Miracle-dz/UniFAR-FTUs huggingface dataset:
The D-dopachrome tautomerase (DDT) gene product is a cytokine and functional homolog of macrophage migration inhibitory factor (MIF)

Macrophage migration inhibitory factor (MIF) is a pivotal regulator of the immune response. Neutralization or genetic deletion of MIF does not completely abrogate activation responses, however, and deletion of the MIF receptor, CD74, produces a more pronounced phenotype than MIF deficiency. We hypothesized that these observations may be explained by a second MIF-like ligand, and we considered a probable candidate to be the protein encoded by the homologous, D-dopachrome tautomerase (D-DT) gene. We show that recombinant D-DT protein binds CD74 with high affinity, leading to activation of ERK1/2 MAP kinase and downstream proinflammatory pathways. Circulating D-DT levels correlate with disease severity in sepsis or malignancy, and the specific immunoneutralization of D-DT protects mice from lethal endotoxemia by reducing the expression of downstream effector cytokines. These data indicate that D-DT is a MIF-like cytokine with an overlapping spectrum of activities that are important for our understanding of MIF-dependent physiology and pathology.
Distinct contributions of nicotinic acetylcholine receptor subunit α4 and subunit α6 to the reinforcing effects of nicotine

Nicotine is the primary psychoactive component of tobacco. Its reinforcing and addictive properties depend on nicotinic acetylcholine receptors (nAChRs) located within the mesolimbic axis originating in the ventral tegmental area (VTA). The roles and oligomeric assembly of subunit α4- and subunit α6-containing nAChRs in dopaminergic (DAergic) neurons are much debated. Using subunit-specific knockout mice and targeted lentiviral re-expression, we have determined the subunit dependence of intracranial nicotine self-administration (ICSA) into the VTA and the effects of nicotine on dopamine (DA) neuron excitability in the VTA and on DA transmission in the nucleus accumbens (NAc). We show that the α4 subunit, but not the α6 subunit, is necessary for ICSA and nicotine-induced bursting of VTA DAergic neurons, whereas subunits α4 and α6 together regulate the activity dependence of DA transmission in the NAc. These data suggest that α4-dominated enhancement of burst firing in DA neurons, relayed by DA transmission in NAc that is gated by nAChRs containing α4 and α6 subunits, underlies nicotine self-administration and its long-term maintenance.
Comparative analysis of a large dataset indicates that internal transcribed spacer (ITS) should be incorporated into the core barcode for seed plants

A two-marker combination of plastid rbcL and matK has previously been recommended as the core plant barcode, to be supplemented with additional markers such as plastid trnH–psbA and nuclear ribosomal internal transcribed spacer (ITS). To assess the effectiveness and universality of these barcode markers in seed plants, we sampled 6,286 individuals representing 1,757 species in 141 genera of 75 families (42 orders) by using four different methods of data analysis. These analyses indicate that (i) the three plastid markers showed high levels of universality (87.1–92.7%), whereas ITS performed relatively well (79%) in angiosperms but not so well in gymnosperms; (ii) in taxonomic groups for which direct sequencing of the marker is possible, ITS showed the highest discriminatory power of the four markers, and a combination of ITS and any plastid DNA marker was able to discriminate 69.9–79.1% of species, compared with only 49.7% with rbcL + matK; and (iii) where multiple individuals of a single species were tested, ascriptions based on ITS and plastid DNA barcodes were incongruent in some samples for 45.2% of the sampled genera (for genera with more than one species sampled). This finding highlights the importance of both sampling multiple individuals and using markers with different modes of inheritance. In cases where it is difficult to amplify and directly sequence ITS in its entirety, just using ITS2 is a useful backup because it is easier to amplify and sequence this subset of the marker. We therefore propose that ITS/ITS2 should be incorporated into the core barcode for seed plants.
Sterilisation Failures in Voluntary Female Surgical Contraception

The failure rates of 1991 tubal ligations performed in Thika Kenya at the Thika District Hospital the Family Planning Association of Kenya clinic and 2 nursing homes from January 1985 to December 1988 were analyzed prospectively. The women were aged 19-50 (mean 33.9 years) and parity 1-15 (mean 6.7). There were 52.8% interval sterilizations 18.6% done 1-6 weeks postpartum or postabortion 10.4% within 1 week of delivery or abortion and 14.8% during cesarean section. There were 10 known sterilization failures among those women who reported their pregnancies to the clinics. These women were aged 26-30 of parity 3-7. 50% of these were thought to be luteal phase pregnancies not found on initial patient screening. The overall failure rate was 0.5%. The rate for laparoscopic silastic ring sterilization was 3.6%. One woman had 2 failed laparoscopic sterilizations with a tubal peritoneal fistula confirmed by hysterosalpingogram. Besides doing better screening for pregnancy in sterilization candidates it was recommended that both tubes be ligated in women with prior ectopic pregnancy.
Symphysis pubis dysfunction: a hidden cause of morbidity

This exploratory study used a Heideggarian phenomenology to describe the experiences of women suffering from Symphysis Pubis Dysfunction (SPD) during pregnancy and three months after childbirth. Data were collected from a purposive sample of nine women, one and three months after birth, using a semi-structured interview schedule. Analysis was based on Colaizzi's (1978) framework for phenomenological analysis. Four main themes emerged: pain, lifestyle adaptation, emotions and health professional's support and information. Each theme illustrated the wide ranging effects of SPD on women and their families. Postnatally, pain prevented the women from caring for themselves, their families and homes.
Nonsteroidal anti-inflammatory drug use and the risk of severe skin and soft tissue complications in patients with varicella or zoster disease.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Three previous epidemiological studies found an increased risk of severe skin and soft tissue infectious complications associated with exposure to NSAIDs in children with varicella. In vitro studies demonstrated that decreases in defences against infections induced by NSAIDs could be due to impairment of neutrophil blood cell function. WHAT THIS STUDY ADDS The use of NSAIDs is associated with an increased risk of severe skin and soft tissue complication of varicella in children. The use of NSAIDs is also associated with a small increased risk of such complications in zoster disease in adults and the elderly. This study supports the limited prescription of NSAIDs in VZV infection. AIMS To assess the risk of severe skin and soft tissue complications associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) in treating patients with varicella zoster virus infection. METHODS The design was a nested case-control study, with matching for age and practice. The setting was primary care in the United Kingdom (United Kingdom's General Practice Research Database). Two population-based cohorts of all patients with a primary varicella (n = 140,111) or zoster (n = 108,257) diagnosis during 1994-2005 were followed up for 2 months after diagnosis. Main outcome measures of severe skin or soft tissue complications (mostly cellulitis and abscess) associated with current NSAID or paracetamol use were estimated, and adjusted for potential confounding factors, including sex, drug use, and comorbidity. RESULTS In patients with varicella, there were 386 cases of severe skin or soft tissue complications (rate 2.8 per 1000) during the 2 month follow-up period (mean age 10.7 years). The rate of complications associated with exposure to NSAIDs was increased (rate ratio 4.9; 95% CI 2.1, 11.4). In patients with zoster disease, there were 681 cases of severe skin or soft tissue complications (rate 6.3 per 1000) during the 2 month follow-up (mean age 60.9 years). The rate ratio of complications associated with exposure to NSAIDs was 1.6 (95% CI 1.1, 2.4). In both conditions, there was no increased risk of complication associated with a current exposure to paracetamol. CONCLUSIONS The use of NSAIDs is associated with an elevated risk of severe skin and soft tissue complications of varicella zoster virus infection, mostly in children with varicella.
Nitrogen‐Doped Graphene Oxide Quantum Dots as Photocatalysts for Overall Water‐Splitting under Visible Light Illumination

Nitrogen-doped graphene oxide quantum dots exhibit both p- and n-type conductivities and catalyze overall water-splitting under visible-light irradiation. The quantum dots contain p-n type photochemical diodes, in which the carbon sp(2) clusters serve as the interfacial junction. The active sites for H2 and O2 evolution are the p- and n-domains, respectively, and the reaction mimics biological photosynthesis.
Retrograde nuclear import of tRNA precursors is required for modified base biogenesis in yeast

The retrograde movement of tRNAs from the cytoplasm to the nucleus occurs constitutively in eukaryotic cells but its functional significance remains unclear. We show evidence suggesting that in Saccharomyces cerevisiae, a spliced tRNA precursor must be imported into the nucleus before the biogenesis of a modified base can occur. Wybutosine (yW) is a modified base adjacent to the anticodon of tRNAPhe and is required for accurate decoding. Glucose starvation or overexpression of the nuclear tRNA binding protein Trz1p both caused nuclear retention of cytoplasmic tRNAs, impaired the yW synthesis, and induced the accumulation of its intermediate, N1-methylgunanosine (m1G), showing that the postspliced tRNAPhe is imported to the nucleus, where m1G is formed by Trm5p, after which it is reexported to the cytoplasm, where the yW synthesis is completed by cytoplasmic enzymes.
Preweaning body weights in Large White Yorkshire Crosses

The body weights of Large White Yorkshire (LWY) crosses (50 and 75 per cent) were analysed at weekly intervals from birth to weaning. The overall birth weight was 1.16 ± 0.01 kg. The 75 per cent LWY cross had significantly (P < 0.01) higher birth weight than 50 per cent cross. The mean body weights at first, second and fourth weeks and at weaning were 1.79 ± 0.03, 2.50 ± 0.04, 4.08 ± 0.08 and 7.82 ± 0.20 kg respectively. Both the crosses grew similarly from first week to seventh week while the 75 per cent LWY cross weighed higher at weaning. The influence of sex was not significant on preweaning body weights of piglets except on first week body weight where the males were significantly (P < 0.05) heavier than females.
Human cystic fibrosis airway epithelia have reduced Cl− conductance but not increased Na+ conductance

Loss of cystic fibrosis transmembrane conductance regulator (CFTR) anion channel function causes cystic fibrosis (CF) lung disease. CFTR is expressed in airway epithelia, but how CF alters electrolyte transport across airway epithelia has remained uncertain. Recent studies of a porcine model showed that in vivo, excised, and cultured CFTR−/− and CFTRΔF508/ΔF508 airway epithelia lacked anion conductance, and they did not hyperabsorb Na+. Therefore, we asked whether Cl− and Na+ conductances were altered in human CF airway epithelia. We studied differentiated primary cultures of tracheal/bronchial epithelia and found that transepithelial conductance (Gt) under basal conditions and the cAMP-stimulated increase in Gt were markedly attenuated in CF epithelia compared with non-CF epithelia. These data reflect loss of the CFTR anion conductance. In CF and non-CF epithelia, the Na+ channel inhibitor amiloride produced similar reductions in Gt and Na+ absorption, indicating that Na+ conductance in CF epithelia did not exceed that in non-CF epithelia. Consistent with previous reports, adding amiloride caused greater reductions in transepithelial voltage and short-circuit current in CF epithelia than in non-CF epithelia; these changes are attributed to loss of a Cl− conductance. These results indicate that Na+ conductance was not increased in these cultured CF tracheal/bronchial epithelia and point to loss of anion transport as key to airway epithelial dysfunction in CF.
Efavirenz concentrations in HIV-infected patients with and without viral hepatitis.

AIMS Data on efavirenz in HIV/viral hepatitis co-infected patients is non-consensual, probably due to liver function heterogeneity in the patients included. METHODS A case control study was performed on 27 HIV-infected patients, with controlled and homogenous markers of hepatic function, either mono-infected or co-infected with HBV/HCV, to ascertain the influence of viral hepatitis on efavirenz concentrations over a 2-year follow-up period. RESULTS No differences were found in efavirenz concentrations between groups both during and at the end of the follow-up period: control (2.43 +/- 1.91 mg l(-1)) vs. co-infected individuals (2.37 +/- 0.37 mg l(-1)). CONCLUSION It was concluded that HBV/HCV infections in themselves do not predispose to an overexposure to efavirenz.
Population pharmacokinetic and pharmacodynamic modelling of the effects of nicorandil in the treatment of acute heart failure.

AIMS The aims of the study were 1) to evaluate the pharmacokinetics of nicorandil in healthy subjects and acute heart failure (AHF) patients and 2) to evaluate the exposure-response relationship with pulmonary arterial wedge pressure (PAWP) in AHF patients and to predict an appropriate dosing regimen for nicorandil. METHODS Based on the data from two healthy volunteer and three AHF patient studies, models were developed to characterize the pharmacokinetics and pharmacodynamics of nicorandil. PAWP was used as the pharmacodynamic variable. An asymptotic exponential disease progression model was used to account for time dependent changes in PAWP that were not explained by nicorandil exposure. The modelling was performed using NONMEM version V. RESULTS The pharmacokinetics of nicorandil were characterized by a two-compartment model with linear elimination. CL, V1 and V2 in AHF patients were 1.96, 1.39 and 4.06 times greater than in healthy subjects. Predicted plasma concentrations were assumed to have an immediate concentration effect relationship on PAWP. An inhibitory E(max) model with E(max) of -11.7 mmHg and EC(50) of 423 microg l(-1) was considered the best relationship between nicorandil concentrations and PAWP. PAWP decreased independently of nicorandil exposure. This drug independent decline was described by an asymptotic decrease of 6.1 mmHg with a half-life of 5.3 h. CONCLUSIONS AHF patients have higher clearance and initial distribution volume of nicorandil compared with healthy subjects. The median target nicorandil concentration to decrease PAWP by 30% is predicted to be 748 microg l(-1), indicating that a loading dose of 200 microg kg(-1) and a maintenance dose of 400 microg kg(-1) h(-1) would be appropriate for the initial treatment of AHF.
Structural basis of chimpanzee APOBEC3H dimerization stabilized by double-stranded RNA

Abstract APOBEC3H (A3H) is a mammal-specific cytidine deaminase that potently restricts the replication of retroviruses. Primate A3Hs are known to exert key selective pressures against the cross-species transmission of primate immunodeficiency viruses from chimpanzees to humans. Despite recent advances, the molecular structures underlying the functional mechanisms of primate A3Hs have not been fully understood. Here, we reveal the 2.20-Å crystal structure of the chimpanzee A3H (cpzA3H) dimer bound to a short double-stranded RNA (dsRNA), which appears to be similar to two recently reported structures of pig-tailed macaque A3H and human A3H. In the structure, the dsRNA-binding interface forms a specialized architecture with unique features. The analysis of the dsRNA nucleotides in the cpzA3H complex revealed the GC-rich palindrome-like sequence preference for dsRNA interaction, which is largely determined by arginine residues in loop 1. In cells, alterations of the cpzA3H residues critical for the dsRNA interaction severely reduce intracellular protein stability due to proteasomal degradation. This suggests that cpzA3H stability is regulated by the dsRNA-mediated dimerization as well as by unknown cellular machinery through proteasomal degradation in cells. Taken together, these findings highlight unique structural features of primate A3Hs that are important to further understand their cellular functions and regulation.
Intravitreal bevacizumab (Avastin) injection for neovascular glaucoma: a survey on 23 cases throughout 12-month follow-up.

AIMS Neovascular glaucoma (NVG) represents one of the most severe forms of secondary glaucoma, caused by a number of ocular and systemic conditions, which share the common element of retinal ischaemia/hypoxia that initiates the subsequent release of angiogenesis factors, with consequent development of new abnormal vessels through the ciliary body. The aim was to examine the potential efficacy and safety of intravitreal injection of bevacizumab (IVB) (Avastin) in the treatment of NVG in patients who had already undergone the standard retinal ablative procedure. METHODS This was a prospective pilot trial. Clinical data of 26 eyes from 23 patients, including diagnosis, visual acuity, iris fluorescein angiography stage and intraocular pressure (IOP), were collected. Three injections of bevacizumab were scheduled for each recruited eye at 4-week intervals from the start. All investigations were repeated the day before the IVB (1.25 mg/0.05 ml) and at the 1-, 3-, 6-, 9- and 12-month follow-up. RESULTS Regression of corneal oedema together with significant pain reduction was achieved in all eyes already after the first IVB, without any noteworthy improvement of visual acuity. At the end of the scheduled protocol (three IVB), regression of iris neovascularization was documented in all patients, together with significant improvement of visual acuity. The IOP reduction from baseline ranged from 30 to 0 mmHg (12.1 +/- 8 mmHg). CONCLUSIONS Intravitreal bevacizumab, as adjunctive treatment to the standard retinal ablative procedure, seems promising for the management of conditions responsible of retinal ischaemia/hypoxia associated with NVG.
Control of the function of the transcription and repair factor TFIIH by the action of the cochaperone Ydj1

Yeast rad3-102, a mutant of the TFIIH complex involved in nucleotide excision repair (NER) and transcription, can perform NER initial steps but not late steps of postincision gap filing. Because removal of early-acting NER proteins prevents rad3-102 deleterious action, we used this feature to explore if chaperones act in early NER. We found that the cochaperone Ydj1 is required for NER and that Ydj1 guarantees TFIIH stoichiometry. Importantly, in the absence of Ydj1, the roles of TFIIH in transcription and transactivation, the ability to activate transcription by nuclear receptors in response to hormones, are strongly impaired. We propose that TFIIH constitutes a multitarget complex for Ydj1, as six of the seven TFIIH core components contain biologically relevant Ydj1- binding motives. Our results provide evidence for a role of chaperones in NER and transcription, with implications in cancer and TFIIH-associated syndromes.
An ATP-binding cassette transporter-like complex governs cell-wall hydrolysis at the bacterial cytokinetic ring

ATP-binding cassette transporters are ubiquitous membrane protein complexes that move substrates across membranes. They do so using ATP-induced conformational changes in their nucleotide-binding domains to alter the conformation of the transport cavity formed by their transmembrane domains. In Escherichia coli, an ATP-binding cassette transporter-like complex composed of FtsE (nucleotide-binding domain) and FtsX (transmembrane domain) has long been known to be important for cytokinesis, but its role in the process has remained mysterious. Here we identify FtsEX as a regulator of cell-wall hydrolysis at the division site. Cell-wall material synthesized by the division machinery is shared initially by daughter cells and must be split by hydrolytic enzymes called “amidases” to drive daughter-cell separation. We recently showed that the amidases require activation at the cytokinetic ring by proteins with LytM domains, of which EnvC is the most critical. In this report, we demonstrate that FtsEX directly recruits EnvC to the septum via an interaction between EnvC and a periplasmic loop of FtsX. Importantly, we also show that FtsEX variants predicted to be ATPase defective still recruit EnvC to the septum but fail to promote cell separation. Our results thus suggest that amidase activation via EnvC in the periplasm is regulated by conformational changes in the FtsEX complex mediated by ATP hydrolysis in the cytoplasm. Since FtsE has been reported to interact with the tubulin-like FtsZ protein, our model provides a potential mechanism for coupling amidase activity with the contraction of the FtsZ cytoskeletal ring.
Disinhibitory gating of retinal output by transmission from an amacrine cell

Inhibitory interneurons help transform the input of a neural circuit into its output. Such interneurons are diverse, and most have unknown function. To study the function of single amacrine cells in the intact salamander retina, we recorded extracellularly from a population of ganglion cells with a multielectrode array, while simultaneously recording from or injecting current into single Off-type amacrine cells that had linear responses. We measured how visual responses of the amacrine cell interacted both with other visual input to the ganglion cell and with transmission between the two cells. We found that on average, visual responses from Off-type amacrine cells inhibited nearby Off-type ganglion cells. By recording and playing back the light-driven membrane potential fluctuations of amacrine cells during white noise visual stimuli, we found that paradoxically, increasing the light-driven modulations of inhibitory amacrine cells increased the firing rate of nearby Off-type ganglion cells. By measuring the correlations and transmission between amacrine and ganglion cells, we found that, on average, the amacrine cell hyperpolarizes before the ganglion cell fires, generating timed disinhibition just before the ganglion cell spikes. In addition, we found that amacrine to ganglion cell transmission is nonlinear in that increases in ganglion cell activity produced by amacrine hyperpolarization were greater than decreases in activity produced by amacrine depolarization. We conclude that the primary mode of action of this class of amacrine cell is to actively gate the ganglion cell response by a timed release from inhibition.