Miracle-dz/UniFAR-FTUs huggingface dataset:
veA‐dependent RNA‐pol II transcription elongation factor‐like protein, RtfA, is associated with secondary metabolism and morphological development in Aspergillus nidulans

In Aspergillus nidulans the global regulatory gene veA is necessary for the biosynthesis of several secondary metabolites, including the mycotoxin sterigmatocystin (ST). In order to identify additional veA‐dependent genetic elements involved in regulating ST production, we performed a mutagenesis on a deletion veA (ΔveA) strain to obtain revertant mutants (RM) that regained the capability to produce toxin. Genetic analysis and molecular characterization of one of the revertant mutants, RM3, revealed that a point mutation occurred at the coding region of the rtfA gene, encoding a RNA‐pol II transcription elongation factor‐like protein, similar to Saccharomyces cerevisiae Rtf1. The A. nidulans rtfA gene product accumulates in nuclei. Deletion of rtfA gene in a ΔveA background restored mycotoxin production in a medium‐dependent manner. rtfA also affects the production of other metabolites including penicillin. Biosynthesis of this antibiotic decreased in the absence of rtfA. Furthermore, rtfA is necessary for normal morphological development. Deletion of the rtfA gene in wild‐type strains (veA+) resulted in a slight decrease in growth rate, drastic reduction in conidiation, and complete loss of sexual development. This is the first study of an Rtf1 like gene in filamentous fungi. We found rtfA putative orthologues extensively conserved in numerous fungal species.
Msx2 Exerts Bone Anabolism via Canonical Wnt Signaling*

Msx2 is a homeodomain transcription factor first identified in craniofacial bone and human femoral osteoblasts. We hypothesized that Msx2 might activate skeletal Wnt signaling. Therefore, we analyzed the effects of CMV-Msx2 transgene (Msx2Tg) expression on skeletal physiology and composition. Skeletal Msx2 expression was increased 2-3-fold by Msx2Tg, with expanded protein accumulation in marrow, secondary ossification centers, and periosteum. Microcomputed tomography established increased bone volume in Msx2Tg mice, with increased numbers of plate-like trabeculae. Histomorphometry revealed increased bone formation in Msx2Tg mice versus non-Tg siblings, arising from increased osteoblast numbers. While decreasing adipogenesis, Msx2Tg increased osteogenic differentiation via mechanisms inhibited by Dkk1, an antagonist of Wnt receptors LRP5 and LRP6. Bone from Msx2Tg mice elaborated higher levels of Wnt7 canonical agonists, with diminished Dkk1, changes that augment canonical signaling. Analysis of non-Tg and Msx2Tg siblings possessing the TOPGAL reporter confirmed this; Msx2Tg up-regulated skeletal β-galactosidase expression (p ≤ 0.01), along with Wnt7a and Wnt7b, and reduced circulating Dkk1. To better understand molecular mechanisms, we studied C3H10T1/2 osteoprogenitor cells. As in bone, Msx2 increased Wnt7 genes and down-regulated Dkk1, while inducing the osteoblast gene alkaline phosphatase. Msx2-directed RNA interference increased Dkk1 expression and promoter activity, while reducing Wnt7a, Wnt7b, and alkaline phosphatase. Moreover, Msx2 inhibited Dkk1 promoter activity and reduced RNA polymerase association with Dkk1 chromatin. RNA interference-mediated knockdown of Wnt7a, Wnt7b, and LRP6 significantly reduced Msx2-induced alkaline phosphatase. Msx2 exerts bone anabolism in part by reducing Dkk1 expression and enhancing Wnt signaling, thus promoting osteogenic differentiation of skeletal progenitors.
Laser treatment of acquired vascular lesions

The term telangiectasia refers to a dilated venule, capillary, or arteriole visible to the human eye and measuring 0.1–1.0 mm in diameter (1). Telangiectasias develop on the face secondary to genetic predisposition, chronic actinic damage, collagen vascular disorders, topical steroid application, and disorders of vascular regulation such as acne rosacea. Linear and “spider” telangiectasias develop on the legs, especially in women, beginning in the second to third decade due to multiple factors including genetic predisposition, gravity, pregnancy, and trauma. Papular telangiectasias are frequently seen as part of genetic syndromes, such as Osler–Weber–Rendu syndrome, and are also seen in collagen vascular disorders (2). Spider telangiectasias typically occur in school-age children, with most persisting into adulthood. They present a cosmetic concern as well as the propensity to bleed with minor trauma (1). The predominant presenting symptom of patients with facial telangiectasia is cosmetic disfigurement. Therefore effective treatment should be as free of adverse sequelae as possible. Traditional treatment modalities for superficial telangiectasias have included sclerotherapy, electrodesiccation, and more recently, laser therapy. Sclerotherapy remains the gold standard of treatment for telangiectasias of the lower extremities, and involves the injection of a chemical sclerosing agent into a vessel in order to cause damage to the vessel wall with subsequent fibrosis. Adverse sequelae include ulceration, scarring, hyperpigmentation, and telangiectatic matting. Facial telangiectasias are less responsive to sclerotherapy than those located on the leg and are additionally more prone to complications (1). Electrodesiccation is generally used in the treatment of smallcaliber facial vessels but has the potential to produce scarring due to its nonspecific thermal effect (3). In addition, electrodessiccation often results in incomplete lesional response or recurrence when used to treat larger caliber vessels. Theoretically lasers and intense pulsed light sources should provide certain advantages over traditional treatment methods (4).
Calcium intake, physical activity and bone mass in pre-menopausal women

Thirty pre-menopausal women aged 35–40 years were assessed with respect to dietary calcium intake, physical activity and other factors related to bone loss (by questionnaire); bone mass in the mid and distal femur measured by computerized tomography; and leg strength and muscle size. Cortical thickness at mid-femur was negatively associated with breast-feeding (r=-0.40). Bone mass in the distal femur was negatively associated with age (r=-0.46) and positively associated with activity (r=0.44) and leg strength (r=0.42). There was no association of bone mass at either site with current dietary calcium intake (range 198–1511 mg/day), nor with body mass index (BMI), hand-grip strength, parity, oral contraceptive use, smoking, or alcohol intake. Thus, in older pre-menopausal women, activity apparently helps to maintain bone mass at the distal femur, a site of high trabecular bone content, while current dietary-calcium intake has no effect on bone mass in the femur. Activity was most strongly associated with bone mass in the distal femur when it was defined as the total number of hours spent standing or moving (i.e. other than sitting or lying down), regardless of the intensity of activity. The strong negative association between bone mass in the distal femur and age in older pre-menopausal women is of concern in relation to long-term risk of osteoporotic related fracture, suggesting that factors relating to bone loss in this age-group should be studied longitudinally. The apparent loss of cortical bone in breast-feeders warrants further investigation.
Homo-oligomerization Is Essential for Toll/Interleukin-1 Receptor Domain-containing Adaptor Molecule-1-mediated NF-κB and Interferon Regulatory Factor-3 Activation*

Toll-IL-1 receptor (TIR) domain-containing adaptor molecule-1 (TICAM-1, also named TIR domain-containing adaptor-inducing interferon (IFN)-β or TRIF)) is a signaling adaptor of Toll-like receptor (TLR) 3/4 that activates the transcription factors, interferon regulatory factor-3 (IRF-3) and NF-κB leading to inducing IFN-β production. The mechanisms by which TICAM-1 is activated by TLR3/4 to serve as a signaling platform are unknown. In this study, we show that homo-oligomerization of TICAM-1 is critical for TICAM-1-mediated activation of NF-κB and IRF-3. Both TIR and C-terminal domain of TICAM-1 mediated TICAM-1 oligomerization. Pro434 located in the TIR domain and the C-terminal region, with the exception of the RIP homotypic-interacting motif, were determinants of TICAM-1 oligomerization. Mutation of TIR domain (P434H) or deletion of C-terminal domain greatly reduced TICAM-1-mediated NF-κB and IFN-β promoter activation. TICAM-1 oligomerization at either the TIR domain or the C-terminal region resulted in recruitment of tumor necrosis factor receptor-associated factor 3, a downstream signaling molecule essential for TICAM-1-mediated IRF-3 activation, but not recruitment of the IRF-3 kinase complex, NF-κB-activating kinase-associated protein 1 and TANK-binding kinase 1. In addition, RIP homotypic-interacting motif mutant, which possesses two oligomerization motifs but not the RIP1 binding motif, also failed to recruit NF-κB-activating kinase-associated protein 1 and TANK-binding kinase 1. Thus, full activation and formation of TICAM-1 signalosomes requires oligomerization induced at two different sites and RIP1 binding.
A molecular signature of tissues with pacemaker activity in the heart and upper urinary tract involves coexpressed hyperpolarization‐activated cation and T‐type Ca2+ channels

Renal pacemakers set the origin and frequency of the smooth muscle contractions that propel wastes from the kidney to the bladder. Although congenital defects impairing this peristalsis are a leading cause of pediatric renal failure, the mechanisms underlying renal pacemaker activity remain unknown. Using ratiometric optical mapping and video microscopy, we discovered that hyperpolarization‐activated cation (HCN) channel block with the specific anatagonist ZD7288 (30 μm; IC50) abolished the pacemaker depolarizations that initiate murine upper urinary tract peristalsis. Optical mapping and immunohistochemistry indicate that pacemaker potentials are generated by cells expressing HCN isoform‐3, and that HCN3+ cells are coupled to definitive smooth muscle via gap junctions. Furthermore, we demonstrate that HCN3+ cells coexpress T‐type Ca2+ (TTC) channels and that TTC channel inhibition with R(–)efonidipine or NNC55‐0396 decreased contractile frequency in a dose‐dependent manner. Collectively, these data demonstrate that HCN3+/TTC+ cells are the pacemakers that set the origin and rate of upper urinary tract peristalsis. These results reveal a conserved mechanism controlling autorhythmicity in 2 distinct muscle types, as HCN and TTC channels also mediate cardiac pacemaker activity. Moreover, these findings have translational applications, including the development of novel diagnostics to detect fetal urinary tract motility defects prior to renal damage. —Hurtado, R. , Bub, G. , Herzlinger, D. A molecular signature of tissues with pacemaker activity in the heart and upper urinary tract involves coexpressed hyperpolarization‐activated cation and T‐type Ca2+ channels. FASEB J. 28, 730–739 (2014). www.fasebj. org
Autism, Brain, and Environment . By Richard Lathe. Pp. 288. (Jessica Kingsley Publishers, London and Philadelphia, 2006.) £15.99, ISBN 1-84310-438-5, hardback.

Autistic Spectrum Disorders (ASDs) constitute a ‘hot topic’ in both media and scientific worlds. It is interesting to consider if this is solely attributable to a rise in the number of cases of such disorders. The best-seller and award-winning book The Curious Incident of the Dog in the Night-Time, about an autistic boy’s inner world, is followed this year with the recent Hollywood release of Snow Cake, about an autistic mother, starring Sigourney Weaver. These stories tend to focus on the unusual way a person with autism looks at the world, and to emphasize the extraordinary talents (particularly involving numbers) of such people. A social argument could be made for our fascination with autism by examining the age-old philosophical question of how similarly we view what we frame as an objective environment around us and the cultural prominence of the idea of individual genius in our meritocracy-focused society. However, Autism, Brain, and Environment does not undermine the suffering behind the label, and seeks to create a broad scientific framework for viewing the causes of autism. The first half of the text outlines a general understanding of autism under the topics ‘diagnosis’, ‘genetics’ and ‘rising rates’. Lathe begins his introduction with case-specific examples, which provide a narrative hook, before arguing for the importance of autism in both rising rates and economic terms. He makes a novel comparison to illustrate the yearly cost to America, by stating that it is approximately the same as that for the damage caused by Hurricane Katrina. This is followed by a noteworthy chapter on the complicating issues for diagnosing autism. Lathe draws attention to the lack of consistency in how autism is defined in research, which thus creates non-comparable results. He compiles a comprehensive list of autism spectrum disorders, which usefully compares the descriptions in the World Health Organization’s International Classification of Disease (ICD-10) with the American Psychiatric Association’s classification (DSM IV). The thorough compiling of information is typical of Lathe’s comprehensive text. Lathe states in the preface, ‘The book, originally intended for professionals, has been broadened to make the material accessible to non-specialists – families, medical practitioners, teachers, support workers, psychologists, political/environmental lobbies, and to autistic individuals themselves. ’ This is an ambitious aim, and for the most part he has achieved this balance. The book is user-friendly, enhanced by a comprehensive approach, clear subheadings and a key-point summary at the end of each chapter. However, often there is a lack of signalling for when the book shifts from a novelist style, to scientific manual, to a controversial argument, or a policy suggestion. As a consequence of this, and as confounded by the increased focus and pace of research into understanding causal mechanisms of ASDs, Lathe’s argument
GLP‐1 suppresses gastrointestinal motility and inhibits the migrating motor complex in healthy subjects and patients with irritable bowel syndrome

Abstract Glucagon‐like peptide‐1 (GLP‐1) is released after food intake to act as an incretin. GLP‐1 also inhibits gastric emptying and increases satiety. In rats, GLP‐1 inhibits small bowel motility. Our aim was to study the effects of GLP‐1 on gastrointestinal motility in healthy subjects and patients with irritable bowel syndrome (IBS). Antro‐duodeno‐jejunal manometry was carried out during a 4‐h control period with saline, followed by a 4‐h period with intravenous GLP‐1 (healthy: 0.7 and 1.2 pmol kg−1 min−1 (n = 16); IBS, 1.2 and 2.5 pmol kg−1 min−1 (n = 14). Plasma was analysed for GLP‐1 and gut hormones, and gut tissue expression of GLP‐1 receptor was studied. In healthy subjects, GLP‐1 0.7 pmol kg−1 min−1 reduced the migrating motor complexes (MMCs) from a median of 2 (range 2–3) to 0.5 (0–2), and motility index from 4.9 ± 0.1 to 4.3 ± 0.3 ln ∑(mmHg*s min−1) in jejunum, while GLP‐1 1.2 pmol kg−1 min−1 diminshed MMCs from 2 (2–3) to 1.5 (1–2.5), and motility index from 5.2 ± 0.2 to 4.4 ± 0.2. In IBS patients, GLP‐1 1.2 pmol kg−1 min−1 reduced the MMCs from 2.5 (2–3.5) to 1 (0–1.5) without affecting motility index. At 2.5 pmol kg−1 min−1 GLP‐1 decreased MMCs from 2 (1.5–3) to 1 (0.5–1.5), and motility index from 5.2 ± 0.2 to 4.0 ± 0.5. Motility responses to GLP‐1 were similar in antrum and duodenum. Presence of the GLP‐1 receptor in the gut was verified by reverse transcriptase PCR. In conclusion, the gut peptide GLP‐1 decreases motility in the antro‐duodeno‐jejunal region and inhibits the MMC in healthy subjects and IBS patients.
Reproducibility and symptomatic predictors of a slow nutrient drinking test in health and in functional dyspepsia

Abstract Impaired accommodation to a meal has been recognized as a pathophysiological mechanism in functional dyspepsia (FD). Based on observations in tertiary care patients, the drinking test has been proposed as a non‐invasive tool to estimate accommodation. Our aim was to assess the reproducibility of the drinking test and its correlation with demographic, symptomatic and pathophysiological parameters in secondary care FD patients and healthy controls. Thirty‐four healthy controls and 78 FD patients completed a drinking test (3 respectively 2 times), a gastric emptying study and an FD symptom questionnaire. Factors influencing maximal volume and gastric emptying were determined, and the reproducibility of the drinking test was investigated. The maximal satiety was reached at a lower volume in patients (489 ± 276 and 503 ± 248 mL for first and second test respectively vs 937 ± 428 and 1048 ± 421 mL, P < 0.0001). The ingested amount depended on age, sex and baseline FD symptom score. Patients’ sex, final satiety score, total score for stomach complaints at screening and total symptom score before test accounted for the total symptom score after the test. The slow nutrient drinking test confirms its possible role as an attractive non‐invasive and reproducible tool for the diagnosis of impaired accommodation and for the assessment of treatment responsiveness.
Profiles in Cognitive Aging

Trivial mental lapses often accompany advancing age, but differentiating these from the early stages of serious cognitive disorders can be a challenge even for experienced clinicians. Such questions have a greater urgency than ever, now that legislatures have largely disbanded mandatory retirement and more older persons remain active in professions that demand high mental acuity. Physicians are often asked to judge an individual's mental competence, yet few of us have the training or time to do detailed cognitive assessment. In addition, the simple screening tools we are familiar with, such as the Mini-Mental State Examination, are notoriously insensitive to early decline in highly functioning persons. Anticipating this problem nearly a decade ago, the Risk Management Foundation of the Harvard Medical Institutions underwrote a series of studies and field tests that led to the development and validation of MicroCog, a cognitive testing battery designed to be administered and scored by a
Usefulness of Whole-Blood Interferon-γ Assay and Interferon-γ Enzyme-Linked Immunospot Assay in the Diagnosis of Active Pulmonary Tuberculosis

Purpose: The aim of this study was to evaluate the usefulness of the whole-blood interferonassay (enzyme-linked immunosorbent assay [ELISA]) and interferon- enzyme-linked immunospot assay (ELISPOT) based on early secretory antigenic target 6 and culture filtrate protein 10 in the diagnosis of active pulmonary tuberculosis (TB) in routine clinical practice. Method: We conducted a prospective study enrolling 144 participants with suspected pulmonary TB in a tertiary referral hospital in Seoul, South Korea, to investigate the diagnostic sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of these tests. Clinical assessment, tuberculin skin test (TST), whole-blood interferon- ELISA (QuantiFERON-TB Gold [QFT-G]; Cellestis Ltd; Victoria, Australia), and an ELISPOT assay (T SPOT.TB; Oxford Immunotec; Oxford, UK) were performed. Test results were compared with the final confirmed diagnoses. Results: Active pulmonary TB was diagnosed in 67 of 144 participants (47%). Sensitivities of QFT-G and T SPOT.TB for active pulmonary TB were 89% (95% confidence interval [CI], 79 to 96%) and 92% (95% CI, 83 to 97%), respectively; and specificities were 49% (95% CI, 37 to 61%) and 47% (95% CI, 36 to 59%). NPVs of QFT-G (84%; 95% CI, 69 to 93%) and T SPOT.TB (87%; 95% CI, 73 to 96%) were higher than that of TST (64%; 95% CI, 51 to 76%) [p 0.001 and p < 0.001, respectively]. Conclusion: High NPVs of QFT-G and T SPOT.TB for the diagnosis of active TB suggest the supplementary role of these tests for the diagnostic exclusion of active TB, although the low PPV limits their usefulness in routine clinical practice in South Korea, where the prevalence of latent TB infection is considerable. (CHEST 2007; 132:959–965)
Early identification, treatment, and interventions for the prevention of benzodiazepine dependence with anxiety disorders

Unintentional substance dependence can develop after taking benzodiazepines for long-term. The aim of this study was to provide treatment for anxiety symptoms with prevention of benzodiazepine dependence through implementation of the Blunk Anxiety Management Protocol (BAMP). The BAMP, for prescribing, tapering, and discontinuation of benzodiazepines, was implemented for new clients who presented with complaints of anxiety symptoms and for clients previously maintained on benzodiazepines. Education was given for those maintained on benzodiazepines for long-term. Rates of continued long-term benzodiazepine maintenance, dose reduction, and dose discontinuation were measured. For new clients entering care, 29% consented for participation. There were 172 existing clients maintained long-term on benzodiazepines. Of these, 37% or 63 clients consented to participate and received education of benzodiazepines and the process of tapering toward discontinuing. In addition, clients who elected to remain on a benzodiaz.
Inhibition of Janus kinase signaling during controlled mechanical ventilation prevents ventilation-induced diaphragm dysfunction

Controlled mechanical ventilation (CMV) is associated with the development of diaphragm atrophy and contractile dysfunction, and respiratory muscle weakness is thought to contribute significantly to delayed weaning of patients. Therefore, therapeutic strategies for preventing these processes may have clinical benefit. The aim of the current study was to investigate the role of the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling pathway in CMV‐mediated diaphragm wasting and weakness in rats. CMV‐induced diaphragm atrophy and contractile dysfunction coincided with marked increases in STAT3 phosphorylation on both tyrosine 705 (Tyr705) and serine 727 (Ser727). STAT3 activation was accompanied by its translocation into mitochondria within diaphragm muscle and mitochondrial dysfunction. Inhibition of JAK signaling during CMV prevented phosphorylation of both target sites on STAT3, eliminated the accumulation of phosphorylated STAT3 within the mitochondria, and reversed the pathologic alterations in mitochondrial function, reduced oxidative stress in the diaphragm, and maintained normal diaphragm contractility. In addition, JAK inhibition during CMV blunted the activation of key proteolytic pathways in the diaphragm, as well as diaphragm atrophy. These findings implicate JAK/STAT3 signaling in the development of diaphragm muscle atrophy and dysfunction during CMV and suggest that the delayed extubation times associated with CMV can be prevented by inhibition of Janus kinase signaling. —Smith, I. J., Godinez, G. L. , Singh, B. K. , McCaughey, K. M. , Alcantara, R. R. , Gururaja, T. , Ho, M. S. , Nguyen, H. N. , Friera, A. M. , White, K. A. , McLaughlin, J. R. , Hansen, D. , Romero, J. M. , Baltgalvis, K. A. , Claypool, M. D. , Li, W. , Lang, W. , Yam, G. C. , Gelman, M. S. , Ding, R. , Yung, S. L. , Creger, D. P., Chen, Y. , Singh, R. , Smuder, A. J., Wiggs, M. P., Kwon, O. ‐S. , Sollanek, K. J., Powers, S. K. , Masuda, E. S. , Taylor, V. C. , Payan, D. G. , Kinoshita, T. , Kinsella, T. M. Inhibition of Janus kinase signaling during controlled mechanical ventilation prevents ventilation‐induced diaphragm dysfunction. FASEB J. 28, 2790–2803 (2014). www.fasebj. org