Miracle-dz/UniFAR-FTUs huggingface dataset:
Noninvasive prenatal determination of twin zygosity by maternal plasma DNA analysis.

BACKGROUND The current methods for distinguishing the zygosities of twins include ultrasound scanning, which is nondefinitive, and amniocentesis, which is invasive. We explored the use of massively parallel sequencing of maternal plasma DNA for the noninvasive prenatal assessment of the zygosities of twin pregnancies. METHODS Plasma DNA was extracted from blood collected from 8 women pregnant with twins. Target enrichment and massively parallel sequencing were performed for each plasma DNA library. Apparent fractional fetal DNA concentrations were calculated for multiple genomic regions by determining the ratio of minor to major alleles among single-nucleotide polymorphism sites. Variations in the apparent fractional fetal DNA concentrations between genomic regions were used to infer whether individual fetuses in a twin pair were genotypically different and hence dizygotic. RESULTS The extent of the variation in the apparent fractional fetal DNA concentration across chromosomes was 0.82-1.35 SDs for monozygotic twin pregnancies and 2.42-4.80 SDs for dizygotic twin pregnancies. The proportions of apparent fractional fetal DNA concentration values that deviated beyond the range expected for stochastic variation were 0.00%-1.93% for monozygotic twin pregnancies and 36.2%-78.1% for dizygotic twin pregnancies. After identifying a pair of twins as likely dizygotic, the method also allowed determination of the fractional fetal DNA concentrations contributed by the individual fetuses of a dizygotic twin pair. CONCLUSIONS Noninvasive prenatal determination of twin zygosity by maternal plasma DNA sequencing is feasible. It is also possible to determine the relative fractional fetal DNA concentrations for each fetus for dizygotic twin pregnancies.
Making Formal Methods More Relevant to Software Engineering Students via Automated Test Generation

The use of formal methods in software engineering has been advocated for a long time, by a lot of people. Unfortunately, advocates of formal methods remain a distinct minority among software engineering educators, as well as industrial practitioners. A number of reasons have been cited for the lack of acceptance of formal methods. Popular among these reasons is that formal methods lack relevance and utility to the everyday work of software engineers. This paper presents a tool intended to increase the practical value of formal methods for software engineering students. The tool, called "Spest'', generates unit testing code from a formal program specification. There have been other such tools developed in the past, but all have been difficult for us to use in our educational setting. With Spest, we hope to overcome some of the difficulties with a tool that is easy to use and which generates readable and extendible testing code. Initial results of using Spest in our classes are promising and we are planning continued development.
Regulation of ptsH and ptsl gene expression in Streptococcus salivarius ATCC 25975

The transcriptional regulation of the Streptococcus salivarius ptsH and ptsl genes coding for the general energy‐coupling proteins HPr and enzyme I of the phosphoenolpyruvate:sugar phosphotransferase system were investigated. These genes form an operon with the gene order ptsH–ptsl. Three distinct mRNA species were detected: a 0.5 kb transcript specific for ptsH, and two long transcripts (2.2 arid 2.4 kb) covering the whole pts operon. Transcription of all these mRNAs initiated at the same nucleotide located 9 bp downstream from a promoter located immediately upstream from the ptsH gene. The presence of a high‐energy stem–loop structure (T0) located at the begining of ptsl was responsible for the premature transcrrption termination generating the 0.5 kb ptsH‐specific transcript. The long transcripts ended in the poly(U) region of two rho‐independent‐like terminators (T1 and T2) at the 3′ end of ptsl. Studies with a 2‐deoxyglucose‐resistant spontaneous mutant of S. salivarius (L26) that produces an HPr–El fusion protein suggest that the regulation of HPr and El expression involves transcriptional as well as translational mechanisms.
PERSPECTIVES IN CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Rational Helicobacter pylori Therapy: Evidence-Based Medicine Rather Than Medicine-Based Evidence

Data are available such that choice of Helicobacter pylori therapy for an individual patient can be reliably predicted. Here, treatment success is defined as a cure rate of 90% or greater. Treatment outcome in a population or a patient can be calculated based on the effectiveness of a regimen for infections with susceptible and with resistant strains coupled with the knowledge of the prevalence of resistance (ie, based on formal measurement, clinical experience, or both). We provide the formula for predicting outcome and we illustrate the calculations. Because clarithromycincontaining triple therapy and 10-day sequential therapy are now only effective in special populations, they are considered obsolete; neither should continue to be used as empiric therapies (ie, 7- and 14-day triple therapies fail when clarithromycin resistance exceeds 5% and 15%, respectively, and 10-day sequential therapy fails when metronidazole resistance exceeds 20%). Therapy should be individualized based on prior history and whether the patient is in a high-risk group for resistance. The preferred choices for Western countries are 14-day concomitant therapy, 14-day bismuth quadruple therapy, and 14-day hybrid sequential-concomitant therapy. We also provide details regarding the successful use of fluoroquinolone-, rifabutin-, and furazolidone-containing therapies. Finally, we provide recommendations for the efficient development (ie, identification and optimization) of new regimens, as well as how to prevent or minimize failures. The trialand-error approach for identifying and testing regimens frequently resulted in poor treatment success. The described approach allows outcome to be predicted and should simplify treatment and drug development.
Obstructive Sleep Apnea in the Formerly Preterm Infant: An Overlooked Diagnosis

Background: Obstructive sleep apnea syndrome (OSA) is a frequent disorder in children. The clinical characteristics of OSA in very young children under 2 years of age, and more particularly, in those born prematurely, and who have respiratory complications such as bronchopulmonary dysplasia (BPD), are not well defined. We therefore retrospectively reviewed our experience in a group of preterm infants with OSAS. Methods: The records of premature infants with BPD followed in the Pediatric Pulmonary Clinic at the University of Chicago who were diagnosed with OSA from 2004 to 2009 were reviewed and analyzed. Results: Twelve children, eight males, and four females with a mean gestational age of 27 weeks were found to have OSA. Mean age at diagnosis was 19 months. Inability to wean nighttime oxygen, the need to resume oxygen after intercurrent respiratory illness, and snoring were the most common presenting symptoms. The apnea–hypopnea index ranged from 1 to 120/h total sleep time (TST; mean: 29). SpO2 nadir ranged from 50 to 91%. Despite adenotonsillectomy (AT), all children had persistent sleep disordered breathing. Conclusion: In preterm infants, while snoring is a frequent symptom, poor weight gain, and inability to wean nighttime oxygen may indicate the need for further investigation for OSA. In the former preterm infant structural changes in the airway may play an important role along with adenotonsillar hypertrophy. A high level of clinical awareness is required to identify OSA in the formerly preterm infant.
XENOPUS LAEVIS: A POSSIBLE VECTOR OF RANAVIRUS INFECTION?

Frog virus 3 (FV3) or FV3-like viruses (Iridoviridae) infect a wide range of amphibian species, and they are becoming increasingly and causally associated with amphibian disease outbreaks worldwide. We have established the frog Xenopus laevis as an experimental model to study host defense and pathogenesis of FV3 infection. Although X. laevis adults usually clear FV3 infection within a few weeks, viral DNA has been detected in the kidneys several months after they had been experimentally infected; virus also has been detected in seemingly healthy nonexperimentally infected adults. Based on this information, we hypothesized that covert FV3 infection may occur in Xenopus. We first conducted a survey that detected FV3 by polymerase chain reaction (PCR) in the kidneys (the main site of FV3 infection) in a significant fraction of X. laevis raised in five different locations in the United States. Asymptomatic FV3 carriers also were detected by initiation of an acute systemic FV3 infection in frogs that had been immunosupressed by sublethal γ-irradiation. Finally, we focused on macrophages as a potential site for viral persistence, and we showed that FV3 can infect peritoneal macrophages in vitro as determined by reverse transcriptase-PCR detection of viral mRNAs. Unlike kidney cell lines that are readily killed by FV3, infected macrophages, like uninfected macrophages, survived up to 12 days. Viral transcription also was detected in macrophages from animals up to 12 days after infection. These results suggest that FV3 can become quiescent in resistant species such as Xenopus, thereby making these species potential viral reservoirs.
Sildenafil therapy is associated with improved hemodynamics in liver transplantation candidates with pulmonary arterial hypertension

Pulmonary arterial hypertension associated with portal hypertension occurs in about 5% of patients being evaluated for liver transplantation. Treatment is required to facilitate safe transplantation, and oral pulmonary vasodilators have yet to be prospectively evaluated for this disease. The objective of this study was to determine the hemodynamic outcome in a consecutive cohort of patients offered sildenafil as first‐line treatment for portopulmonary hypertension. We identified consecutive patients at the University of Rochester referred by the liver transplant team. All had catheter‐confirmed disease and were treated with sildenafil. Patients were excluded from analysis if they did not have follow‐up catheterizations. The change in pulmonary vascular resistance at the time of first follow‐up was the primary outcome. Eleven patients began sildenafil, and 9 had follow‐up right heart catheterizations during a 3‐year period. Pulmonary vascular resistance dropped in each patient; as a group, the mean dropped from 575 to 375 dynes/second/cm5. Four of 9 patients achieved a mean pulmonary artery pressure ≤ 35 mm Hg at the time of first recatheterization, and 1 patient received a successful cadaveric transplant. Four of 6 patients with more than 1 follow‐up catheterization had sustained hemodynamic benefit. One patient initially responded to therapy with favorable hemodynamics but was found in the operating room to have recrudescent disease (on therapy) that precluded safe transplantation. In conclusion, sildenafil was associated with improved hemodynamics in this small, uncontrolled cohort. A multicenter, prospective evaluation is warranted in this group uniformly excluded from phase III clinical trials. Liver Transpl 15:30–36, 2009. © 2008 AASLD.
Mutations in SERPINF1 Cause Osteogenesis Imperfecta Type VI

Osteogenesis imperfecta (OI) is a spectrum of genetic disorders characterized by bone fragility. It is caused by dominant mutations affecting the synthesis and/or structure of type I procollagen or by recessively inherited mutations in genes responsible for the posttranslational processing/trafficking of type I procollagen. Recessive OI type VI is unique among OI types in that it is characterized by an increased amount of unmineralized osteoid, thereby suggesting a distinct disease mechanism. In a large consanguineous family with OI type VI, we performed homozygosity mapping and next‐generation sequencing of the candidate gene region to isolate and identify the causative gene. We describe loss of function mutations in serpin peptidase inhibitor, clade F, member 1 (SERPINF1) in two affected members of this family and in an additional unrelated patient with OI type VI. SERPINF1 encodes pigment epithelium–derived factor. Hence, loss of pigment epithelium–derived factor function constitutes a novel mechanism for OI and shows its involvement in bone mineralization. © 2011 American Society for Bone and Mineral Research
Angiogenin Mediates Androgen-Stimulated Prostate Cancer Growth and Enables Castration Resistance

The androgen receptor (AR) is a critical effector of prostate cancer development and progression. Androgen-dependent prostate cancer is reliant on the function of AR for growth and progression. Most castration-resistant prostate cancer (CRPC) remains dependent on AR signaling for survival and growth. Ribosomal RNA (rRNA) is essential for both androgen-dependent and castration-resistant growth of prostate cancer cells. During androgen-dependent growth of prostate cells, androgen-AR signaling leads to the accumulation of rRNA. However, the mechanism by which AR regulates rRNA transcription is unknown. Here, investigation revealed that angiogenin (ANG), a member of the secreted ribonuclease superfamily, is upregulated in prostate cancer and mediates androgen-stimulated rRNA transcription in prostate cancer cells. Upon androgen stimulation, ANG undergoes nuclear translocation in androgen-dependent prostate cancer cells, where it binds to the rDNA promoter and stimulates rRNA transcription. ANG antagonists inhibit androgen-induced rRNA transcription and cell proliferation in androgen-dependent prostate cancer cells. Interestingly, ANG also mediates androgen-independent rRNA transcription through a mechanism that involves its constitutive nuclear translocation in androgen-insensitive prostate cancer cells, resulting in a constant rRNA overproduction and thereby stimulating cell proliferation. Critically, ANG overexpression in androgen-dependent prostate cancer cells enables castration-resistant growth of otherwise androgen-dependent cells. Thus, ANG-stimulated rRNA transcription is not only an essential component for androgen-dependent growth of prostate cancer but also contributes to the transition of prostate cancer from androgen-dependent to castration-resistant growth status. Implications: The ability of angiogenin to regulate rRNA transcription and prostate cancer growth makes it a viable target for therapy. Mol Cancer Res; 11(10); 1203–14. ©2013 AACR.
Regulation of the HDM2-p53 pathway by ribosomal protein L6 in response to ribosomal stress

The HDM2-p53 loop is crucial for monitoring p53 level and human pathologies. Therefore, identification of novel molecules involved in this regulatory loop is necessary for understanding the dynamic regulation of p53 and treatment of human diseases. Here, we characterized that the ribosomal protein L6 binds to and suppresses the E3 ubiquitin ligase activity of HDM2, and subsequently attenuates HDM2-mediated p53 polyubiquitination and degradation. The enhanced p53 activity further slows down cell cycle progression and leads to cell growth inhibition. Conversely, the level of p53 is dramatically decreased upon the depletion of RPL6, indicating that RPL6 is essential for p53 stabilization. We also found that RPL6 translocalizes from the nucleolus to nucleoplasm under ribosomal stress, which facilitates its binding with HDM2. The interaction of RPL6 and HDM2 drives HDM2-mediated RPL6 polyubiquitination and proteasomal degradation. Longer treatment of actinomycin D increases RPL6 ubiquitination and destabilizes RPL6, and thereby putatively attenuates p53 response until the level of L6 subsides. Therefore, RPL6 and HDM2 form an autoregulatory feedback loop to monitor the level of p53 in response to ribosomal stress. Together, our study identifies the crucial function of RPL6 in regulating HDM2-p53 pathway, which highlights the importance of RPL6 in human genetic diseases and cancers.
Periodic Limb Movements in Sleep and Cardiovascular Disease: Time to Act

Periodic limb movements in sleep (PLMS) is a common sleep disorder in both the general population and in patients with chronic diseases such as patients receiving hemodialysis therapy. PLMS can be assessed during an overnight polysomnographic examination and are described as repetitive, stereotypical, and unconscious leg movements that occur during sleep. It is noteworthy, that PLMS are present in up to 80% of patients with a condition occurring during wakefulness, called restless legs syndrome (RLS). Indeed, the presence of PLMS is considered to be one of the supportive criteria for the diagnosis of the later condition (1). PLMS may also occur in patients with sleep apnea, narcolepsy, and rapid eye movement behavior disorder or even can be present in patients without any sleep or medical-related pathological condition, and especially in the elderly (2). PLMS could cause significant sleep disturbance and result in non-restorative sleep via its associated arousals and motor restlessness. It is logical then to assume that as PLMS interferes with the expected sleep associated dipping of blood pressure (3), it may constitute a risk factor for cardiac disease and mortality. Notably, a role of PLMS as a predictor of mortality has been proposed in small survival study by Benz et al. (4) in which PLMS was strongly and independently associated with mortality in renal patients. Recently direct observations on cardiac structure added strong support on the association between the severity of PLMS and cardiovascular (CV) mortality and morbidity first in secondary RLS by us (5) and then verified in idiopathic RLS patients (6) as well.
Chondroitin sulfate activates B cells in vitro, expands CD138+ cells in vivo, and interferes with established humoral immune responses

Glycosaminoglycans have anti‐inflammatory properties and interact with a variety of soluble and membrane‐bound molecules. Little is known about their effects on B cells and humoral immune responses. We show that CS but not dextran or other glycosaminoglycans induces a pronounced proliferation of B cells in vitro compared with TLR4 or TLR9 ligands. With the use of inhibitors and KO mice, we demonstrate that this proliferation is mediated by the tyrosine kinases BTK and Syk but independent of CD44. Antibodies against Ig‐α or Ig‐β completely block CS‐induced B cell proliferation. Injection of CS in mice for 4–5 days expands B cells in the spleen and results in a marked increase of CD138+ cells in the spleen that is dependent on BTK but independent of CD4+ T cells. Long‐term treatment with CS for 14 days also increases CD138+ cells in the bone marrow. When mice were immunized with APC or collagen and treated with CS for up to 14 days during primary or after secondary immune responses, antigen‐specific humoral immune responses and antigen‐specific CD138+ plasma cells in the bone marrow were reduced significantly. These data show that CD138+ cells, induced by treatment with CS, migrate into the bone marrow and may displace other antigen‐specific plasma cells. Overall, CS is able to interfere markedly with primary and fully established humoral immune responses in mice.
Focus on psychiatry in India

India is a country with a population of over 1 billion, and immense diversity in the languages spoken, levels of literacy, and social and cultural practices. Organising mental health services for this predominantly rural population is indeed a daunting task. Compounding this problem are low budgetary resources, the presence of competing and conflicting healing systems, scarcity of mental health personnel, ‘brain drain’, and the stigma of seeking help for problems related to the mind. This paper looks at the mental health scene in India with respect to services and research. It deals with conditions such as schizophrenia, acute psychoses, minor mental morbidity and drug misuse, highlighting aspects unique to the Indian scene. Indian families exhibit great tenacity in caring for relatives who are ill, and are a great resource in treatment and rehabilitation.
Secreted Factors from Bone Marrow Stromal Cells Upregulate IL-10 and Reverse Acute Kidney Injury

Acute kidney injury is a devastating syndrome that afflicts over 2,000,000 people in the US per year, with an associated mortality of greater than 70% in severe cases. Unfortunately, standard-of-care treatments are not sufficient for modifying the course of disease. Many groups have explored the use of bone marrow stromal cells (BMSCs) for the treatment of AKI because BMSCs have been shown to possess unique anti-inflammatory, cytoprotective, and regenerative properties in vitro and in vivo. It is yet unresolved whether the primary mechanisms controlling BMSC therapy in AKI depend on direct cell infusion, or whether BMSC-secreted factors alone are sufficient for mitigating the injury. Here we show that BMSC-secreted factors are capable of providing a survival benefit to rats subjected to cisplatin-induced AKI. We observed that when BMSC-conditioned medium (BMSC-CM) is administered intravenously, it prevents tubular apoptosis and necrosis and ameliorates AKI. In addition, we observed that BMSC-CM causes IL-10 upregulation in treated animals, which is important to animal survival and protection of the kidney. In all, these results demonstrate that BMSC-secreted factors are capable of providing support without cell transplantation, and the IL-10 increase seen in BMSC-CM-treated animals correlates with attenuation of severe AKI.
Streptococcus dysgalactiae subsp. equisimilis Bacteremia, Finland, 1995–2004

We conducted a retrospective population-based study of 140 episodes of Streptococcus dysgalactiae subsp. equisimilis bacteremia occurring in Finland during 1995–2004. Rare emm types were associated with more severe disease and increased mortality rates. Skin and soft tissue infections were more frequent clinical signs among cases caused by common emm types.
Ecological Momentary Assessment and Smartphone Application Intervention in Adolescents with Substance Use and Comorbid Severe Psychiatric Disorders: Study Protocol

Context Substance use disorders (SUDs) are highly prevalent among inpatient adolescents with psychiatric disorders. In this population, substance use and other psychiatric outcomes can reinforce one another. Despite the need for integrated interventions in youths with dual diagnoses, few specific instruments are available. App-based technologies have shown promising results to help reduce substance use in adolescents, but their applicability in youths with associated severe psychiatric disorders is poorly documented. We aim to evaluate the feasibility of an ecological momentary assessment (EMA) intervention for all substance users, and of a smartphone application for cannabis users (Stop-Cannabis), for outpatient treatment after hospital discharge. Methods and analysis All inpatient adolescents with psychiatric disorders hospitalized between 2016 and 2018 in a university hospital will be systematically screened for SUD and, if positive, will be assessed by an independent specialist addiction team. Participants with confirmed SUDs will be invited and helped to download an EMA app and, if required, the Stop-Cannabis app, the week preceding hospital discharge. Information about the acceptability and use of both apps and the validity of EMA data in comparison to clinical assessments will be assessed after 6 months and 1 year. Discussion This research has been designed to raise specific issues for consideration regarding the sequence between substance use, contextual factors, and other psychiatric symptoms among adolescents with comorbid severe psychiatric disorders. A better understanding of the mechanisms involved will inform the development of integrated treatment for dual disorders at that age. Ethics and dissemination The study has already been approved and granted. Dissemination will include presentations at international congresses as well as publications in peer-reviewed journals. Trial registration European Clinical Trials Database: Number 2016-001999-30.