Miracle-dz/UniFAR-FTUs huggingface dataset:
Live birth following the first mutation specific pre-implantation genetic diagnosis for haemophilia A

Summary Haemophilia A is an X-linked, recessive, inherited bleeding disorder which affects 1 in 5000 males born worldwide. It is caused by mutations in the FactorVIII (F8) gene on chromosome Xq28. We describe for the first time two mutation specific, single cell protocols for pre-implantation genetic diagnosis (PGD) of haemophilia A that enable the selection of both male and female unaffected embryos. This approach offers an alternative to sexing, frequently used for X-linked disorders, that results in the discarding of all male embryos including the 50% that would have been normal. Two families witha history of severe haemophilia A requested carrier diagnosis and subsequently proceeded to PGD. The mutation in family1 isa single nucleotide substitution c. 5953C>T, R1966X in exon 18 and in family 2, c. 5122C>T, R1689C in exon 14 of the F8 gene. Amplification efficiency was compared between distilled water and SDS/proteinase K cell lysis (98.0%, 96/98 and 80%, 112/140 respectively) using 238 single lymphocytes. Blastomeres from spare IVF cleavage-stage embryos donated for research showed amplification efficiencies of 83.3% (45/54) for the R1966X and 92.9% (13/14) for the R1689C mutations. The rate of allele dropout (ADO) on heterozygous lymphocytes was 1.1% (1/93) for R1966X and 5.94% (6/101) for R1689C mutations. A single PGD treatment cycle for family1 resulted in two embryos for transfer but these failed to implant. However, with family 2, two embryos were transferred to the uterus on day 4 resulting in a successful singleton pregnancy and subsequent live birth of a normal non-carrier female.
Characterization of new microsatellite markers derived from sequence databases for the emu (Dromaius novaehollandiae)

The emu (Dromaius novaehollandiae), a member of ratite family, is native to Australia and has been introduced to other countries worldwide. In this work, 10 polymorphic microsatellite loci were isolated and characterized for emu from public sequences. Polymorphism was surveyed in 22 individuals from two different populations kept in captivity. Between two and 11 alleles were found per locus, and the observed heterozygosity ranged from 0.05 to 0.85, in accordance with expectations. These markers will be useful as tools for detecting levels of genetic variation, reconstructing pedigrees (for quantitative genetic analysis) and identifying markers associated to fitness traits in emu populations.
Multiple Authorship Trends in Scientific Papers

Since 1946 biomedical writers have shown no marked trend toward multiple authorship; the average number of authors per paper remains steady at about 2.3. This is in strong contrast tothe conclusion of Price from a study of Chemical Abstracts that the chemists' trend toward four or more authors per paper has been during this period, and continues to be, steeply exponential.
Interventions for increasing pedestrian and cyclist visibility for the prevention of death and injuries.

BACKGROUND Pedestrians and cyclists account for nearly one in three of all road users killed and seriously injured in road traffic crashes. Late detection of other road users is one of the basic driver failures responsible for collisions. Aids to improve pedestrians and cyclist visibility have been used to avert potential collisions. However, the impact of these strategies on drivers' responses, and on pedestrian and cyclist safety is not known. OBJECTIVES 1. To quantify the effect of visibility aids vs no visibility aids, and of different visibility aids on the occurrence of pedestrian and cyclist-motor vehicle collisions and injuries. 2. To quantify the effect of visibility aids vs no visibility aids, and of different visibility aids on drivers' detection and recognition responses. SEARCH STRATEGY We searched the Cochrane Controlled Trials Register, the Injuries Group Specialised Register, MEDLINE, TRANSPORT, TRANSDOC from ECMT (European Conference of Ministers of Transport), IRRD (International Road Research Documentation), TRIS (Transportation Research Information Services), NRR (National Research Register), PsycInfo and PsycLit. SELECTION CRITERIA 1. Randomised controlled trials and controlled before/after trials of the effect of visibility aids on the occurrence of pedestrian and cyclist-motor collisions and injuries. 2. Randomised controlled trials of the effect of visibility aids on drivers' detection and recognition responses. This included trials where the order of presentation of visibility aids was randomised or balanced using a Latin square design. DATA COLLECTION AND ANALYSIS Two reviewers independently screened records, extracted data and assessed trial quality. MAIN RESULTS We found no trials assessing the effect of visibility aids on the occurrence of pedestrian and cyclist-motor vehicle collisions and injuries. We identified 37 trials assessing the effect of visibility aids on drivers' responses. Fluorescent materials in yellow, red and orange colours improve detection and recognition in the daytime. For night-time visibility, lamps, flashing lights and retroreflective materials in red and yellow colours increase detection and recognition. Retroreflective materials arranged in a 'biomotion' configuration also enhance recognition. Substantial heterogeneity between and within the trials limited the possibility for meta-analysis. Summary statistics and descriptive summaries of the outcomes were presented for individual trials when appropriate. REVIEWER'S CONCLUSIONS Visibility aids have the potential to increase visibility and enable drivers to detect pedestrians and cyclists earlier. Public acceptability of these strategies would merit further development. However, the effect of visibility aids on pedestrian and cyclist safety remains unknown. Studies which collect data on simple, meaningful outcomes are required.
Sharp increase in rates of HIV transmitted drug resistance at antenatal clinics in Botswana demonstrates the need for routine surveillance.

OBJECTIVES The aim of the study was to evaluate for the presence of drug resistance to HIV medications in treatment-naive individuals in Botswana. METHODS Two different populations were evaluated for evidence of HIV drug resistance at three different geographical locations in Botswana. In the first study population, consisting of pregnant females diagnosed with HIV during pregnancy, participants were enrolled at the time of their HIV diagnosis. The second population included pre-ART enrollees at Infectious Diseases Care Clinics (IDCCs) who had a CD4 T cell count >350 cells/μL. RESULTS A total of 422 genotypes were determined: 234 for samples from antenatal clinic (ANC) participants and 188 for samples from IDCC participants. Between 2012 and 2014, 6 of 172 (3.5%) genotypes from ANC participants exhibited transmitted drug resistance (TDR), with 3 (1.7%) showing resistance to first-line ART. In a subset of samples from Gaborone, Botswana's capital and largest city, the TDR rate was 3 in 105 (2.9%), but only 1 in 105 (1.0%) showed first-line ART resistance. Between December 2014 and April 2015, the rate of resistance to any ART in Gaborone was 6 in 62 (9.7%), with 5 (8.1%) exhibiting first-line ART resistance. CONCLUSIONS These data demonstrate that TDR rates for HIV differ geographically and temporally in Botswana, with significant increases in TDR observed at ANCs in Gaborone between 2012 and 2015. These findings stress the importance of continued testing for TDR, particularly as access to HIV treatment increases and guidelines recommend treatment at the time of HIV diagnosis.
Detection of unknown deletions in β‐globin gene cluster using relative quantitative PCR methods

β‐Thalassemia is mainly caused by mutations involving single base substitution and small deletions. However, a considerable number of carriers are suspected to have large deletions in β‐globin gene cluster. Common strategy for identifying deletions with definite breakpoints is based on Gap PCR. There are, however, some cases with indefinite breakpoints which usually cannot be detected by this method. We developed and optimized a quantitative real‐time PCR assay for copy number analysis of β‐globin gene cluster. The copy number of target fragments (i.e. β, δ or Gγ‐globin genes) was determined using comparative threshold cycle method. In addition, gene dosage was analyzed using multiplex ligation‐dependent probe amplification (MLPA) method in all suspected carriers. Using these relative quantitative assays, normal or carrier statuses of all 26 unknown samples were successfully determined according to the ranges obtained from the ratios of normal and definite carrier samples. Interestingly, large deletions involving the entire β‐globin gene cluster were observed in six carrier individuals. This study showed that the MLPA as a preliminary screening test can be followed by SYBR Green real‐time PCR for analysis of copy number variations in β‐globin gene cluster. Combination of these relative quantitative PCR methods could be an appropriate approach for accurate diagnosis of unknown β‐thalassemia deletions in routine diagnosis of β‐thalassemia mutations.
Left Ventricular Diastolic Dysfunction as Assessed by Echocardiography in Metabolic Syndrome

The purpose of the present study was to elucidate the cardiac structure and function in patients who have metabolic syndrome but no history of cardiovascular disease by analyzing echocardiographic findings. Echocardiographic examination was performed to screen for cardiovascular disease in 135 patients who were in their sixties. Patients were divided into metabolic syndrome (n=65, age: 65±2.7 years) and non–metabolic syndrome (n=70, age: 66±2.5 years) groups based on the criteria for metabolic syndrome proposed by the Japanese Society of Hypertension and seven other societies in 2005. The left ventricular (LV) wall thickness and dimension were measured by M-mode echocardiography. The relative wall thickness, LV mass index, and LV ejection fraction (LVEF) were calculated. LV diastolic function was assessed by the peak velocity of early rapid filling (E velocity) and the peak velocity of atrial filling (A velocity), and the ratio of E to A (E/A) was assessed by the transmitral flow. The Tei index, which reflects both LV diastolic and systolic function, was also calculated. There were no differences in relative wall thickness, LV mass index, or LVEF between the two groups. However, both the E/A and Tei index were significantly different between the metabolic syndrome (0.66±0.14 and 0.36±0.07, respectively) and non–metabolic syndrome (0.88±0.25 and 0.29±0.09) groups (p<0.001). These results indicate that patients with metabolic syndrome can have cardiac diastolic dysfunction even if they have neither LV hypertrophy nor systolic dysfunction.
Stakeholder Risk Management in Ethical Decision Making: An Organic Model

Stakeholder management has for the last three decades been concerned either with strategic business management or business ethics, values and quality. Many models have been developed, but recently the literature asks for more dynamic models instead of the staticism that characterizes some models. This paper offers an ‘Organic Stakeholder Model’ based on decision making theory, risk assessment and adaption to a rapidly changing world combined with appropriate stakeholder theory for ethical purposes in decision making processes in businesses. The ‘Organic Stakeholder Model’ is based on empirical evidence from hybrid organizations as Publicly Owned Enterprises (POEs) mixed of private corporations and political administration. The model offers a new way of combining risk management with ethical decisionmaking processes by the inclusion of multiple stakeholders. Not only does the model apply to these kinds of hybrid organizations, but it is easily adopted and tested for other private business models too. The findings and the conceptualization of the model enhances business ethics in decision making by managing and balancing stakeholder concerns with the same concerns as the traditional risk management models does – for the sake of the wider social responsibilities of the businesses and its stakeholders.
Release of preformed Fas ligand in soluble form is the major factor for activation‐induced death of Jurkat T cells

Interaction of Fas/APO‐1 (CD95) and its ligand (FasL) plays an important role in the activation‐induced cell death (AICD) of T lymphocytes. In the present work, the contribution of soluble FasL to AICD of the human T‐cell line Jurkat has been studied. Jurkat cells prestimulated with phytohaemagglutinin (PHA) induced the death of non‐activated Jurkat cells, and also of L1210Fas, but not that of Fas‐negative L1210 cells. Culture supernatants from prestimulated Jurkat cells were highly toxic to their non‐activated counterparts. Time–course analysis revealed that PHA‐stimulated Jurkat cells quickly release (less than 15 min) to the medium a toxic molecule following a biphasic pattern, with maximal cytotoxic activities at 1 hr and 7 hr after stimulation. The cytotoxic effect of those supernatants was prevented by the addition of a blocking anti‐Fas monoclonal antibody, suggesting that PHA‐stimulated Jurkat cells exert Fas‐based cytotoxicity mainly through the release of soluble FasL. The constitutive intracellular expression of FasL in non‐activated Jurkat cells and its release as a consequence of PHA activation were detected by immunostaining and immunoblotting using an anti‐FasL antibody. These data indicate that, at least in Jurkat cells, AICD is mainly mediated by the rapid release of preformed FasL in soluble form upon stimulation.
Trade-offs between burst performance and maximal exertion capacity in a wild amphibian, Xenopus tropicalis

SUMMARY Trade-offs are thought to impose barriers to phenotypic diversification and may limit the evolutionary responses of organisms to environmental changes. In particular, locomotor trade-offs between endurance or maximal exertion capacity and burst performance capacity have been observed in some species and may constrain the ability of organisms to disperse. Here, we tested for the presence of locomotor trade-offs between maximal exertion and burst performance capacity in an aquatic frog, the tropical clawed frog (Xenopus tropicalis). Given the importance of overland dispersal for this species, we focused on terrestrial exertion capacity (time and distance jumped until exhaustion) and tested whether it trades-off with aquatic burst performance capacity (maximum instantaneous velocity and acceleration), which is likely to be relevant in the context of predator escape and prey capture. Our data show that in both sexes, individuals with longer hindlimbs display higher endurance. Additionally, in females forelimb length was positively correlated with aquatic burst performance capacity and negatively correlated with terrestrial exertion. Trade-offs between endurance and burst performance capacity were detected, but were significant in males only. Finally, males and females differ in morphology and performance. Our data suggest that trade-offs are not universal and may be driven by sex-dependent selection on locomotor capacity. Moreover, our results suggest that locomotor trade-offs may result in sex-biased dispersal under selection for improved endurance capacity as is expected under habitat fragmentation scenarios.
Clustered vehicular networks: Decentralized detection “on the move”

In this paper, we analyze the performance of vehicular decentralized detection schemes, based on the observation, by all vehicles of a Vehicular Ad-hoc NETwork (VANET), of a spatially constant phenomenon of interest. Our approach consists of the creation, during a downlink phase, of a clustered VANET topology during fast broadcast data dissemination, from the Access Point (AP), through a novel clustering protocol, denoted as Cluster-head Election Irresponsible Forwarding (CEIF). This clustered topology is then exploited, during an uplink phase, to collect information from the vehicles and perform distributed detection. Our results highlight the existing trade-off between decision delay and energy efficiency. Unlike classical sensor networks for distributed detection, the proposed vehicular distributed detection schemes exploit the natural vehicle clustering and have to cope with their “ephemeral” nature. More precisely, vehicle mobility has a direct impact on the maximum amount of data which can be collected, thus leading to the concept of decentralized detection “on the move”.
Baclofen-induced cough suppression in cervical spinal cord injury.

OBJECTIVE To determine the effect of the GABA-agonist baclofen on cough reflex sensitivity in subjects with cervical spinal cord injury (C-SCI). Baclofen has been shown to inhibit the cough reflex in able-bodied volunteers. DESIGN Prospective, nonrandomized control trial. SETTING Veterans Affairs medical center with large outpatient SCI population. PARTICIPANTS Twelve adult males (11 outpatients) with C-SCI chronically maintained on oral baclofen for the treatment of muscle spasm. INTERVENTION Subjects underwent cough challenge testing with inhaled capsaicin. The concentrations (microM) of capsaicin inducing 2 or more (C2) and 5 or more (C5) coughs were determined. Mean values for log C2 and log C5 were compared with a control group of outpatients with C-SCI not receiving baclofen. RESULTS Subjects treated with baclofen had a significantly higher cough threshold (diminished cough reflex sensitivity) than control subjects. Mean (+/- standard error of the mean) values for log C2 in study subjects and controls were 1.28 +/- . 16 and . 65 +/- . 15, respectively (p = .009). Mean values for log C5 in subjects receiving baclofen and in control subjects were 2.20 +/- . 22 and 1.43 +/- . 23, respectively (p = .024). Subjects and controls did not differ in terms of age, spirometric parameters, or duration of injury. CONCLUSIONS The results suggest that chronic therapy with baclofen diminishes cough reflex sensitivity in subjects with C-SCI. The clinical significance of this finding remains to be elucidated.
Retinal S-antigen and retinoblastoma: a monoclonal antibody and flow cytometric study.

Retinal S-antigen was demonstrated in the WERI-Rb1 and to a lesser extent the Y-79 tissue cultured retinoblastoma cell lines as well as an ethanol-fixed, paraffin-embedded retinoblastoma by an indirect immunoperoxidase technique using monoclonal antibody MAbA9-C6, and by flow cytometric analysis (FCM) using MAbA9-C6 and MAbA1-G5. In fixed tissue sections, S-antigen immunoreactivity was restricted and localized to small numbers of retinoblastoma cells, including Flexner-Wintersteiner rosettes. By FCM, MAbA9-C6 bound to 15.4% of WERI-Rb1 cells and to 10.99. 7% of Y-79 cells whereas MAbA1-G5 bound to 14.66% of WERI-Rb1 and to 4.23% of Y-79 cells respectively. Cell cycle analysis showed that S-antigen was predominately expressed in the resting (G0/G1) phase. The usefulness of MAbA9-C6 in studying the embryological development of the retina and as a marker protein for studying antigenic expression and modulation in retinoblastomas is discussed.
Can Allocation-Based Water Rates Promote Conservation and Increase Welfare? A California Case Study

An allocation-based rate (ABR) is a special type of increasing block rate (IBR) price structure that is receiving increased attention from urban water suppliers in places like California where population growth and climate change continue to increase water scarcity. Previous work by Baerenklau et al. [Baerenklau, KA, KA Schwabe and A Dinar (2014a). Allocation-based water pricing promotes conservation while keeping user costs low. Agricultural and Resource Economics Update, 17(6), 1–14; Baerenklau, KA, KA Schwabe and A Dinar (2014b). The residential water demand effect of increasing block rate water budgets. Land Economics, 90(4), 683–699. ] investigates the conservation potential of ABR and finds that consumption under ABR was 10–15% below that of a comparable uniform rate structure for a southern California case study. This paper extends that work by using the discrete–continuous choice framework to estimate household-level welfare effects of ABR for the same dataset. We find that despite the observed decrease in consumption, average household welfare actually increased under ABR due to its non-linear structure. We also find that similar results would have been achievable with a simpler standard IBR structure. While either of these block rate structures is welfare-preferred to uniform price and quantity instruments, neither clearly dominates the other.
SUMO Binding by the Epstein-Barr Virus Protein Kinase BGLF4 Is Crucial for BGLF4 Function

ABSTRACT An Epstein-Barr virus (EBV) protein microarray was used to screen for proteins binding noncovalently to the small ubiquitin-like modifier SUMO2. Among the 11 SUMO binding proteins identified was the conserved protein kinase BGLF4. The mutation of potential SUMO interaction motifs (SIMs) in BGLF4 identified N- and C-terminal SIMs. The mutation of both SIMs changed the intracellular localization of BGLF4 from nuclear to cytoplasmic, while BGLF4 mutated in the N-terminal SIM remained predominantly nuclear. The mutation of the C-terminal SIM yielded an intermediate phenotype with nuclear and cytoplasmic staining. The transfer of BGLF4 amino acids 342 to 359 to a nuclear green fluorescent protein (GFP)-tagged reporter protein led to the relocalization of the reporter to the cytoplasm. Thus, the C-terminal SIM lies adjacent to a nuclear export signal, and coordinated SUMO binding by the N- and C-terminal SIMs blocks export and allows the nuclear accumulation of BGLF4. The mutation of either SIM prevented SUMO binding in vitro. The ability of BGLF4 to abolish the SUMOylation of the EBV lytic cycle transactivator ZTA was dependent on both BGLF4 SUMO binding and BGLF4 kinase activity. The global profile of SUMOylated cell proteins was also suppressed by BGLF4 but not by the SIM or kinase-dead BGLF4 mutant. The effective BGLF4-mediated dispersion of promyelocytic leukemia (PML) bodies was dependent on SUMO binding. The SUMO binding function of BGLF4 was also required to induce the cellular DNA damage response and to enhance the production of extracellular virus during EBV lytic replication. Thus, SUMO binding by BGLF4 modulates BGLF4 function and affects the efficiency of lytic EBV replication.
Demographic and Genetic Constraints on Evolution

Populations unable to evolve to selectively favored states are constrained. Genetic constraints occur when additive genetic variance in selectively favored directions is absent (absolute constraints) or present but small (quantitative constraints). Quantitative—unlike absolute—constraints are presumed surmountable given time. This ignores that a population might become extinct before reaching the favored state, in which case demography effectively converts a quantitative into an absolute constraint. Here, we derive criteria for predicting when such conversions occur. We model the demography and evolution of populations subject to optimizing selection that experience either a single shift or a constant change in the optimum. In the single‐shift case, we consider whether a population can evolve significantly without declining or else declines temporarily while avoiding low sizes consistent with high extinction risk. We analyze when populations in constantly changing environments evolve sufficiently to ensure long‐term growth. From these, we derive formulas for critical levels of genetic variability that define demography‐caused absolute constraints. The formulas depend on estimable properties of fitness, population size, or environmental change rates. Each extends to selection on multivariate traits. Our criteria define the nearly null space of a population’s G matrix, the set of multivariate directions effectively inaccessible to it via adaptive evolution.