences between cancers. Poor pathologic features (e.g., perineural invasion, lymph node metastasis) are associated with increased pain. The use of syngeneic/immunocompetent animal models, as well as a new mouse model of perineural invasion, provides novel insights into the pathobiology of HNC pain. Glial and immune modulation of the tumor microenvironment affect not only cancer progression but also pain signaling. For example, Schwann cells promote cancer cell proliferation, migration, and secretion of nociceptive mediators, whereas neutrophils are implicated in sex differences in pain in animal models of HNC. Emerging evidence supports the existence of a functional loop of cross-activation between the tumor microenvironment and peripheral nerves, mediated by a molecular exchange of bioactive contents (pronociceptive and protumorigenic) via paracrine and autocrine signaling. Brain-derived neurotrophic factor, tumor necrosis factor α, legumain, cathepsin S, and A disintegrin and metalloprotease 17 expressed in the HNC microenvironment have recently been shown to promote HNC pain, further highlighting the importance of proinflammatory cytokines, neurotrophic factors, and proteases in mediating HNC-associated pain. Pronociceptive mediators, together with nerve injury, cause nociceptor hypersensitivity. Oncogenic, pronociceptive mediators packaged in cancer cell–derived exosomes also induce nociception in mice. In addition to increased production of pronociceptive mediators, HNC is accompanied by a dampened endogenous antinociception system (e.g., downregulation of resolvins and µ-opioid receptor expression). Resolvin treatment or gene delivery of µ-opioid receptors provides pain relief in preclinical HNC models. Collectively, recent studies suggest that pain and HNC progression share converging mechanisms that can be targeted for cancer treatment and pain management.
Mitochondrial calcium uniporter drives metastasis and confers a targetable cystine dependency in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease with few effective treatments. Here we show that the mitochondrial calcium uniporter (MCU) promotes PDAC cell migration, invasion, metastasis, and metabolic stress resistance by activating the Keap1-Nrf2 antioxidant program. The cystine transporter SLC7A11 was identified as a druggable target downstream of the MCU-Nrf2 axis. Paradoxically, despite the increased ability to uptake cystine, MCU-overexpressing PDAC demonstrated characteristics typical of cystine-deprived cells and were hypersensitive to cystine deprivation-induced ferroptosis. Pharmacological inhibitors of SLC7A11 effectively induced tumor regression and abrogated MCU-driven metastasis in PDAC. In patient-derived organoid models in vitro and patient-derived xenograft models in vivo, MCU-high PDAC demonstrated increased sensitivity to SLC7A11 inhibition compared to MCU-low tumors. These data suggest that MCU is able to promote resistance to metabolic stress and drive PDAC metastasis in a cystine-dependent manner. MCU-mediated cystine addiction could be exploited as a therapeutic vulnerability to inhibit PDAC tumor growth and prevent metastasis.
Comparison of mouse and human cytochrome P450 mediated-drug metabolising activities in hepatic and extrahepatic microsomes

Abstract Despite the importance of mice as a preclinical species in drug testing, their hepatic and extrahepatic drug-metabolising characteristics are poorly understood. Here, we compared the P450-dependent drug oxidation activity in tissue microsomes and distribution patterns of P450 protein/mRNA between humans and mice. The activities of midazolam 1′-/4-hydroxylation in the liver and intestine and chlorzoxazone 6-hydroxylation in the liver were similar in humans and mice. The activities of coumarin 7-hydroxylation, flurbiprofen 4′-hydroxylation, and S-mephenytoin 4′-hydroxylation in the liver were higher in humans than in mice. The activities of 7-ethoxyresorufin O-deethylation in the liver, 7-pentoxyresorufin O-depentylation in the lung/liver/intestine, bufuralol 1′-hydroxylation in the liver/intestine, propafenone 4′-hydroxylation in liver/intestine, and diazepam N-demethylation in the liver/intestine were higher in mice than in humans. CYP1A2/2E1 mRNAs were mainly expressed in the livers of humans and mice. Cyp2b9/2b10 mRNAs were abundant in the mouse lung/liver/intestine, but CYP2B6 was mainly expressed in the human liver. CYP2C/2D/3A mRNAs were expressed in the liver and intestine, with the respective proteins detected in tissue microsomes of both humans and mice. These information on P450-dependent drug-metabolising characteristics in hepatic and extrahepatic tissues is useful to understand the similarities and differences between humans and mice in drug metabolism.