Miracle-dz/UniFAR-FTUs huggingface dataset:
Substitution of transmembrane residues with hydrogen-bonding potential in the alpha subunit of Na,K-ATPase reveals alterations in ouabain sensitivity.

The role of H-bonding amino acids as determinants of ouabain affinity in the Na,K-ATPase was examined. Site-directed mutagenesis was used to substitute 21 conserved amino acid residues in the sheep alpha-subunit transmembrane regions. The amino acids were changed from residues which possess side chains capable of forming H-bonds with specific cardiac glycoside moieties such as the lactone ring or sugar(s) to residues unable to participate in H-bonding. The effect of each of these amino acid replacements on the affinity of the Na,K-ATPase for ouabain was initially assessed by screening the altered enzymes for the ability to confer ouabain resistance when expressed in otherwise sensitive HeLa cells. Three of the substitutions (Tyr-108 to Ala, Cys-104 to Ala, and Cys-104 to Phe) were able to confer resistance to the normally sensitive HeLa cells. Stable cell lines, each expressing one of the altered enzymes, were further characterized in terms of ouabain-inhibitable cell growth and Na,K-ATPase activity. Cell lines expressing the alpha 1-isoform substitution Y108A, C104A, or C104F contained a Na,K-ATPase activity which gave an I50 value for enzyme inhibition 9-, 6-, and 150-fold greater, respectively, than the endogeneous HeLa or sheep enzyme. These data show that Tyr-108 and Cys-104 of the alpha subunit are determinants of ouabain affinity. Cys-104 has also been shown to be a determinant of ouabain sensitivity in Xenopus laevis [Canessa, C. M. , Horisberger, J.-D. , Louvard, D. , & Rossier, B. C. (1992) EMBO J. 11, 1681-1687]. (ABSTRACT TRUNCATED AT 250 WORDS)
Face-Blind for Other-Race Faces: Individual Differences in Other-Race Recognition Impairments

We report the existence of a previously undescribed group of people, namely individuals who are so poor at recognition of other-race faces that they meet criteria for clinical-level impairment (i.e., they are “face-blind” for other-race faces). Testing 550 participants, and using the well-validated Cambridge Face Memory Test for diagnosing face blindness, results show the rate of other-race face blindness to be nontrivial, specifically 8.1% of Caucasians and Asians raised in majority own-race countries. Results also show risk factors for other-race face blindness to include: a lack of interracial contact; and being at the lower end of the normal range of general face recognition ability (i.e., even for own-race faces); but not applying less individuating effort to other-race than own-race faces. Findings provide a potential resolution of contradictory evidence concerning the importance of the other-race effect (ORE), by explaining how it is possible for the mean ORE to be modest in size (suggesting a genuine but minor problem), and simultaneously for individuals to suffer major functional consequences in the real world (e.g., eyewitness misidentification of other-race offenders leading to wrongful imprisonment). Findings imply that, in legal settings, evaluating an eyewitness’s chance of having made an other-race misidentification requires information about the underlying face recognition abilities of the individual witness. Additionally, analogy with prosopagnosia (inability to recognize even own-race faces) suggests everyday social interactions with other-race people, such as those between colleagues in the workplace, will be seriously impacted by the ORE in some people.
Impaired Postural Balance in Turner Syndrome

Abstract An impaired body balance has been found in Turner syndrome (TS) in clinical tests like Rombergs’s test and walking on a balance beam. The aim of the study was to assess postural balance in TS subjects with specific balance testing using dynamic posturography and relate to body composition. Nineteen TS subjects (20–57 years) were included. Balance was measured with dynamic posturography (Equitest) and compared with 19 sex and age-matched controls (22–59 years). Equitest, visual, vestibular, and somatosensory systems were provoked with increasing difficulty (6 tests, SO1–SO6) and body sway was measured with a dual forceplate. Body composition was measured with DXA. No difference was found between the TS subjects and the controls on fixed platform with open eyes (SO1), with closed eyes (SO2), with stable platform and visual disorientation (SO3), or on unstable platform with open eyes (SO4). In the difficult tests on unstable platform the TS subjects did worse compared with controls both in the test with eyes closed (SO5), p<0.01, and in the test with visual disorientation (SO6), p<0.05. Composite (a merge of all six recordings) was significantly lower in the TS-group, p<0.05. In the TS group high total body weight was related to worse outcome on tests SO5, SO6, and composite, while total bone mass, age, height, or waist showed no significant association with balance scores. Our findings indicate that TS could have an increased risk for falling due to impaired ability to manage complex coordination tasks.
VDR‐mediated inhibition of DKK1 and SFRP2 suppresses adipogenic differentiation of murine bone marrow stromal cells

Osteoblasts and adipocytes are thought to derive from a common bone marrow stromal cell (BMSC) precursor. Activation of the canonical Wnt signaling pathway plays a pivotal role in the differentiation of BMSCs along either of these two lineages, promoting osteogenesis and inhibiting adipogenesis. Liganded nuclear receptors, including the vitamin D receptor (VDR) and peroxisomal proliferator‐activated receptor γ (PPARγ), can also affect BMSCs differentiation. To address whether VDR ablation modulates the differentiation of BMSCs into the osteoblast or adipogenic lineages, BMSCs were isolated from VDR null mice and from their wild‐type littermates. VDR ablation did not alter osteoblastic differentiation. However, when cultured under adipogenic conditions, BMSCs from the VDR null mice expressed higher mRNA levels of PPARγ and of markers of adipogenic differentiation. An increase in the size and number of mature adipocyte foci was also observed in cultures isolated from VDR null mice relative to those isolated from wild‐type mice. To address whether the increased adipogenesis observed in the VDR null cultures was associated with inhibition of the canonical Wnt signaling pathway, mRNA levels for DKK1 and SFRP2 were examined. Cultures from the VDR null mice expressed higher levels of mRNA encoding DKK1 and SFRP2 than did the wild‐type cultures. This difference is, at least in part, due to ligand‐dependent actions of the VDR, since 1,25‐dihydroxyvitamin D3 suppressed DKK1 and SFRP2 expression in wild‐type cultures. Thus, the VDR inhibits adipogenesis of BMSCs at least in part by suppressing the expression of inhibitors of the canonical Wnt signaling pathway. J. Cell. Biochem. 101: 80–88, 2007. © 2007 Wiley‐Liss, Inc.
Blocking the regulatory T cell molecule LAG-3 augments in vivo anti-tumor immunity in an autochthonous model of prostate cancer.

2573 Background: LAG-3 is a CD4 homolog expressed on activated T cells, NK cells, tumor infiltrating lymphocytes (TIL), and plasmacytoid dendritic cells. Recently, we showed that LAG-3 was relatively overexpressed in specific T cells rendered unresponsive in vivo by the presence of cognate self-antigen. These anergic T cells display regulatory function both in vitro and in vivo, and blockade of LAG-3 with a non-depleting monoclonal antibody significantly mitigates their regulatory T cell activity. METHODS Using a novel model of prostate cancer in which a tumor-specific antigen is expressed in autochthonous tumors, we tested whether treatment with a non-depleting anti-LAG-3 antibody affected trafficking and function of tumor-specific T cells. RESULTS LAG-3 blockade significantly augments specific CD8 T cell trafficking to antigen-expressing tumors, but not to normal tissue. Most significantly, LAG-3 blockade functionally reversed CD8 T cell tolerance as assayed by an in vivo cytotoxic T lymphocyte (CTL) assay. Combining LAG-3 blockade with specific anti-tumor vaccination results in a dramatic increase in activated CD8 T cells in the tumor parenchyma. CONCLUSIONS Taken together, these data support the concept that treatment with a LAG-3 blocking antibody may significantly delay disease progression in patients with cancer. We have recently generated a panel of monoclonal antibodies directed against human LAG-3; several of these antibodies significantly augment human T cell responses in vitro. No significant financial relationships to disclose.
Firm anchoring between a calcium phosphate-hybridized tendon and bone for anterior cruciate ligament reconstruction in a goat model

Using an alternative soaking process improved the tendon–bone attachment for a calcium phosphate (CaP)-hybridized tendon graft. We characterized the deposited CaP on and in tendons and analyzed the histology and mechanical properties of the tendon–bone interface in anterior cruciate ligament (ACL) reconstruction in goats. The tendon grafts to be implanted were soaked ten times alternately in a Ca-containing solution and a PO4-containing solution for 30 s each. Needlelike CaP nanocrystals including low-crystalline apatite were deposited on and between collagen fibrils from the surface to a depth of 200 µm inside the tendon. The structure resembles the extracellular matrix of bone. In animal experiments, the CaP-hybridized tendon directly bonded with newly formed bone at 6 weeks (n = 3), while fibrous bonding was observed in the control (n = 3). The ultimate failure load was not statistically different between the CaP (n = 7) and control (n = 7). However, in the failure mode, all the tendon–bone interfaces were intact in the CaP group, while three of seven specimens were pulled out from bone tunnels in the control. The result suggested that the strength of the tendon–bone interface in the CaP group is superior to that in the control group. Clinically, firm tendon–bone anchoring may lead to good results without the knee instability associated with the loosening of the bone–tendon junction in ACL reconstruction.
Randomized comparison of chloroquine plus sulfadoxine-pyrimethamine versus artesunate plus mefloquine versus artemether-lumefantrine in the treatment of uncomplicated falciparum malaria in the Lao People's Democratic Republic.

BACKGROUND Recent clinical trials in the Lao People's Democratic Republic have demonstrated that chloroquine and sulfadoxine-pyrimethamine, which are national malaria treatment policy, are no longer effective in the treatment of uncomplicated Plasmodium falciparum malaria. METHODS A randomized comparison of 3 oral antimalarial combinations--chloroquine plus sulfadoxine-pyrimethamine versus artesunate plus mefloquine versus artemether-lumefantrine--with 42-day follow-up period, was conducted among 330 patients with acute uncomplicated falciparum malaria in southern Laos. RESULTS The 42-day cure rates, as determined by intention-to-treat analysis and adjusted for reinfection, were 100%, 97%, and 93% for the groups receiving artesunate plus mefloquine, artemether-lumefantrine, and chloroquine plus sulfadoxine-pyrimethamine, respectively. Of 8 patients receiving chloroquine plus sulfadoxine-pyrimethamine who experienced treatment failure, 6 had early treatment failure. The mean parasite clearance time was significantly longer in patients treated with chloroquine plus sulfadoxine-pyrimethamine (2.9 days; 95% confidence interval [CI], 2.8-3.0 days) than in those treated with artesunate plus mefloquine (2.07 days; 95% CI, 2.0-2.1 days; P<.001) and artemether-lumefantrine (2.08 days; 95% CI, 2.0-2.1 days; P<.001). Cure rates with artemether-lumefantrine were high despite low mean daily dietary fat intake (13.8 g; 95% CI, 12.5-15.1 g) and day 7 plasma lumefantrine concentrations (0.47 mu g/mL; 95% CI, 0.38-0.56 mu g/mL). CONCLUSION Oral artesunate plus mefloquine and artemether-lumefantrine are highly effective for the treatment of uncomplicated falciparum malaria in Laos.
Down-regulation of gut-enriched Kruppel-like factor expression in esophageal cancer.

AIM Esophageal carcinoma is one of the most common malignant tumors in China. But the molecular mechanisms of esophageal carcinoma remains unclear. Gut-enriched Kruppel-like factor (GKLF) is a newly identified transcription factor which is expressed abandantly in the epithelial cells of the gastrointestinal tract and deregulation of GKLF was linked to several types of cancer. It is of interest to study the expression and role of GKLF in esophageal carcinoma. METHODS Semi-quantitative RT-PCR was used to compare GKLF expression in esophageal squamous cell carcinoma to normal mucosa of the same patients. The serum deprivation inducibility of GKLF was observed in an esophageal squamous cancer cell line by comparison to the primary culture of human fibroblast. The effect of antisense GKLF transfection on the proliferation and adhesion of esophageal squamous cancer cell line was also observed. RESULTS The level of GKLF transcript is lower in esophageal squamous cell carcinoma compared to paired normal-appearing mucosa in 14 of 17 of the tumors analyzed. The serum deprivation inducibility of GKLF was greatly decreased in an esophageal squamous cancer cell line compared to the primary culture of human fibroblast. Decreased expression of GKLF in the esophageal cancer cell by antisense GKLF transfection increased its proliferation rate compared with that of vector transfected cell control (P<0.05). Transfection of antisense GKLF decreased its adhesion ability (P<0.05). CONCLUSION The findings of this study demonstrate the down-regulation of GKLF in esophageal squamous cancer, and suggest that deregulation of GKLF may play a role in initiation and/or progression as well as the metastasis of esophageal squamous cancer.
Continuous low‐dose oestrogen and progestogen hormone replacement therapy: a randomised trial

To establish the efficacy and acceptability of combined continuous low‐dose oestrogen and low‐dose progestogen therapy, to determine whether any of three commercially available progestogens had any advantages or disadvantages in these circumstances and whether use of the lowest clinically effective oestrogen dose affected other outcomes being measured.
Effectiveness of Methoprene, an Insect Growth Regulator, Against Temephos-Resistant Aedes aegypti Populations from Different Brazilian Localities, Under Laboratory Conditions

Abstract The susceptibility of Aedes aegypti (L.) larvae from several Brazilian populations to the juvenile hormone analog methoprene and the organophosphate insecticide temephos were investigated. Populations from Natal (northeastern region), Macapá (northern region), and Jardim América, Rio de Janeiro (southeastern region) are temephos-resistant (RR90 = 24.4, 13.3, and 15.8, respectively), whereas populations from Presidente Prudente (southeastern region) and Porto Velho (northern region) exhibit only an incipient temephos-altered susceptibility status (RR90 = 1.8 and 2.6, respectively). Biochemical assays revealed alterations of the enzymes implicated in metabolic resistance, glutathione S-transferase, mixed function oxidases and esterases, among these populations. Dose–response assays showed at most a low resistance to methoprene of all populations tested, irrespective of their temephos resistance level. However, sequential exposure of Macapá and Natal populations to temephos and methoprene indicated a potential cross-resistance when larvae are exposed to both insecticides. Nevertheless, susceptibility of the Brazilian Ae. aegypti populations to methoprene alone suggests this insect growth regulator could substitute for temephos in the control of the dengue vector in the country.
Assessment of the Reliability of Human Corneal Endothelial Cell-Density Estimates Using a Noncontact Specular Microscope

Purpose. We sought to determine the variance in endothelial cell density (ECD) estimates for human corneal endothelia. Methods. Noncontact specular micrographs were obtained from white subjects without any history of contact lens wear, or major eye disease or surgery; subjects were within four age groups (children, young adults, older adults, senior citizens). The endothelial image was scanned, and the areas from ≥75 cells measured from an overlay by planimetry. The cell-area values were used to calculate the ECD repeatedly so that the intra-and intersubject variation in an average ECD estimate could be made by using different numbers of cells (5, 10, 15, etc.). Results. An average ECD of 3,519 cells/mm2 (range, 2,598–5,312 cells/mm2) was obtained of counts of 75 cells/endothelium from individuals aged 6–83 years. Average ECD estimates in each age group were 4,124, 3,457, 3,360, and 3,113 cells/mm2, respectively. Analysis of intersubject variance revealed that ECD estimates would be expected to be no better than ±10% if only 25 cells were measured per endothelium, but approach ±2% if 75 cells are measured. Conclusion. In assessing the corneal endothelium by noncontact specular microscopy, cell count should be given, and this should be ≥75/endothelium for an expected variance to be at a level close to that recommended for monitoring age-, stress-, or surgery-related changes.
Effect of Zataria multiflora Boiss. essential oil on colony morphology and ultrastructure of Aspergillus flavus

The mode of inhibitory action of Zataria multiflora Boiss. essential oil (EO) on the fungus, Aspergillus flavus, was studied by colony morphology examination, light microscopy, scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The EO at concentrations used in this study suppressed the size of the colony as well as sporulation. SEM of mycelia treated with given concentrations of EO showed morphological alterations ranging from loss of turgidity and uniformity of mycelia at low concentrations of EO to evident destruction of the hyphae at higher concentration of EO. Semi‐thin sections of mycelia exposed to different concentrations of EO were analysed by light microscopy and revealed that the major change at level as low as 50 ppm of EO was limited to vacuolisation of cytoplasm resulting in cell swelling, while at higher concentrations, detachment of the cell membrane from the cell wall, deformation of mycelia and shedding the cytoplasm from the cell were the main alterations. These damages were well documented by TEM, which showed that the main sites of action of EO were the plasma membrane and cell wall. In conclusion, morphological and structural changes observed in this study may be one of the mechanisms involved in growth inhibition of the fungi and reducing aflatoxin production.
Metastasectomy of Krukenberg tumors may be associated with survival benefits in patients with metastatic gastric cancer.

BACKGROUND The current standard treatment for patients with metastatic gastric cancer (MGC) is systemic chemotherapy. For gastric cancer patients with ovarian metastases, i.e. Krukenberg tumors, it is not known whether metastasectomy is associated with additional benefits. PATIENTS AND METHODS All patients who were diagnosed with gastric cancer and ovarian metastases between March 2000 and July 2010 in a medical center were included in the current study. The clinicopathological features and the treatment records were reviewed in detail and their association with overall survival (OS) was analyzed. RESULTS A total of 85 patients were identified. Thirty five (41.2%) and 50 (58.8%) patients did and did not undergo metastasectomy of Krukenberg tumors, respectively. The performance status and the proportion of patients receiving subsequent systemic therapy were well-matched between the two groups. Regarding disease status, patients who underwent metastasectomy had significantly larger Krukenberg tumors, pronounced bilateral disease and less extensive metastases outside the ovaries than patients who did not undergo metastasectomy. Patients who underwent metastasectomy had a better OS [median=14.1 months; 95% confidence interval (CI)=8.6-19.6 months] than patients who did not undergo metastasectomy (median OS=8 months; 95% CI=5.6-10.4 months, p=0.001). There was no aberrant postoperative morbiditie rate observed, and the median length of hospital stay after metastasectomy alone was 6 days. Based on multivariate analysis, metastasectomy remained an independent predictor of better OS (hazard ratio=0.36, p=0.002). The administration of subsequent systemic therapy, the use of platinum-based chemotherapy, and a better performance status also predict a better OS. CONCLUSION Metastasectomy of Krukenberg tumors may be associated with survival benefits in patients with MGC. Further prospective studies are warranted.
Global dissemination of extensively drug‐resistant carbapenemase‐producing Enterobacteriaceae: clinical perspectives on detection, treatment and infection control

The prevalence of carbapenem‐resistant Gram‐negative bacilli is on the rise worldwide, posing a major public health threat. Previously, this was mostly a problem in Pseudomonas and Acinetobacter, but during the last decade, carbapenem resistance has escalated in medically important species such as Klebsiella pneumoniae and Escherichia coli. In particular, the rising trend in E. coli is of concern, as this may lead to almost untreatable community‐acquired infections. Resistance is conferred by carbapenemases, which are beta‐lactamases that can breakdown essentially all beta‐lactams. Moreover, bacteria carrying these resistance determinants are often resistant to other treatment options, due to the frequent co‐acquisition of non‐beta‐lactam resistance genes located on the same mobile genetic elements. The detection of carbapenemase‐producing Enterobacteriaceae (CPE) is a challenge, because some carbapenemases produce relatively discrete levels of carbapenem resistance. Current clinical evidence for treatment guidance is limited and based on retrospective observational studies and case reports. Existing data support the use of combination therapy for treatment of severe infections caused by CPE. Combination regimens including colistin, carbapenems, tigecycline, aminoglycosides and fosfomycin have been used. Randomized controlled studies of combination regimens are ongoing and may help to determine the optimal therapy. Novel beta‐lactamase inhibitors may also have a role in future treatment of these infections. Strict infection control measures including isolation or cohort care of affected patients as well as contact tracing and active screening are needed to curb the spread of CPE. In this review, we provide a clinical perspective on the management of patients infected or colonized with CPE.