Miracle-dz/UniFAR-FTUs huggingface dataset:
A Genomic Screening Approach to the Structure‐Guided Identification of Drug Candidates from Natural Sources

The potential of actinomycetes to produce natural products has been exploited for decades. Recent genomic sequence analyses have revealed a previously unrecognized biosynthetic potential and diversity. In order to rationally exploit this potential, we have developed a sequence‐guided genetic screening strategy. In this “genome mining” approach, genes that encode tailoring enzymes from natural product biosyntheses pathways serve as indicator genes for the identification of strains that have the genetic potential to produce natural products of interest. We chose halogenases, which are known to be involved in the synthesis of halometabolites as representative examples. From PCR screening of 550 randomly selected actinomycetes strains, we identified 103 novel putative halogenase genes. A phylogenetic analysis of the corresponding putative halogenases, and the determination of their sequential context with mass spectrometric analysis of cultures filtrates revealed a distinct correlation between the sequence and secondary metabolite class of the halometabolite. The described screening strategy allows rapid access to novel natural products with predetermined structural properties.
47,XXY (KLINEFELTER SYNDROME) AND 47,XYY: ESTIMATED RATES OF AND INDICATION FOR POSTNATAL DIAGNOSIS WITH IMPLICATIONS FOR PRENATAL COUNSELLING

Cytogenetic surveys of neonates have found that approximately one boy in 500 is born with an extra sex chromosome. Some of these boys are now being diagnosed when prenatal karyotyping is done for the detection of Down syndrome and other major aneuploidies. This study estimates what proportion of those not detected prenatally will be diagnosed postnatally and what the indications for karyotyping are likely to be. We ascertained all 47,XXY and 47,XYY males detected prenatally and postnatally (during the 4 years 1990–1993) in the three cytogenetic laboratories in the North Thames (West) region. The age at diagnosis and indication for karyotyping were noted for cases diagnosed postnatally. Less than 10 per cent of the estimated number of affected fetuses were detected prenatally. This study suggests that most males born with these chromosome patterns will go through life without being karyotyped, that the commonest indication for a 47,XYY male to be karyotyped will be developmental delay and/or behaviour problems, and that the commonest indication for a Klinefelter male to be karyotyped will be hypogonadism and/or infertility. It would appear that most undiagnosed 47,XXY and 47,XYY males do not look or behave in a manner which prompts testing for a chromosome abnormality. © 1997 by John Wiley & Sons, Ltd.
Relations of serum phosphorus and calcium levels to the incidence of cardiovascular disease in the community.

BACKGROUND Higher levels of serum phosphorus and the calcium-phosphorus product are associated with increased mortality from cardiovascular disease (CVD) in patients with chronic kidney disease (CKD) or prior CVD. However, it is unknown if serum phosphorus levels influence vascular risk in individuals without CKD or CVD. METHODS We prospectively evaluated 3368 Framingham Offspring study participants (mean age, 44 years; 51% were women) free of CVD and CKD. We used multivariable Cox models to relate serum phosphorus and calcium levels to CVD incidence. RESULTS On follow-up (mean duration, 16.1 years), there were 524 incident CVD events (159 in women). In multivariable analyses and adjusting for established risk factors and additionally for glomerular filtration rate and for hemoglobin, serum albumin, proteinuria, and C-reactive protein levels, a higher level of serum phosphorus was associated with an increased CVD risk in a continuous fashion (adjusted hazard ratio per increment of milligrams per deciliter, 1.31; 95% confidence interval, 1.05-1.63; P=.02; P value for trend across quartiles = .004). Individuals in the highest serum phosphorus quartile experienced a multivariable-adjusted 1.55-fold CVD risk (95% confidence interval, 1.16%-2.07%; P=.004) compared with those in the lowest quartile. These findings remained robust in time-dependent models that updated CVD risk factors every 4 years and in analyses restricted to individuals without proteinuria and an estimated glomerular filtration rate greater than 90 mL/min per 1.73 m(2). Serum calcium was not related to CVD risk. CONCLUSION Higher serum phosphorus levels are associated with an increased CVD risk in individuals free of CKD and CVD in the community. These observations emphasize the need for additional research to elucidate the potential link between phosphorus homeostasis and vascular risk.
Chitin and chitosan: biopolymers for wound management

Chitin and chitosan are biopolymers with excellent bioactive properties, such as biodegradability, non‐toxicity, biocompatibility, haemostatic activity and antimicrobial activity. A wide variety of biomedical applications for chitin and chitin derivatives have been reported, including wound‐healing applications. They are reported to promote rapid dermal regeneration and accelerate wound healing. A number of dressing materials based on chitin and chitosan have been developed for the treatment of wounds. Chitin and chitosan with beneficial intrinsic properties and high potential for wound healing are attractive biopolymers for wound management. This review presents an overview of properties, biomedical applications and the role of these biopolymers in wound care.
Role of dermal cells from normal and ultraviolet B-damaged skin in induction of contact hypersensitivity and tolerance.

With conventional regimens for induction of contact hypersensitivity with highly reactive haptens, circumstantial evidence implicates both epidermal and dermal APC. However, similar applications of hapten to skin that has been treated with an acute, low dose UVB radiation protocol induce contact hypersensitivity only in certain genetically defined strains of mice, termed UVB-resistant. Moreover, mice that fail to acquire contact hypersensitivity when hapten is painted on UVB-exposed skin display hapten-specific tolerance. In the present study, dermal cell suspensions have been prepared from normal and UVB-exposed mouse skin as a means of identifying the cell(s) that: 1) provide APC function after UVB radiation in UVB-resistant mice; and 2) confer tolerance after UVB radiation in UVB-susceptible mice. The results confirm that the normal murine dermis contains Ia+ cells that, when hapten-derivatized in vitro and injected s.c. into naive, syngeneic mice, possess typical Ag-presenting function. Cells with similar function are retained in the dermis of UVB-resistant mice after exposure to UVB radiation, whereas dermal cells of UVB-exposed skin of UVB-susceptible mice display no ability to induce contact hypersensitivity. Instead, the latter dermal cells, when hapten-conjugated and injected s.c. , induce tolerance. Thus, doses of UVB radiation that deplete the epidermis of Langerhans cells do not deplete the dermis of UVB-resistant mice of contact hypersensitivity-inducing APC, but do confer upon cells within the dermis of UVB-susceptible mice the capacity to induce unresponsiveness.
Predictors and reference values of CD4 and CD8 T lymphocyte counts in pregnancy: a cross sectional study among HIV negative women in Zimbabwe.

OBJECTIVE To identify predictors and define reference values for T lymphocyte subsets in HIV negative pregnant black women. DESIGN Cross sectional study. SETTING Edith Opperman Martenity Hospital, Harare, Zimbabwe. STUDY POPULATION 1113 HIV negative women 22 to 35 weeks pregnant registering for routine antenatal care. METHODS A questionnaire was used to collect demographic and obstetric data. CD4 and CD8 T lymphocyte counts were determined by manual immunocytochemistry. Concentrations in serum, of retinol, beta-carotene, ferritin, folate and 1-antichymotrypsin were also measured. Multiple linear regression analysis was employed to identify and estimate effects of potential predictors. MAIN OUTCOME MEASURES CD4 and CD8 T lymphocyte levels, demographic, obstetric data and micronutrient status. RESULTS Predictors of CD4 counts were gestational age, serum retinol and season. CD4 counts declined by 25 (95% confidence interval [CI]; 11 to 40; p = 0.001) cells/L for each week's increase in gestation among women with low serum retinol, while low serum retinol was independently associated with lower CD4 counts (-127; 95% CI, -233 to 20 cells/L; p = 0.02) at 35 weeks gestation. The late rainy season was associated with higher CD4 counts (137; 95% CI, 67 to 207 cells/L; p < 0.001). CD8 counts were higher in women with low serum folate (87; 95% CI, 6 to 166 cells/L; p = 0.036) and were slightly higher in gravida 4+ compared to gravida one to three. Reference values of CD4 but not CD8 count and percentage markedly differed from flow cytometry values of pregnant and non-pregnant women in developed and developing countries reported in the literature, even after controlling for the differences in methods of T lymphocyte subset immunophenotyping. CONCLUSION Gestational age, gravidity, micronutrient status and season influence T lymphocyte subset levels and need to be considered when designing clinical management and intervention strategies for pregnant women. The data underscores the need for local reference values.
Determination of Timing of Brain Injury in Preterm Infants With Periventricular Leukomalacia With Serial Neonatal Electroencephalography

Objective. The aim of this study was to determine the timing of brain injury in infants with periventricular leukomalacia (PVL) with serial electroencephalography (EEG) recordings during the neonatal period. Patients and Methods. We evaluated 172 preterm infants having a gestational age <33 weeks and weighing <2000 g. Initial EEG was recorded within 72 hours of life and then recorded once every 1 to 4 weeks. Serial cranial ultrasonography was performed and cystic PVL was diagnosed when multiple cystic formations of >3 mm in diameter were observed. Results. Of the172 infants studied, 26 were diagnosed as having cystic PVL by ultrasonography. EEG abnormalities were observed in 25 of 26 infants with PVL, although EEG abnormalities were seen in 20 of 146 infants without PVL. The initial EEG recordings were normal in 7 infants, but EEG abnormalities were observed later in 6 of these infants. In these 6 infants, the timing of injury was presumed to be postpartum. Only acute stage abnormalities were observed on initial EEG recording in 14 infants, and the timing of injury was presumed to be just before or around birth. Chronic stage abnormalities were recognized already on initial EEG recordings in the other 5 infants, and the timing of injury was presumed to be some time before birth. Conclusions. Our study indicates that it may be possible to determine the timing of injury in infants with PVL by serial EEG recordings.
Structural Design, Synthesis and Structure–Activity Relationships of Thiazolidinones with Enhanced Anti‐Trypanosoma cruzi Activity

Pharmacological treatment of Chagas disease is based on benznidazole, which displays poor efficacy when administered during the chronic phase of infection. Therefore, the development of new therapeutic options is needed. This study reports on the structural design and synthesis of a new class of anti‐Trypanosoma cruzi thiazolidinones (4 a–p). (2‐[2‐Phenoxy‐1‐(4‐bromophenyl)ethylidene)hydrazono]‐5‐ethylthiazolidin‐4‐one (4 h) and (2‐[2‐phenoxy‐1‐(4‐phenylphenyl)ethylidene)hydrazono]‐5‐ethylthiazolidin‐4‐one (4 l) were the most potent compounds, resulting in reduced epimastigote proliferation and were toxic for trypomastigotes at concentrations below 10 μM, while they did not display host cell toxicity up to 200 μM. Thiazolidinone 4 h was able to reduce the in vitro parasite burden and the blood parasitemia in mice with similar potency to benznidazole. More importantly, T. cruzi infection reduction was achieved without exhibiting mouse toxicity. Regarding the molecular mechanism of action, these thiazolidinones did not inhibit cruzain activity, which is the major trypanosomal protease. However, investigating the cellular mechanism of action, thiazolidinones altered Golgi complex and endoplasmic reticulum (ER) morphology, produced atypical cytosolic vacuoles, as well as induced necrotic parasite death. This structural design employed for the new anti‐T. cruzi thiazolidinones (4 a–p) led to the identification of compounds with enhanced potency and selectivity compared to first‐generation thiazolidinones. These compounds did not inhibit cruzain activity, but exhibited strong antiparasitic activity by acting as parasiticidal agents and inducing a necrotic parasite cell death.
Purified TMEM16A is sufficient to form Ca2+-activated Cl− channels

Significance Calcium-activated chloride channels play key roles in physiology, from mediating sensory transduction and nociception to regulating mucine secretion in airway epithelia and controlling excitability of smooth muscle fibers. Recently, TMEM16A was identified as the pore-forming subunit of these channels. It remains unclear, however, whether this protein is sufficient to form calcium-activated chloride channels, or whether association with other subunits is required for function. Recently, association with calmodulin has been proposed to be required for the calcium-dependent activation and ion selectivity of these channels. Here we show that purified and reconstituted TMEM16A is necessary and sufficient to recapitulate the properties of native and heterologously expressed calcium-activated chloride currents. Thus, association of TMEM16A with other proteins is not required for function. Ca2+-activated Cl− channels (CaCCs) are key regulators of numerous physiological functions, ranging from electrolyte secretion in airway epithelia to cellular excitability in sensory neurons and muscle fibers. Recently, TMEM16A (ANO1) and -B were shown to be critical components of CaCCs. It is still unknown whether they are also sufficient to form functional CaCCs, or whether association with other subunits is required. Recent reports suggest that the Ca2+ sensitivity of TMEM16A is mediated by its association with calmodulin, suggesting that functional CaCCs are heteromultimers. To test whether TMEM16A is necessary and sufficient to form functional CaCCs, we expressed, purified, and reconstituted human TMEM16A. The purified protein mediates Ca2+-dependent Cl− transport with submicromolar sensitivity to Ca2+, consistent with what is seen in patch–clamp experiments. The channel is synergistically gated by Ca2+ and voltage, so that opening is promoted by depolarizing potentials. Mutating two conserved glutamates in the TM6-7 intracellular loop selectively abolishes the Ca2+ dependence of reconstituted TMEM16A, in a manner similar to what was reported for the heterologously expressed channel. Well-characterized CaCC blockers inhibit Cl− transport with Kis comparable to those measured for native and heterologously expressed CaCCs. Finally, direct physical interactions between calmodulin and TMEM16A could not be detected in copurification experiments or in functional assays. Our results demonstrate that purified TMEM16A is necessary and sufficient to recapitulate the biophysical and pharmacological properties of native and heterologously expressed CaCCs. Our results also show that association of TMEM16A with other proteins, such as calmodulin, is not required for function.
Impacts of implementing case payment system to medical aid hemodialysis patients on dialysis frequencies and expenditure.

OBJECTIVES To assess the impacts of implementing case payment system (CPS) to Medical Aid (MA) hemodialysis patients on the frequencies and expenditure of dialysis. METHODS Fifty-eight clinics and 35 tertiary care hospitals were identified as having a minimum of 10 hemodialysis patients for each of the MA and Medical Insurance (MI) programs, who received hemodialysis from the same dialysis facilities for both periods of July 2001 and July 2002. From these facilities, a total of 2, 167 MA and 2, 928 MI patients were identified as the study subjects. Using electronic claims data, the changes in the total number of monthly treatments and charges for outpatient hemodialysis treatments for each patient after the introduction of the CPS were compared between the MA and MI patients. Multiple regression analyses were performed to examine the independent impact of the CPS on the utilization and expenditure of dialysis treatments among the MA patients. RESULTS There was a significant decrease in the total charges for the hemodialysis treatments of the MA patients, 3.4% (p< 0.05), whereas a significant increase was observed for the MI patients, 2.5% (p< 0.05). For both the MA and MI patients, the frequency of the monthly hemodialysis treatments were significantly increased, 5.5 (from 12.1 to 12.7) and 7.8% (from 11.6 to 12.5), for the MA and MI patients, respectively. However, a multivariate regression analysis showed no significant difference in the changes in the total number of monthly hemodialysis treatments between the MA and MI patients after implementation of the CPS. Another regression model, regressing on the changes in the monthly claims of dialysis treatments, showed a significant negative coefficient for the MA ( (=-70725, p< 0.05). CONCLUSIONS The significant decrease in the total charges for hemodialysis treatments among MA as compared to MI patients suggests that there was a cost reduction in the MA program following the introduction of the CPS.
An acute psychosocial stressor does not potentiate alcohol cue reactivity in non-treatment-seeking alcoholics.

BACKGROUND Relapse risk factors, such as psychological stress and alcohol cues, are often encountered together. Understanding how they interact has the potential to improve alcoholism treatments. This study was conducted to examine whether an acute psychosocial stressor enhanced alcohol cue reactivity in non-treatment-seeking alcoholics. METHODS Seventy-nine alcohol-dependent individuals (39 women) randomly received either the Trier Social Stress Test or a no-stress control condition. Stress reactivity was measured with serum adrenocorticotropic hormone and cortisol, mean arterial blood pressure, and subjective distress. Immediately following the stress manipulation, participants held and sniffed a neutral cue then their preferred alcoholic beverage. Cue reactivity was measured by 2 subjective measures of craving following each cue. Additionally, general craving was assessed with the Alcohol Urge Questionnaire at the beginning and end of the laboratory procedure. RESULTS The stress manipulation showed internal validity on all measures of stress reactivity. There was not a main effect of stress nor a stress × cue interaction on either cue reactivity measure. As expected, there was a main effect of cue (alcohol > neutral cue) on both measures of cue reactivity. General craving increased during the challenge, but not differently by stress group. Magnitude of stress reactivity was not associated with magnitude of cue reactivity, and all results were independent of gender. CONCLUSION In this well-controlled clinical laboratory study of non-treatment-seeking alcoholics, an acute psychological stressor did not make an alcohol cue a more potent urge-inducing stimulus, and stress had no effect on general alcohol craving.
EDEM3, a Soluble EDEM Homolog, Enhances Glycoprotein Endoplasmic Reticulum-associated Degradation and Mannose Trimming*

Quality control in the endoplasmic reticulum ensures that only properly folded proteins are retained in the cell through mechanisms that recognize and discard misfolded or unassembled proteins in a process called endoplasmic reticulum-associated degradation (ERAD). We previously cloned EDEM (ER degradation-enhancing α-mannosidase-like protein) and showed that it accelerates ERAD of misfolded glycoproteins. We now cloned mouse EDEM3, a soluble homolog of EDEM. EDEM3 consists of 931 amino acids and has all the signature motifs of Class I α-mannosidases (glycosyl hydrolase family 47) in its N-terminal domain and a protease-associated motif in its C-terminal region. EDEM3 accelerates glycoprotein ERAD in transfected HEK293 cells, as shown by increased degradation of misfolded α1-antitrypsin variant (null (Hong Kong)) and of TCRα. Overexpression of EDEM3 also greatly stimulates mannose trimming not only from misfolded α1-AT null (Hong Kong) but also from total glycoproteins, in contrast to EDEM, which has no apparent α1,2-mannosidase activity. Furthermore, overexpression of the E147Q EDEM3 mutant, which has the mutation in one of the conserved acidic residues essential for enzyme activity of α1,2-mannosidases, abolishes the stimulation of mannose trimming and greatly decreases the stimulation of ERAD by EDEM3. These results show that EDEM3 has α1,2-mannosidase activity in vivo, suggesting that the mechanism whereby EDEM3 accelerates glycoprotein ERAD is different from that of EDEM.
Enabling Supply Chain Collaboration in a Hybrid Cloud

Social networking based collaboration applications or platforms are the most likely use cases to adopt cloud models as per IDC market research survey. Extending social networking concepts to enable collaboration among users in large enterprises and their partners is on the rise. Collaboration among extended partners has been one of the top challenges of large supply chain companies while security is the top most concern for cloud adoption. This paper discusses the successful enablement of collaboration among several supply chain partners using Cisco's enterprise collaboration platform, Quad at an Infrastructure-as-a-Service public cloud provider, Savvis. Several defense-in-depth security mechanisms are implemented including federated authentication & authorization, data level security, user to site SSL-VPN, web application vulnerability assessment, multiple level firewalls, host hardening, end-to-end transport layer security in order to enhance security posture of collaboration among supply chain communities in a hybrid cloud deployment model.
Clinical Features and Outcomes of Takayasu Arteritis with Neurological Symptoms in China: A Retrospective Study

Objective. To describe the clinical features and longterm outcomes of patients with Takayasu arteritis (TA) in China who experienced neurological symptoms. Methods. A retrospective study was undertaken of patients with TA who attended a single study center from 2002 to 2013, who also exhibited neurological symptoms (n = 274). Clinical and imaging features were analyzed, as well as longterm outcomes. Results. The mean age at disease onset was 28.2 ± 11.2 years, with a female-to-male ratio of 4.3:1. The most common neurological manifestation was dizziness (214, 78.1%), the most frequent type of TA was type III (112, 40.9%), and the most common affected artery was the left subclavian (147, 53.6%). Involvement of 3 or 4 branches of the aortic arch was observed in 28% of patients. Among 30 patients experiencing a stroke (10.9%), steno-occlusive lesions of the subclavian artery and common carotid artery were frequently observed in patients with ischemic stroke, while steno-occlusive lesions of the descending aorta, abdominal aorta, and/or renal arteries were more frequently observed with hemorrhagic stroke. Heart failure was the most common cardiovascular event in those who died (n = 6) and in surviving cohorts. Conclusion. Neurological features in patients with TA were variable, and correlated with the number of arteries and the site of artery involvement. Resistant hypertension was one of the most important risk factors for hemorrhagic stroke in patients with TA.