Miracle-dz/UniFAR-FTUs huggingface dataset:
A novel membrane receptor with high affinity for lysosphingomyelin and sphingosine 1‐phosphate in atrial myocytes.

Activation of IK(ACh) is the major effect of the vagal neutrotransmitter acetylcholine in the heart. We report that both lysosphingomyelin (D‐erythro‐sphingosyl‐phosphorylcholine; SPC) and sphingosine 1‐phosphate (SPP) activate IK(ACh) in guinea pig atrial myocytes through the same receptor with an EC50 of 1.5 and 1.2 nM, respectively. Pertussis toxin abolished the activation of IK(ACh) by either lipid. The putative receptor showed an exquisite stereoselectivity for the naturally occurring D‐erythro‐(2S,3R)‐SPC stereoisomer, the structure of which was confirmed by mass spectroscopy and NMR. These lipids caused complete homologous and heterologous desensitization with each other but not with ACh, indicating that both act on the same receptor. This receptor displays a distinct structure‐activity relationship: it requires an unsubstituted amino group because N‐acetyl‐SPC, lysophosphatidic acid and lysophosphatidylcholine were inactive. Because SPP and SPC are naturally occurring products of membrane lipid metabolism, it appears that these compounds might be important extracellular mediators acting on a family of bona fide G protein‐coupled receptors. Expression of these receptors in the heart raises the possibility that sphingolipids may be a part of the physiological and/or pathophysiological regulation of the heart. Based on their ligand selectivity we propose a classification of the sphingolipid receptors.
Long-Term Follow-up of Tacrolimus Treatment in Immune Posterior Uveitis

Purpose To study the efficacy of tacrolimus in immune posterior uveitis. Methods Twenty-one eyes of 11 patients with immune posterior uveitis under tacrolimus treatment were prospectively followed for 1 to 5 years. Tacrolimus dosage was adjusted to maintain blood levels in the range of 7 to 10 ng/mL. Systemic and ophthalmic evaluations were performed at baseline and during follow-up. Results After a mean follow-up of 45 months, no treatment other than tacrolimus was necessary to control the inflammation in 6 cases (54.5%). The number of annual recurrences decreased from 3.2 to 1.29 during tacrolimus treatment (p=0.021). In four patients, tacrolimus was suspended after a treatment period of 27±3.5 months and a follow-up period of 12 months free of uveitis relapses. All four were free from relapses following tacrolimus withdrawal. Visual acuity remained unchanged in 16/21 (76%) eyes, deteriorated in 4/21 (19%), and improved in 1/21 (5%). Renal function transiently deteriorated in four patients from basal serum creatinine levels of 0.84, 1.1, 0.88, and 0.78 mg/dL to maximum levels of 1.33, 2.48, 1.38, and 1.39 mg/dL, respectively. This deterioration was directly related with elevated tacrolimus serum levels, returning to normal when doses were reduced. During the overall controlled evolution period, a slight increase of serum creatinine from a basal value of 0.89±0.2 mg/dL to a final of 1±0.19 mg/dL was detected, which was not statistically significant. All secondary effects were mild, transient, and did not require interruption of long-term treatment to be controlled. Conclusions Tacrolimus was well tolerated and useful in controlling posterior immune uveitis. Tacrolimus could be considered a real alternative to cyclosporine, and not only in cases of cyclosporine resistance or toxicity. (Eur J Ophthalmol 2007; 17: 69–74)
Efficacy and Compatibility for Fenamiphos and EPTC Applied in Irrigation Water for Nematode and Weed Control in Snapbean Production.

A nematicide (fenamiphos) and a herbicide (EPTC) were injected into a sprinkler irrigation system separately and as tank mixtures and applied in 25.4 kl water/ha for nematode and weed control on snapbean. There were no differences (P = 0.05) between methods of injection of fenamiphos + EPTC on efficacy or crop response. The root-gall indices of cultivars Eagle and GV 50 were lower in fenamiphos-treated plots than those treated with EPTC alone and untreated plots. The yield and crop value were greater (P = 0.05) for cultivars Eagle and Nemasnap than GV 50. Fenamiphos 4.48 kg a.i./ha + EPTC 3.36 kg a.i./ha controlled root-knot nematodes, Meloidogyne incognita, ring nematodes, Criconemella ornata, and weeds, and resulted in greater plant growth, yield, and crop value than those from untreated plots. No benefits (P = 0.05) resulted from treatment with fenamiphos at 6.72 kg a.i./ha + EPTC treatment compared with fenamiphos at 4.48 kg a.i. + EPTC.
Tapetum Degeneration Retardation , Wax-Deficient Anther 1 , CYP 704 B 2 , C 6 , Post-meiotic Deficient Anther 1 , and Persistent Tapetal Cell

Male Sterile2 (MS2) is predicted to encode a fatty acid reductase required for pollen wall development in Arabidopsis (Arabidopsis thaliana). Transient expression of MS2 in tobacco (Nicotiana benthamiana) leaves resulted in the accumulation of significant levels of C16 and C18 fatty alcohols. Expression of MS2 fused with green fluorescent protein revealed that an aminoterminal transit peptide targets the MS2 to plastids. The plastidial localization of MS2 is biologically important because genetic complementation of MS2 in ms2 homozygous plants was dependent on the presence of its amino-terminal transit peptide or that of the Rubisco small subunit protein amino-terminal transit peptide. In addition, two domains, NAD(P)H-binding domain and sterile domain, conserved in MS2 and its homologs were also shown to be essential for MS2 function in pollen exine development by genetic complementation testing. Direct biochemical analysis revealed that purified recombinant MS2 enzyme is able to convert palmitoyl-Acyl Carrier Protein to the corresponding C16:0 alcohol with NAD(P)H as the preferred electron donor. Using optimized reaction conditions (i.e. at pH 6.0 and 30 C), MS2 exhibits a Km for 16:0-Acyl Carrier Protein of 23.3 6 4.0 mM, a Vmax of 38.3 6 4.5 nmol mg 21 min, and a catalytic efficiency/Km of 1,873 M 21 s. Based on the high homology of MS2 to other characterized fatty acid reductases, it was surprising that MS2 showed no activity against palmitoylor other acyl-coenzyme A; however, this is consistent with its plastidial localization. In summary, genetic and biochemical evidence demonstrate an MS2-mediated conserved plastidial pathway for the production of fatty alcohols that are essential for pollen wall biosynthesis in Arabidopsis.
In vivo, noninvasive functional measurements of bone sarcoma using diffuse optical spectroscopic imaging

Abstract. Diffuse optical spectroscopic imaging (DOSI) is an emerging near-infrared imaging technique that noninvasively measures quantitative functional information in thick tissue. This study aimed to assess the feasibility of using DOSI to measure optical contrast from bone sarcomas. These tumors are rare and pose technical and practical challenges for DOSI measurements due to the varied anatomic locations and tissue depths of presentation. Six subjects were enrolled in the study. One subject was unable to be measured due to tissue contact sensitivity. For the five remaining subjects, the signal-to-noise ratio, imaging depth, optical properties, and quantitative tissue concentrations of oxyhemoglobin, deoxyhemoglobin, water, and lipids from tumor and contralateral normal tissues were assessed. Statistical differences between tumor and contralateral normal tissue were found in chromophore concentrations and optical properties for four subjects. Low signal-to-noise was encountered during several subject’s measurements, suggesting increased detector sensitivity will help to optimize DOSI for this patient population going forward. This study demonstrates that DOSI is capable of measuring optical properties and obtaining functional information in bone sarcomas. In the future, DOSI may provide a means to stratify treatment groups and monitor chemotherapy response for this disease.
Adipose tissue ATGL modifies the cardiac lipidome in pressure-overload-induced left ventricular failure

Adipose tissue lipolysis occurs during the development of heart failure as a consequence of chronic adrenergic stimulation. However, the impact of enhanced adipose triacylglycerol hydrolysis mediated by adipose triglyceride lipase (ATGL) on cardiac function is unclear. To investigate the role of adipose tissue lipolysis during heart failure, we generated mice with tissue-specific deletion of ATGL (atATGL-KO). atATGL-KO mice were subjected to transverse aortic constriction (TAC) to induce pressure-mediated cardiac failure. The cardiac mouse lipidome and the human plasma lipidome from healthy controls (n = 10) and patients with systolic heart failure (HFrEF, n = 13) were analyzed by MS-based shotgun lipidomics. TAC-induced increases in left ventricular mass (LVM) and diastolic LV inner diameter were significantly attenuated in atATGL-KO mice compared to wild type (wt) -mice. More importantly, atATGL-KO mice were protected against TAC-induced systolic LV failure. Perturbation of lipolysis in the adipose tissue of atATGL-KO mice resulted in the prevention of the major cardiac lipidome changes observed after TAC in wt-mice. Profound changes occurred in the lipid class of phosphatidylethanolamines (PE) in which multiple PE-species were markedly induced in failing wt-hearts, which was attenuated in atATGL-KO hearts. Moreover, selected heart failure-induced PE species in mouse hearts were also induced in plasma samples from patients with chronic heart failure. TAC-induced cardiac PE induction resulted in decreased PC/ PE-species ratios associated with increased apoptotic marker expression in failing wt-hearts, a process absent in atATGL-KO hearts. Perturbation of adipose tissue lipolysis by ATGL-deficiency ameliorated pressure-induced heart failure and the potentially deleterious cardiac lipidome changes that accompany this pathological process, namely the induction of specific PE species. Non-cardiac ATGL-mediated modulation of the cardiac lipidome may play an important role in the pathogenesis of chronic heart failure.
Breeder-Helper Conflict in a Cichlid Fish With Broodcare Helpers: an Experimental Analysis

This paper reports an experimental analysis of conflicting interests in the cooperatively breeding Lamprologus brichardi (Cichlidae). Helpers clearly prefer to stay in the family territory rather than leave for an aggregation of same-size young or for an unoccupied area-even when their chances of reproducing independently are superior to those in the field. Helpers usually attain independence when the breeders force them to leave the territory. Breeders' toleration of helpers depends on the stage in the reproductive cycle, the size of helpers and the need for helpers. Large, previously expelled helpers are reaccepted when competition is increased. In these circumstances breeders prefer their own former helpers to strange young. Experimental and field evidence suggests that 3 factors are ultimately important for the breeder/helper relationship: reproductive parasitism by mature helpers, eventual cannibalism on breeders' eggs and competition for shelter within the territory. A graphical model shows how the initially common interests of breeders and helpers develop divergently when helpers reach the size at which they become sexually mature and less susceptible to predation. Large helpers pay to stay. The relationship of breeders and large helpers meets the criterion of reciprocal altruism.
Structural analysis of glyceraldehyde 3-phosphate dehydrogenase from Escherichia coli: direct evidence of substrate binding and cofactor-induced conformational changes.

The crystal structures of gyceraldehyde 3-phosphate dehydrogenase (GAPDH) from Escherichia coli have been determined in three different enzymatic states, NAD(+)-free, NAD(+)-bound, and hemiacetal intermediate. The NAD(+)-free structure reported here has been determined from monoclinic and tetragonal crystal forms. The conformational changes in GAPDH induced by cofactor binding are limited to the residues that bind the adenine moiety of NAD(+). Glyceraldehyde 3-phosphate (GAP), the substrate of GAPDH, binds to the enzyme with its C3 phosphate in a hydrophilic pocket, called the "new P(i)" site, which is different from the originally proposed binding site for inorganic phosphate. This observed location of the C3 phosphate is consistent with the flip-flop model proposed for the enzyme mechanism [Skarzynski, T. , Moody, P. C. , and Wonacott, A. J. (1987) J. Mol. Biol. 193, 171-187]. Via incorporation of the new P(i) site in this model, it is now proposed that the C3 phosphate of GAP initially binds at the new P(i) site and then flips to the P(s) site before hydride transfer. A superposition of NAD(+)-bound and hemiacetal intermediate structures reveals an interaction between the hydroxyl oxygen at the hemiacetal C1 of GAP and the nicotinamide ring. This finding suggests that the cofactor NAD(+) may stabilize the transition state oxyanion of the hemiacetal intermediate in support of the flip-flop model for GAP binding.
Mycobacterial lymphadenitis in eastern Sydney.

BACKGROUND There has been a resurgence of tuberculosis (TB) in the developed world, especially extrapulmonary manifestations, of which lymphadenitis is the most common. We reviewed all cases of mycobacterial lymphadenitis notified in the eastern suburbs of Sydney from 1989 to 1996. AIMS To review all cases of mycobacterial adenitis in eastern Sydney. METHODS This was a retrospective review of the medical records of 54 patients (aged 1.2 to 84 years), recruited from all notifications of TB presenting as lymphadenitis at Prince of Wales, Sydney Children's and St Vincent's Hospitals. RESULTS There were two distinct groups: Group 1, patients with Mycobacterium tuberculosis (MTB), n = 37 (68.5%), Group 2, patients with atypical mycobacteria, n = 17 (31.5%). For Group 1, 83.3% were foreign born and 18.9% were positive for the human immunodeficiency virus (HIV). Disease involved single node groups in 73% (the cervical chain was involved in 70.1%). Complete resolution of lymphadenopathy at conclusion of treatment occurred in 73.1%. Outcome was not documented in 13.5%, of the rest; 83.8% completed treatment; 2.7% were lost to follow up before treatment concluded; 2.7% were still being seen at the time of writing and 10.8% died within six months of treatment starting (all were HIV positive). HIV positive patients had more diffuse disease. Group 2 were all Australian born. They comprised children less than six years who were all HIV negative and adults (aged 30-55 years) who were all HIV positive. The children were all treated surgically with 80% having complete resolution of their modes. Those adults with HIV had a mortality of 83.3% during treatment. CONCLUSIONS In eastern Sydney lymphadenitis caused by MTB in the HIV negative population is mostly seen in those who are immigrants. Our large proportion of HIV positive patients tended to have diffuse disease and a high mortality. The reporting of outcomes was poor and in a greater than expected number of outcome and follow up were inadequately documented.
Can Geriatric Hip Fractures be Managed Effectively Within a Level 1 Trauma Center?

Objectives: To determine whether geriatric hip fractures can be managed effectively within a level 1 trauma center. Design: A prospective observational cohort study with a historical control group. Setting: Level 1 trauma center. Patients: A total of 199 patients admitted under our hip fracture service were prospectively identified from 2011–2012. These were compared with 191 hip fracture patients who were admitted before the service. Intervention: The hip fracture service includes coadmission under an orthopaedic and a geriatric team. A daily, consultant-led operating list was made available for hip fracture surgery. A “neck of femur” nurse was employed to coordinate patient care. Main Outcome Measurements: Time to surgery, length of stay, discharge destination, and mortality. A cost-benefit analysis and a comparison with a lower acuity hospital were also performed. Results: Since the hip fracture service, more patients underwent surgery within 48 hours (67% vs. 52%; P = 0.004), the length of stay significantly decreased from 26 to 22 days (P = 0.004), significantly more patients were admitted to the rehabilitation unit (58.7% vs. 3.5%; P < 0.001) and ultimately discharged to their own residence (51.6% vs. 40.5%; P = 0.034). Inpatient mortality rates did not change significantly (7.5% vs. 6.8%; P = 0.780). The estimated cost saving in 2011 was $981,040. Conclusions: Only minor changes are required to significantly improve the management of geriatric hip fracture patients. These patients can be managed effectively within a level 1 trauma center when an organized service prioritizing these patients is used. Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.
Cutting Edge: Anti-Tumor Necrosis Factor Therapy in Rheumatoid Arthritis Inhibits Memory B Lymphocytes via Effects on Lymphoid Germinal Centers and Follicular Dendritic Cell Networks1

Rheumatoid arthritis (RA) is mediated by a proinflammatory cytokine network with TNF at its apex. Accordingly, drugs that block TNF have demonstrated significant efficacy in the treatment of RA. A great deal of experimental evidence also strongly implicates B cells in the pathogenesis of RA. Yet, it remains unclear whether these two important players and the therapies that target them are mechanistically linked. In this study we demonstrate that RA patients on anti-TNF (etanercept) display a paucity of follicular dendritic cell networks and germinal center (GC) structures accompanied by a reduction in CD38+ GC B cells and peripheral blood memory B cell lymphopenia compared with healthy controls and RA patients on methotrexate. This study provides initial evidence in humans to support the notion that anti-TNF treatment disrupts GC reactions at least in part via effects on follicular dendritic cells.
Smoking cessation after surgery. A randomized trial.

BACKGROUND Cigarette smoking is the greatest cause of preventable mortality in the United States. Because most smokers would like to quit and most hospitals are smoke free, surgical admissions represent a window of opportunity for tobacco cessation interventions. METHODS A total of 324 patients (98% men), aged 25 to 82 years, who were current smokers and who underwent noncardiac surgery were enrolled in a randomized controlled trial at the Veterans Affairs Medical Center, San Francisco, Calif. One hundred sixty-eight participants (52%) received a multicomponent intervention designed to increase self-efficacy and coping skills that included face-to-face in-hospital counseling, viewing a smoking cessation videotape, self-help literature, nicotine replacement therapy, and 3 months of telephone follow-up. One hundred fifty-six participants (48%) received self-help literature and brief counseling lasting 10 minutes. Serum or saliva cotinine levels were measured to confirm self-reported smoking cessation. RESULTS At 12 months of follow-up, the self-reported quit rate was 27% among the intervention group and 13% among the comparison group (relative risk, 2.1; 95% confidence interval, 1.2-3.5; P < .01). Based on biochemical confirmation, 15% of the intervention group, compared with 8% of the comparison group, quit smoking at 12 months (relative risk, 2.0; 95% confidence interval, 1.0-3.9; P = .04). CONCLUSIONS A smoking cessation intervention targeted at smokers hospitalized for noncardiac surgery can increase long-term quit rates. Surgical hospitalizations provide an opportunity to reach smokers who want to quit smoking.
[Remote Ischaemic Conditioning - an overview].

The strategy of Remote Ischaemic Conditionings (RIC) is easy to apply, cost effective, low in side effects and belongs to the most potent cardioprotective strategies evaluated within recent years. Its practical application is carried out by simple use of a blood pressure cuff, more precise by 4 repetitive cycles of inflating the cuff above 200 mmHg for 5 minutes followed by an equal long break between the cycles. First experimental and clinical data repetitively demonstrated a significant reduction in myocardial injury following ischemia/reperfusion. Nevertheless, given the neutral results of two recent clinical multicentre trials, the clinical significance and benefits of RIC in cardiac surgery patients remains uncertain. The combination of co-medication and narcotic agents is thought to be responsible for the failed transfer into the clinical practice.
Nosematosis in a Squirrel Monkey (Saimiri sciureus) 1

A two‐month‐old squirrel monkey (Saimiri sciureus) succumbed following a month of frequent petit mal seizures. At autopsy, the bacterial stains revealed gram‐positive, slightly curved bacilli typical of the protozoal parasite Nosema cuniculi. This was confirmed by electron microscopy. The authors believe this to be the first case of nosematosis reported in the squirrel monkey.
Flesinoxan, a 5-HT1A receptor agonist/a 1-adrenoceptor antagonist, lowers intraocular pressure in NZW rabbits

Purpose. a 1 -Adrenoceptor antagonists and 5-HT 1A receptor agonists reduce intraocular pressure (IOP) in the rabbit. The aims of this study were firstly, to determine the IOP-lowering effects of flesinoxan and selected other hybrid 5-HT1A receptor agonists/a 1 -adrenoceptor antagonists, and secondly, to investigate the mechanism of action of the IOP response to flesinoxan. Methods. IOP and total outflow facility were measured in rabbits after administration of hybrid drugs. Inositol phosphates accumulation assays were performed using standard methodologies. Results. Topical unilateral instillation of the drugs caused dose-related reductions of IOP. Comparison of the compounds tested revealed a potency order of WB 4101 > flesinoxan > 5-methyl-urapidil = BMY7378 > urapidil. WB-4101 caused a small increase in total outflow facility whereas flesinoxan had no effect. Measurement of the IC 50 values for inhibition of phenylephrine-stimulated inositol phosphates accumulation in rabbit iris-ciliary body revealed a potency order of WB 4101 > 5-methyl-urapidil > flesinoxan > BMY 7378 = urapidil. Topical flesinoxan was ineffective in reversing phenylephrine-induced mydriasis, yet, pretreatment with the 5-HT 1A receptor antagonists MDL 73005EF and pindolol only partially blocked the hypotensive effect of topical flesinoxan. Conclusions. The present studies indicate the potent and efficacious IOP-lowering capabilities of flesinoxan and certain other ligands with affinity for 5-HT 1A receptors/a 1 -adrenoceptors. The exact mechanisms by which these drugs lower IOP in the rabbit are complex but our results indicate that flesinoxan likely reduces aqueous secretion.