Miracle-dz/UniFAR-FTUs huggingface dataset:
Mechanistic insights into c-di-GMP–dependent control of the biofilm regulator FleQ from Pseudomonas aeruginosa

Significance Pseudomonas aeruginosa, an opportunistic pathogen that can cause fatal chronic infections, relies on the intracellular second-messenger c-di-GMP to form robust multicellular biofilms during host tissue colonization. c-di-GMP is sensed directly by the transcription regulator FleQ, which inversely regulates flagellar motility and exopolysaccharide secretion to secure a planktonic to sessile life-form transition. FleQ belongs to the diverse family of AAA+ ATPase enhancer-binding proteins, but how its noncanonical function on transcriptional regulation is controlled by c-di-GMP remains enigmatic. Here, we report structural and functional data that identify an unusual mode of c-di-GMP recognition accompanied by a major quaternary structure reorganization. Our analyses offer a consensus to previous studies and unique insights into the mechanism of action of FleQ and FleQ-like proteins. Bacterial biofilm formation during chronic infections confers increased fitness, antibiotic tolerance, and cytotoxicity. In many pathogens, the transition from a planktonic lifestyle to collaborative, sessile biofilms represents a regulated process orchestrated by the intracellular second-messenger c-di-GMP. A main effector for c-di-GMP signaling in the opportunistic pathogen Pseudomonas aeruginosa is the transcription regulator FleQ. FleQ is a bacterial enhancer-binding protein (bEBP) with a central AAA+ ATPase σ54-interaction domain, flanked by a C-terminal helix-turn-helix DNA-binding motif and a divergent N-terminal receiver domain. Together with a second ATPase, FleN, FleQ regulates the expression of flagellar and exopolysaccharide biosynthesis genes in response to cellular c-di-GMP. Here we report structural and functional data that reveal an unexpected mode of c-di-GMP recognition that is associated with major conformational rearrangements in FleQ. Crystal structures of FleQ’s AAA+ ATPase domain in its apo-state or bound to ADP or ATP-γ-S show conformations reminiscent of the activated ring-shaped assemblies of other bEBPs. As revealed by the structure of c-di-GMP–complexed FleQ, the second messenger interacts with the AAA+ ATPase domain at a site distinct from the ATP binding pocket. c-di-GMP interaction leads to active site obstruction, hexameric ring destabilization, and discrete quaternary structure transitions. Solution and cell-based studies confirm coupling of the ATPase active site and c-di-GMP binding, as well as the functional significance of crystallographic interprotomer interfaces. Taken together, our data offer unprecedented insight into conserved regulatory mechanisms of gene expression under direct c-di-GMP control via FleQ and FleQ-like bEBPs.
Effects of vitamin D supplementation to children diagnosed with pneumonia in Kabul: a randomised controlled trial

Aim Vitamin D has a role in regulating immune function and deficiency is a risk factor for childhood pneumonia. The authors investigated whether: (1) Supplementation of 100 000 IU of vitamin D3 (cholecalciferol) along with antibiotics reduces the duration of illness in children with pneumonia; (2) vitamin D3 supplementation reduces the risk of repeat episodes. Methods Design: Double-blind individually randomised placebo-controlled trial. Setting: Outpatient clinics and inpatient department in an inner-city Kabul hospital, Afghanistan. Participants: 453, 1–36 months old children, from an area with known high vitamin D deficiency, clinically diagnosed with non-severe or severe pneumonia (WHO’s IMCI diagnostic criteria) at the outpatient clinic from December 2006 to February 2007. Exclusions: Children diagnosed with rickets, other concurrent severe diseases, very severe pneumonia or wheeze. Intervention: Identical-looking syringes with unique identifiers containing vitamin D3 or placebo were randomised and administered orally at diagnosis with regular pneumonia treatment. Follow-up: Daily until signs of pneumonia resolved and then two-weekly for 3 months. Outcome measure: (1) Mean number of days recovery (resolution of IMCI signs of pneumonia) ascertained through daily home-visit or inpatient examinations; (2) incidence of repeat episodes of pneumonia from 14–90 days after the resolution of the index episode ascertained through two-weekly home visits and passive case detection at the outpatients. Results 224 received vitamin D3 and 229 placebo; randomisation successful with balanced background characteristics in the two arms. Intention to treat survival analysis: (1) No significant difference in the mean number of days to recovery between the vitamin D3 (4.74 days; SD 2.22) and placebo arms (4.98 days; SD 2.89), p=0.17. (2) Risk of a repeat episode of pneumonia within 90 days of supplementation lower in the vitamin D3 (92/204; 45%) compared to the placebo group (122/211; 58%) (RR 0.78; 95% CI 0.64 to 0.94; p=0.01). Vitamin D3 arm went longer without experiencing a repeat episode of pneumonia (mean 72 days vs 59 days; HR 0.71; 95% CI 0.53 to 0.95; p=0.02). Conclusion A single high-dose oral vitamin D3 supplementation to young children along with antibiotic treatment for pneumonia does not affect length of pneumonia, but reduces the risk of recurrence of pneumonia episodes.
Further Tests of the Validity of the Industry Approach to Investment Analysis

Investment literature, particularly materials made available to investors by financial magazines, brokerage houses, and investment services, places a great deal of stress upon analysis of investment opportunities by industry groups. Examples are industry analyses, such as those of Forbes and Financial Analysts Journal, as well as the industry segregations of popular services such as Value Line, Standard & Poor's and Moody's.
First Paleoparasitological Report on the Animal Feces of Bronze Age Excavated from Shahr-e Sukhteh, Iran

Shahr-e Sukhteh (meaning burnt city in Persian) in Iran is an archeological site dated back to around 3,200-1,800 BC. It is located in Sistan and Baluchistan Province of Iran and known as the junction of Bronze Age trade routes crossing the Iranian plateau. It was appointed as current study area for paleoparasitological investigations. Excavations at this site have revealed various archeological materials since 1967. In the present study, sheep and carnivore coprolites excavated from this site were analyzed by means of rehydration technique using TSP solution for finding helminth eggs. Dicrocoelium dendriticum, Capillaria sp. , and Taenia sp. eggs were identified, while some other objects similar to Anoplocephalidae and Toxocara spp. eggs were also retrieved from the samples but their measured parameters did not match those of these species. The present paper illustrates the first paleoparasitological findings of Bronze Age in eastern Iran supporting the economic activities, peopling, and communication as well as the appropriate condition for zoonotic helminthiasis life cycle in Shahr-e Sukhteh archeological site.
Indonesian Manufacturing Sector Output and Productivity: An Australian Comparative Perspective, 1975–90

This paper provides industry-of-origin comparative estimates of real output and labour productivity in the Indonesian and Australian manufacturing sectors. It makes binary comparisons for the benchmark year 1987, and extrapolates the 1987 benchmark backward and forward using national time series, to derive comparisons for the years 1975-90. Expressed in 'purchasing power parities' (PPPs), the gross value of output and value added in Indonesian manufacturing in 1987 was 40% and 34% of the respective Australian levels. In 1987 the Indonesian manufacturing price level was 74% of the Australian level, and Indonesian manufacturing labour productivity was 16% of that in Australia. 1975 to 1990 was a period of catch-up. The Indonesian manufacturing price level declined from 105% to 60% of the Australian level, while labour productivity increased from 12% to 17% of the Australian level. The catch-up was greater from the early 1980s onwards.
IFNγ‐responsiveness of endothelial cells leads to efficient angiostasis in tumours involving down‐regulation of Dll4

Although IFNγ is regarded as a key cytokine in angiostatic response, our poor understanding of its effective cellular target drastically limits its clinical trials against angiogenesis‐related disorders. Here, we investigated the effect of IFNγ on endothelial cells (ECs) and possible molecular mechanisms in angiostasis. By employing Tie2IFNγR mice, in which IFNγR expression was reconstituted under the control of Tie2 promoter in IFNγR‐deficient mice, we found that the response of ECs to IFNγ was highly effective in inhibiting blood supply and retarding tumour growth. Interestingly, the expression of IFNγR on Tie2− cells did not inhibit, but promoted tumour growth in control wild‐type mice. Mechanism studies showed that IFNγ reacting on ECs down‐regulated the delta‐like ligand 4 (Dll4)/Notch signalling pathway. Accordingly, overexpression of Dll4 in human ECs diminished the effect of IFNγ on ECs. This study demonstrates that the action of IFNγ on ECs, but not other cells, is highly effective for tumour angiostasis, which involves down‐regulating Dll4. It provides insights for EC‐targeted angiostatic therapy in treating angiogenesis‐associated disorders in the clinic. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Development of the Paranasal Sinuses in Children

The development of computed tomography and functional endoscopic sinus surgery has improved diagnosis and management of sinusitis. It has also renewed interest in the developmental anatomy of the paranasal sinuses. There are significant differences between adult and pediatric sinus anatomy, and to safely perform functional endoscopic sinus surgery in children, the surgeon must be aware of these differences. To define the developmental anatomy of the paranasal sinuses, we analyzed 145 computed tomograms from patients under 18 years of age. The study emphasized landmarks at the level of the maxillary sinus ostium. In addition, distances and angles from the nasal spine to various points in the sinuses were determined. The structures were identified and traced on a digitizing tablet. Means and standard deviations were calculated for each measure as a function of age. This study can aid a better understanding of sinus development in children and provide guidance to the endoscopic sinus surgeon.
Equity or Debt Financing: Does Good Corporate Governance Matter?

Manuscript Type: Empirical. Research Question/Issue: We examine whether corporate governance plays a role in influencing a firm's choice of financing, i.e., equity versus debt. We hypothesize that the likelihood of equity financing increases with governance because of a reduction in agency costs between investors and managers in these firms. While the reduction in agency costs occurs for both equity and debt financing, we argue that there is a more significant effect on equity financing. Research Findings/Insights: Using a sample of over 2,000 US equity and debt issuances over the period 1998 to 2006, we find that our measures of corporate governance effectiveness have a positive impact on the likelihood of choosing equity compared to debt. This association is more pronounced in small firms where information asymmetry is higher between managers and investors. Theoretical/Academic Implications: Our findings refine and extend the pecking order hypothesis, which suggests that firms will issue equity as their last resort because of the high information asymmetry associated with equity financing. We provide some of the first evidence that the pecking order hypothesis can be mitigated by corporate governance. Specifically, we find that the likelihood of issuing equity increases as governance increases. Further, we find that where agency costs due to information asymmetry are greater, the positive impact of governance on the likelihood of equity financing is also greater. That is, in support of agency cost theory, we find that firms facing high agency costs benefit the most from investing in corporate governance mechanisms that lower the agency costs. We are not aware of any prior study, published or unpublished, that has documented this result. Practitioner/Policy Implications: From a practical perspective, our study suggests that firms wishing to access equity capital markets should pay attention to their corporate governance. Specifically, by investing in corporate governance systems, firms facing high agency costs may be able to obtain easier access to not just debt but also equity markets. From a practice standpoint, in the years prior to securing financing, firms should consider making improvements to their governance (e.g., changes to board structure and/or auditor), carefully weighing the costs of making these improvements against the benefits of securing better and cheaper access to equity markets.
[Psychic aspects of the premenstrual dysphoric disorders. New therapeutic strategies: our experience with Vitex agnus castus].

AIM The premenstrual dysphoric disorder (PMDD) is one of the main problems of the premenstrual phase. It consists of symptoms that sometimes invalidate the scope of employment, social and psycho-affective of patients, requiring thus a diagnostic and therapeutic approach as detailed and accurate as possible. The therapeutic strategies available for this disease are many, but recently the emphasis has been on Vitex agnus castus (VAC), considered by many as evidence drug of choice for both PMS and for the PMDD, being with satisfactory therapeutic properties and small side effects. METHODS AND RESULTS Our study evaluated a group of patients suffering from PMDD and the clinical efficacy of treatment with VAC (and compared the effectiveness of the results of a more homogeneous group of patients treated with fluoxetine). CONCLUSION This study confirms the data reported in the literature regarding the effectiveness of VAC therapy with no side effects.
The Threshold Effect of Advertising on the Intensity of Price Promotions: Using a Rational Expectations Model

Due to the downward sloping demand curve, a retailer can use price promotions to induce store traffic. On the other hand, price promotions can bring negative effects that increase consumers' conditional risks over quality, so that the results expected by retailers may not be achieved. This study investigates whether manufacturer advertising can mitigate the negative effects caused by retailer price promotions. A rational expectation model shows that the relation between advertising and price promotions is not unidirectional. A threshold exists that can ensure whether an increase in advertising expenditures reduces negative effects from price promotions. When advertising coverage exceeds this threshold, an increase in advertising expenditures mitigates negative effects and makes price promotions an effective way to build store traffic. Below the threshold, an increase in advertising expenditures might aggravate the negative effects from price promotions and decrease price sensitivity. Accordingly, marketing practitioners can design product pricing decisions depending on whether advertising information crosses this threshold.
Detection of Borrelia burgdorferi DNA in tissues from dogs with presumptive Lyme borreliosis.

OBJECTIVE To develop a quantitative PCR assay for detection of Borrelia burgdorferi DNA in formalin-fixed, paraffin-embedded tissues; compare results of this assay with results of immunohistochemical staining of tissues from seropositive dogs; and determine whether B burgdorferi DNA could be detected in renal tissues from dogs with presumptive Lyme nephritis. DESIGN Cohort study. SAMPLE POPULATION Archived tissue samples from 58 dogs. PROCEDURES A quantitative PCR assay was performed on formalin-fixed, paraffin-embedded tissue sections from the dogs. Results were compared with results of immunohistochemical staining, B burgdorferi serostatus, clinical signs, and necropsy findings. RESULTS 38 dogs were classified as having positive or equivocal results for Lyme borreliosis, and 20 were classified as having negative results on the basis of clinical signs, serologic findings, and pathologic abnormalities. Borrelia burgdorferi DNA was amplified from tissue samples from only 4 (7%) dogs, all of which had been classified as having positive or equivocal results for Lyme borreliosis and had signs of presumptive Lyme nephritis. Results of PCR assays of renal tissue were positive for only 1 dog, and there was no agreement between results of immunohistochemical staining (ie, detection of B burgdorferi antigen) and results of the PCR assay (ie, detection of B burgdorferi DNA) for renal tissues. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that detection of B burgdorferi DNA in formalin-fixed, paraffin-embedded tissues is feasible, but that intact B burgdorferi DNA is rarely found in tissues from naturally infected dogs, even tissues from dogs with presumptive Lyme borreliosis. Further, findings support the contention that Lyme nephritis may be a sterile, immune complex disease.
Institutional and Economic Determinants of FDI: A Comparison between the European Union and the MENA Region

Abstract FDI flows to the MENA region have been relatively low when compared to neighboring countries. This paper aims at investigating whether there are significant region-specific factors for FDI performance in MENA and EU regions. We employ a panel data approach and use the inward FDI performance index as dependent variable, including both institutional and macroeconomic variables as FDI determinants. The results reveal similar impact of the economic factors but significant differences between the two regions with regard to institutional determinants particularly investment climate, government size and trade barriers. This leads to the conclusion that more appropriate policies are needed in the MENA region in order to develop a friendly economic and institutional environment to attract foreign investors.
L-glutamine Induces Expression of Listeria monocytogenes Virulence Genes

The high environmental adaptability of bacteria is contingent upon their ability to sense changes in their surroundings. Bacterial pathogen entry into host poses an abrupt and dramatic environmental change, during which successful pathogens gauge multiple parameters that signal host localization. The facultative human pathogen Listeria monocytogenes flourishes in soil, water and food, and in ~50 different animals, and serves as a model for intracellular infection. L. monocytogenes identifies host entry by sensing both physical (e.g., temperature) and chemical (e.g., metabolite concentrations) factors. We report here that L-glutamine, an abundant nitrogen source in host serum and cells, serves as an environmental indicator and inducer of virulence gene expression. In contrast, ammonia, which is the most abundant nitrogen source in soil and water, fully supports growth, but fails to activate virulence gene transcription. We demonstrate that induction of virulence genes only occurs when the Listerial intracellular concentration of L-glutamine crosses a certain threshold, acting as an on/off switch: off when L-glutamine concentrations are below the threshold, and fully on when the threshold is crossed. To turn on the switch, L-glutamine must be present, and the L-glutamine high affinity ABC transporter, GlnPQ, must be active. Inactivation of GlnPQ led to complete arrest of L-glutamine uptake, reduced type I interferon response in infected macrophages, dramatic reduction in expression of virulence genes, and attenuated virulence in a mouse infection model. These results may explain observations made with other pathogens correlating nitrogen metabolism and virulence, and suggest that gauging of L-glutamine as a means of ascertaining host localization may be a general mechanism.
Bipolar spectrum disorders in patients diagnosed with velo-cardio-facial syndrome: does a hemizygous deletion of chromosome 22q11 result in bipolar affective disorder?

OBJECTIVE The purpose of this study was to conduct a systematic assessment of psychiatric illness in patients diagnosed with velo-cardio-facial syndrome, a genetic syndrome that involves over 40 somatic anomalies, learning disabilities, and behavioral disorders and is associated with a microdeletion on chromosome 22q11. METHOD Subjects were referred for psychiatric diagnostic evaluation without regard to age or previous psychiatric history. In order to establish DSM-III-R consensus clinical diagnoses for patients who ranged in age from 5 to 34 years, the Diagnostic Interview for Children and Adolescents--Revised or the Structured Clinical Interview for DSM-III-R (SCID) was used. A review of available medical and psychiatric records and a clinical interview performed by two research psychiatrists to validate specific symptoms and syndromes reported in the Diagnostic Interview for Children and Adolescents--Revised and the SCID were used to elucidate the chronological appearance and duration of symptoms. RESULTS Sixty-four percent (N = 16 of 25) of this unselected series of patients with velo-cardio-facial syndrome met DSM-III-R criteria for a spectrum of bipolar disorders with full syndromal onset in late childhood or early adolescence (mean age at onset = 12 years, SD = 3). In addition, 20% (N = 5) met DSM-III-R criteria for attention deficit hyperactivity disorder (ADHD), while 16% (N = 4) met criteria for attention deficit disorder without hyperactivity. In contrast to previous reports of a high prevalence of schizophrenia, none of the patients was diagnosed with schizophrenia, and only four had psychotic symptoms during a phase of their illness, all in their 20s or 30s. CONCLUSIONS Given that the prevalence of bipolar disorder in the general population is estimated to be 1.5% and that the average age at onset is 24, these findings support an unusually strong association between velo-cardio-facial syndrome and early-onset bipolar disorder and suggest that a gene deleted at the 22q11 chromosomal locus may be involved in its pathogenesis. If confirmed, these findings may provide a new and fruitful line of investigation into the molecular basis of bipolar spectrum disorders.
Randomized trial of hypotensive epidural anesthesia in older adults.

BACKGROUND Data are sparse on the incidence of postoperative cognitive, cardiac, and renal complications after deliberate hypotensive anesthesia in elderly patients. METHODS This randomized, controlled clinical trial included 235 older adults with comorbid medical illnesses undergoing elective primary total hip replacement with epidural anesthesia. The patients were randomly assigned to one of two levels of intraoperative mean arterial blood pressure management: either to a markedly hypotensive mean arterial blood pressure range of 45-55 mmHg or to a less hypotensive range of 55-70 mmHg. Cognitive outcome was assessed by within-patient change on 10 neuropsychologic tests assessing memory, psychomotor, and language skills from before surgery to 1 week and 4 months after surgery. Prospective standardized surveillance was performed for cardiovascular and renal outcomes, delirium, thromboembolism, and blood loss and replacement. RESULTS The two groups were similar at baseline in terms of age (mean, 72 yr), sex (50% women), comorbid conditions, and cognitive function. After operation, no significant differences in the incidence of early or long-term cognitive dysfunction were observed between the two blood pressure management groups. There were no significant differences in the rates of other adverse consequences, including cardiac, renal, and thromboembolic complications. In addition, no differences occurred in the duration of surgery, intraoperative estimated blood loss, or transfusion rates. CONCLUSIONS Elderly patients can safely receive controlled hypotensive epidural anesthesia with this protocol. There was no evidence of greater risks, or early benefits, with the use of the more markedly hypotensive range.