Miracle-dz/UniFAR-FTUs huggingface dataset:
Residues in the HIV-1 Capsid Assembly Inhibitor Binding Site Are Essential for Maintaining the Assembly-competent Quaternary Structure of the Capsid Protein*

Morphogenesis of infectious HIV-1 involves budding of immature virions followed by proteolytic disassembly of the Gag protein shell and subsequent assembly of processed capsid proteins (CA) into the mature HIV-1 core. The dimeric interface between C-terminal domains of CA (C-CA) has been shown to be important for both immature and mature assemblies. We previously reported a CA-binding peptide (CAI) that blocks both assembly steps in vitro. The three-dimensional structure of the C-CA/CAI complex revealed an allosteric effect of CAI that alters the C-CA dimer interface. Based on this structure, we now investigated the phenotypes of mutations in the binding pocket. CA variants carrying mutations Y169A, L211A, or L211S had a reduced affinity for CAI and were unable to form mature-like particles in vitro. These mutations also blocked morphological conversion to mature virions in tissue culture and abolished infectivity. X-ray crystallographic analyses of the variant C-CA domains revealed that these alterations induced the same allosteric change at the dimer interface observed in the C-CA/CAI complex. These results point to a role of key interactions between conserved amino acids in the CAI binding pocket of C-CA in maintaining the correct conformation necessary for mature core assembly.
Pilot study on the effects of high cutoff hemofiltration on the need for norepinephrine in septic patients with acute renal failure*

Objective:High cutoff hemofilters are characterized by an increased effective pore size designed to facilitate the elimination of inflammatory mediators in sepsis. Clinical data on this new renal replacement modality are lacking. Design:Prospective, randomized clinical trial. Setting:University hospital, intensive care units. Patients:Thirty patients with sepsis-induced acute renal failure. Intervention:Patients were allocated to high cutoff (n = 20) or conventional (n = 10) hemofiltration in a 2:1 ratio. Median renal replacement dose was 31 mL/kg/hr. For high cutoff hemofiltration, a high-flux hemofilter with an in vivo cutoff point of approximately 60 kilodaltons was used. Conventional hemofiltration was performed with a standard high-flux hemofilter (PF11S). The impacts of high cutoff hemofiltration on the need for norepinephrine and on plasma levels and clearance rates for interleukin (IL)-6 and IL-1 receptor antagonist (IL-1ra) were analyzed. Absolute values, but also adjusted values (expressed as proportion of baseline), were analyzed. The observation period was restricted to 48 hrs. Main Results:Apart from higher antithrombin III levels at entry into the study, main clinical and laboratory parameters were comparable between both groups. The median norepinephrine dose at entry into the study was 0.30 &mgr;g/kg/min in the high cutoff group and 0.21 &mgr;g/kg/min in the conventional hemofiltration group (p = .448). Only the high cutoff group showed a significant decline (p = .0002) in “adjusted” norepinephrine dose over time. Clearance rates for IL-6 and IL-1ra were significantly higher in the high cutoff hemofiltration group (p < .0001), which translated into a significant decline of the corresponding plasma levels (p = .0465 for IL-6; p = .0293 for IL-1ra). Conclusion:In this pilot study, high cutoff hemofiltration has been shown to exert a beneficial effect on the need for norepinephrine in septic patients with acute renal failure. In addition, we demonstrate that high cutoff hemofiltration is superior to conventional hemofiltration in the elimination of IL-6 and IL-1ra from the circulating blood of septic patients.
Impact of labour market reforms on economic activity in European Union: short term costs and long term benefits

The main objective of this paper was to quantify the long- and short-term impacts of labour market reforms on economic activity in EU countries, including Croatia. Therefore, we derived a model using the pooled mean group estimator (PMG) for the period from 2000 to 2011. Before performing dynamic panel analysis based on the PMG estimator, the unit root and panel cointegration tests were performed. According to the results, labour market reforms have positive and statistically significant long-term impact on GDP per capita. On the other hand, labour market reforms also have a statistically significant and negative effect on GDP per capita in the short-run. Control variables (industrial production and the rate of the active population) also have significant impacts on GDP per capita. In addition to econometric analysis, we also present an overview of empirical and theoretical research on labour market reforms in developed, developing and transition countries.
Simultaneous signalling through c‐mpl, c‐kit and CXCR4 enhances the proliferation and differentiation of human megakaryocyte progenitors: possible roles of the PI3‐K, PKC and MAPK pathways

We assessed the effect of signalling through CXCR4 on the proliferation and differentiation of human megakaryocytic progenitor cells (CFU‐Meg) in the presence or absence of stem cell factor (SCF) and/or thrombopoietin (TPO), using peripheral blood‐derived CD34+IL‐6R− cells as a target. TPO alone induced a significant number of CFU‐Meg colonies. Although stromal cell‐derived factor‐1 (SDF‐1) or SCF alone did not support CFU‐Meg colony formation, these factors had a synergistic effect on CFU‐Meg colony formation in the presence of TPO. The combination of SDF‐1, SCF and TPO induced twice as many CFU‐Meg colonies as TPO alone. To investigate the mechanism of this synergistic action, we examined the effects of various protein kinase inhibitors on CFU‐Meg colony formation. LY294002 and GF109203X (inhibitors of PI3‐K and PKC respectively) completely or partially inhibited this synergistic action. In contrast, a MEK inhibitor (PD98059) did not inhibit CFU‐Meg colony formation. It significantly increased the higher ploidy classes (16N to 64N) of megakaryocytes supported by TPO, TPO + SCF, TPO + SDF‐1, and TPO + SCF + SDF‐1, whereas it abolished the effect of SDF‐1 on the increase of higher ploidy classes of megakaryocytes supported by TPO. These results suggest that MAPK may negatively or positively regulate the nuclear maturation of megakaryocytes, known as endomitosis. In the presence of PD98059, proplatelet formation (PPF) was significantly augmented, suggesting that the MAPK pathway may also inhibit the initiation of PPF. In conclusion, simultaneous activation of three signals through c‐mpl, c‐kit and CXCR4 can induce the in vitro proliferation and differentiation of CFU‐Meg, and SDF‐1 is a potentiator of human megakaryocytopoiesis.
1.3-μm AlGaInAs-InP buried-heterostructure lasers with mode profile converter

AlGaInAs buried-heterostructure (BH) lasers with a mode profile converter (MPC) have been successfully fabricated for the first time. The thickness of the multiple-quantum-well (MQW) waveguide was vertically tapered by selective area growth (SAG). The threshold current I/sub th/ was 14.6 mA with a 600-/spl mu/m-long cavity and a high-reflective-coated rear facet. The full-width at half-maximum of the far-field pattern in the perpendicular and horizontal directions were 9.2/spl deg/ and 12.6/spl deg/, respectively. The optical coupling loss between lasers with MPC and a single-mode fiber was 3.0 dB when the distance between the laser and fiber was 20 /spl mu/m.
Comparative Utility of Cytokine Levels and Quantitative RD-1-Specific T Cell Responses for Rapid Immunodiagnosis of Tuberculous Meningitis

ABSTRACT The rapid diagnosis of tuberculous meningitis (TBM) is problematic. We found in 150 patients with suspected TBM that, similar to RD-1-specific quantitative cerebrospinal fluid (CSF) T-cell responses, unstimulated CSF gamma interferon (IFN-γ) levels when used together with other rapid confirmatory tests (Gram stain and cryptococcal latex agglutination test) may allow the accurate and rapid diagnosis of TBM in a setting in which tuberculosis (TB) and HIV are endemic. In resource-poor settings, a clinical prediction rule (CPR) may be useful to clinicians, and thus the IFN-γ assay may potentially need to be used only when the clinical score is below a prespecified threshold. These preliminary findings will need to be confirmed in further studies.
A potential role of heat shock proteins and nicotinamide N‐methyl transferase in predicting response to radiation in bladder cancer

The use of definitive radiotherapy for treatment of invasive bladder cancer has the advantage of preserving bladder function, but tumour regression is only achieved in approximately 40–50% of patients. Knowledge of the molecular basis of sensitivity to ionizing radiation and identification of potential molecular predictors will provide useful information regarding patient response and thus help clinicians to individualize treatment. The recent application of cDNA expression array technology provides a useful tool to investigate hundreds or even thousands of genes in a single experiment. In our study, we have used the Atlas human stress cDNA array™ to investigate the expression profile of stress‐related and DNA repair genes in a radioresistant bladder carcinoma cell line (MGH‐U1) and its radiosensitive subclone (S40b). This provides an ideal situation to study genes related to radiation because the genotypes of both cell lines are basically similar and differential changes detected are likely to be related to the different radiosensitivity phenotype. Of 234 genes blotted on the array, 3 genes (Heat shock protein 90, Heat shock protein 27 and Nicotinamide N‐methyl transferase) showed consistent downregulation in the radiosensitive clone in 2 independent experiments. These results were further confirmed for HSP27 and NNMT using Sybr Green I‐based real‐time QRT‐PCR. The role of heat shock proteins (HSPs) in response to radiation remains to be determined; however, the results of our present work suggest a possible role of HSP27 in determining radiosensitivity. Our study also opens avenues for the investigation of genes, such as NNMT, which has not previously been linked to response to radiation. © 2002 Wiley‐Liss, Inc.
Cannabinoids may worsen gastric dysmotility induced by chronic cisplatin in the rat

Background Although cannabinoids have traditionally been used for the treatment and/or prevention of nausea and/or emesis, anorexia and weight loss induced by clinical use of antineoplastic drugs, their efficacy and safety in long‐term treatments are still controversial. Our aim was to analyze the effects of the non‐selective cannabinoid agonist WIN 55 212‐2 (WIN) on gastrointestinal (GI) dysmotility and other adverse effects induced by repeated cisplatin administration in the rat.
Protein modification and replicative senescence of WI‐38 human embryonic fibroblasts

Oxidized proteins as well as proteins modified by the lipid peroxidation product 4‐hydroxy‐2‐nonenal (HNE) and by glycation (AGE) have been shown to accumulate with aging in vivo and during replicative senescence in vitro. To better understand the mechanisms by which these damaged proteins build up and potentially affect cellular function during replicative senescence of WI‐38 fibroblasts, proteins targeted by these modifications have been identified using a bidimensional gel electrophoresis‐based proteomic approach coupled with immunodetection of HNE‐, AGE‐modified and carbonylated proteins. Thirty‐seven proteins targeted for either one of these modifications were identified by mass spectrometry and are involved in different cellular functions such as protein quality control, energy metabolism and cytoskeleton. Almost half of the identified proteins were found to be mitochondrial, which reflects a preferential accumulation of damaged proteins within the mitochondria during cellular senescence. Accumulation of AGE‐modified proteins could be explained by the senescence‐associated decreased activity of glyoxalase‐I, the major enzyme involved in the detoxification of the glycating agents methylglyoxal and glyoxal, in both cytosol and mitochondria. This finding suggests a role of detoxification systems in the age‐related build‐up of damaged proteins. Moreover, the oxidized protein repair system methionine sulfoxide reductase was more affected in the mitochondria than in the cytosol during cellular senescence. Finally, in contrast to the proteasome, the activity of which is decreased in senescent fibroblasts, the mitochondrial matrix ATP‐stimulated Lon‐like proteolytic activity is increased in senescent cells but does not seem to be sufficient to cope with the increased load of modified mitochondrial proteins.
Bed‐building in captive chimpanzees (Pan troglodytes): the importance of early rearing

In the wild, great apes sleep in beds they make by successively bending branches into an interwoven platform. These beds are functionally more closely related to human beds than they are to the nests and tree‐holes used by other primate species. The idea that bed‐building by great apes is learned behavior that is dependent on appropriate early experiences has been proposed but never fully tested. In the present study this hypothesis was indirectly tested in 73 captive adult chimpanzees (Pan troglodytes; 27 wild‐born and 46 captive‐born). Bed‐building and use were tested experimentally by the introduction of three sets of bedding materials. Over 200 hr of scan‐sampling data were collected during 45‐min observations following introduction of the bedding material. The wild‐born subjects built and used beds significantly more often than the captive‐born subjects. Also, wild‐born subjects used more complex techniques during construction. Captive‐born subjects that were mother‐reared through early adolescence spent more time building and using beds than their nursery‐reared counterparts. These differences remained consistent even when previous adult experience with bedding (measured as naturalistic vs. traditional housing) was accounted for. These results suggest that bed‐building is a learned behavior that requires early experience and practice for acquisition. Am. J. Primatol. 68:745–751, 2006. © 2006 Wiley‐Liss, Inc.
High‐density linkage maps fail to detect any genetic component to sex determination in a Rana temporaria family

Sex chromosome differentiation in Rana temporaria varies strikingly among populations or families: whereas some males display well‐differentiated Y haplotypes at microsatellite markers on linkage group 2 (LG2), others are genetically undistinguishable from females. We analysed with RADseq markers one family from a Swiss lowland population with no differentiated sex chromosomes, and where sibship analyses had failed to detect any association between the phenotypic sex of progeny and parental haplotypes. Offspring were reared in a common tank in outdoor conditions and sexed at the froglet stage. We could map a total of 2177 SNPs (1123 in the mother, 1054 in the father), recovering in both adults 13 linkage groups (= chromosome pairs) that were strongly syntenic to Xenopus tropicalis despite > 200 My divergence. Sexes differed strikingly in the localization of crossovers, which were uniformly distributed in the female but limited to chromosome ends in the male. None of the 2177 markers showed significant association with offspring sex. Considering the very high power of our analysis, we conclude that sex determination was not genetic in this family; which factors determined sex remain to be investigated.
Early-pregnancy glucose screening for gestational diabetes mellitus.

OBJECTIVE To determine the accuracy of the 50-g, one-hour glucose screening test administered at 16 weeks of pregnancy for identifying women with gestational diabetes mellitus. STUDY DESIGN Two hundred fifty-five women underwent 50-g, one-hour glucose screening tests at 16 weeks of pregnancy. Those with results > or = 135 mg/dL underwent 100-g, three-hour glucose tolerance tests. All patients without diagnoses of gestational diabetes during the second trimester of pregnancy underwent standard third-trimester glucose testing. RESULTS Gestational diabetes mellitus was diagnosed in 25 patients. Glucose screening tests administered at 16 weeks of pregnancy identified 96% (24) of these patients. Patients with 16-week glucose screening test results > or = 135 mg/dL had a 55% risk of developing diabetes during pregnancy, while the risk was 0.6% for patients with 16-week test results < or = 110 mg/dL. Patients with 16-week glucose screening test results in the intermediate range, 111-134 mg/dL, had a 4.8% risk of developing diabetes during pregnancy. CONCLUSION Glucose screening at 16 weeks of pregnancy is a useful alternative to third-trimester screening for gestational diabetes. The negative predictive value of screening test results < or = 110 mg/dL is 99.4%. The positive predictive value for screening test results > or = 135 mg/dL is 55%. This latter finding is superior to the 8.6-22% found during the third-trimester.
Interobserver Variability in Retreatment Decisions of Recurrent and Residual Aneurysms

BACKGROUND AND PURPOSE: The degree of variation in retreatment decisions for residual or recurrent aneurysms among endovascular therapists remains poorly defined. We performed a multireader study to determine what reader and patient variables contribute to this variation. MATERIALS AND METHODS: Seven endovascular therapists (4 neuroradiologists, 3 neurosurgeons) independently reviewed 66 cases of patients treated with endovascular coil embolization for ruptured or unruptured aneurysm. Cases were rated on a 5-point scale recommending for whether to retreat and a recommended retreatment type. Reader agreement was assessed by intraclass correlation coefficient and by identifying cases with a “clinically meaningful difference” (a difference in score that would result in a difference in treatment). Variables that affect reader agreement and retreatment decisions were examined by using the Wilcoxon signed-rank test, Pearson χ2 test, and linear regression. RESULTS: Overall interobserver variability for decision to retreat was moderate (ICC = 0.50; 95% CI, 0.40–0.61). Clinically meaningful differences between at least 2 readers were present in 61% of cases and were significantly more common among neuroradiologists than neurosurgeons (P = .0007). Neurosurgeons were more likely to recommend “definitely retreat” than neuroradiologists (P < .0001). Previously ruptured aneurysms, larger remnant size, and younger patients were associated with more retreat recommendations. Interobserver variability regarding retreatment type was fair overall 0.25 (95% CI, 0.14–0.41) but poor for experienced readers 0.14 (95% CI, 0–0.34). CONCLUSIONS: There is a large amount of interobserver variability regarding the decision to retreat an aneurysm and the type of retreatment. This variability must be reduced to increase consistency in these subjective outcome measurements.
METABOLIZABLE PROTEIN AND AMINO ACID NUTRITION OF THE COW: WHERE ARE WE IN 2007

Considerable progress has been made over the last 30 years in the United States to develop systems that describe protein requirements and protein adequacy of diets for dairy cows. Ration formulation systems have moved from balancing diets for crude protein (CP) and digestible protein to the use of nutritional models (e.g., NRC, 2001; CNCPS, CPM-Dairy, and Amino Cow) that recognize that the cow has two sets of dietary protein requirements (RDP and RUP) and that metabolically, she has requirements for individual amino acids (AA) rather than metabolizable protein (MP) per se. While current models and feed inputs are less than perfect, and our understanding of the N requirements of rumen bacteria and the AA requirements of the cow at different physiological states and levels of milk production are not clearly defined, current knowledge and consistent use of a model allows for more precise formulation of diets for RDP, RUP and AA.
Soleus Hoffmann-reflex modulation during walking in healthy elderly and young adults.

Soleus Hoffmann-reflex (H-reflex) modulation during walking was examined in 7 young and 13 elderly adults. H-reflex size was measured in 16 equal time divisions (phases) of the step cycle. In both the elderly and the young groups, the H reflex was minimal at the time of heel contact, rose to a maximum shortly after midstance, decreased rapidly as toe-off neared, then was minimal during swing. There was a significant interaction between age group and step cycle phase (p < .05). During midstance of walking, the elderly participants had a smaller H-reflex size during two of the 16 time phases of the step cycle (p < .05), despite no significant difference in H-reflex size between the age groups while standing. The smaller H-reflex size during the stance phase of walking may reflect changes in central reflex mechanisms that may impact stretch reflex contribution to ankle extensor neural drive and ankle stiffness in elderly persons during walking.
Formation of oligosaccharides during enzymatic lactose: Part I: State of art

Enzymatic lactose hydrolysis by β‐galactosidase (lactase) was investigated with respect to the formation of oligosaccharides. An analysis of the formation of oligosaccharides and their control is important in the development of technical applications for enzymatic lactose hydrolysis. The available literature data on transfer reactions of lactase were reviewed, compared, and presented in a concise tabular form. Mechanisms and possible ways of modelling enzymatic lactose hydrolysis, including formation of oligosaccharides, are presented.
Prediction of spontaneous preterm birth in patients with congenital uterine anomalies using combined fetal fibronectin and cervical length

Objective: To evaluate cervical length (CL) and fetal fibronectin (fFN) as predictors of spontaneous preterm birth (SPTB) in patients with congenital uterine anomalies. Methods: A retrospective cohort of patients with uterine anomalies and singleton pregnancies >22 weeks delivered by one maternal fetal medicine practice from 2005-2012 who underwent routine CL and fFN testing from 22-32 weeks was identified. We excluded patients with a cerclage, and patients who had an indicated preterm birth <37 weeks. A short CL was defined as ≤25 mm. We compared rates of spontaneous preterm birth <37 weeks based on CL and fFN results. Results: 120 patients with uterine anomalies were identified (47 septate, 36 bicornuate, 12 unicornuate, 10 arcuate, 9 T-shaped, 6 didelphys). Seventeen (14.2%) of patients had a short CL; these patients had a higher incidence of spontaneous preterm birth <37 weeks (64.7% vs. 13.6%, p<0.001). Six of 89 patients (6.7%) had a positive fFN; these patients did not have an increased incidence of spontaneous preterm birth than patients with a negative fFN. The addition of fFN to CL testing did not improve the positive or negative predictive values, nor the positive or negative likelihood ratios for spontaneous preterm birth <37 weeks. Conclusions: In women with uterine anomalies, a short CL is significantly associated with spontaneous preterm birth <37 weeks. The addition of fFN testing in these patients does not improve the prediction of preterm birth.
On the relationship between the number of spermatozoa and the probability of conception.

A simple model is proposed to relate spermatozoan numbers to the probability of conception, based on the Poisson distribution. It is compared with van Duijn’s (1964) model. Both models are fitted to several series of data taken from the literature and either model gives a satisfactory fit. The Poisson model may be preferred because it is easier to apply and has a simpler biological interpretation.