Miracle-dz/UniFAR-FTUs huggingface dataset:
Ruxolitinib: The First FDA Approved Therapy for the Treatment of Myelofibrosis

The BCR-ABL1–negative myeloproliferative neoplasms (e.g., essential thrombocythemia, polycythemia vera, and primary myelofibrosis) are a group of heterogeneous hematologic malignancies that involve a clonal proliferation of hematopoietic stem cells. Thrombosis, bleeding, and transformation to acute leukemia reduce the overall survival of patients with myelofibrosis, a disease typified by progressive splenomegaly and disease-related symptoms such as fatigue, pruritus, and bony pains. Hematopoietic stem cell transplant offers the only potential for cure in a minority of eligible patients, leaving a serious unmet need for improved therapies. Recent advances in our understanding of the pathogenetic mechanisms underlying these diseases have led to an explosion of clinical trials evaluating novel therapies. The discovery of an activating mutation in the Janus-activated kinase 2 (JAK2) gene provided a therapeutic target to downregulate this activated signaling pathway, which influences the phenotype of these diseases. Ruxolitinib (Jakafi; Incyte) is a small-molecule inhibitor of JAK1/2 that has proved to be effective at reducing splenomegaly and ameliorating symptoms in myeloproliferative neoplasms. Based on the results of 2 pivotal randomized phase III clinical trials, ruxolitinib has become the first therapeutic to be approved by the U.S. Food and Drug Administration for treatment of patients with myelofibrosis. Ruxolitinib offers a well-tolerated oral therapeutic option for patients with myelofibrosis with symptomatic splenomegaly and debilitating disease-related symptoms, but it does not seem to be effective at eliminating the underlying hematological malignancy. Clin Cancer Res; 18(11); 3008–14. ©2012 AACR.
Solid advice: Complementary feeding experiences among disadvantaged parents in two countries.

The initiation of complementary feeding (CF; introducing infants to food/drink other than milk) is recommended close to 6 months and not before 4 months of age. Low socio-economic status (SES) is a determinant of nonadherence to CF recommendations, but there is an evidence gap around reasons for nonadherence among these parents. This study investigated knowledge, attitudes, and practices of disadvantaged families (in terms of SES and social support) and use of guidance for CF, in the Republic of Ireland and Northern Ireland. Parents of infants aged 3-14 months were recruited via community groups. Semistructured focus groups aided by vignettes were used. Data were analysed using an inductive thematic approach. Nineteen focus groups took place with parents (n = 83). A range of factors influence parents when introducing solids. Sources of guidance extend to family, friends, the internet, and commercial resources. Parents experience uncertainty and anxiety during this time, driven by lack of knowledge and conflicting advice. Five major themes were identified: (a) more guidance that is accessible, timely, and respectfully needed; (b) the challenge of choosing safe, nutritious food; (c) "everybody has an opinion"; (d) feelings of inadequacy, embarrassment, and guilt; and (e) decisions are ultimately based on individual circumstances. CF advice should be culturally appropriate, practical, and empowering, emphasising the rationale behind updates to recommendations and consequences of nonadherence. Future training of health professionals for delivery of CF advice and guidance should consider these findings. Compliance with CF recommendations is influenced by health professionals, the wider family, and the commercial baby-food sector.
Role of pelvic chemoradiation therapy in patients with initially metastatic anal canal cancer: A National Cancer Database review

Although the management of localized anal canal squamous cell carcinomas is well established, the role of pelvic chemoradiation (CRT) in the treatment of patients presenting with synchronous metastatic (stage IV) disease is poorly defined. This study used a national cancer database to compare the overall survival (OS) rates of patients with synchronous metastatic disease receiving CRT to the pelvis and patients treated with chemotherapy (CT) alone.
Recognizing Taste: Coding Patterns Along the Neural Axis in Mammals.

The gustatory system encodes information about chemical identity, nutritional value, and concentration of sensory stimuli before transmitting the signal from taste buds to central neurons that process and transform the signal. Deciphering the coding logic for taste quality requires examining responses at each level along the neural axis-from peripheral sensory organs to gustatory cortex. From the earliest single-fiber recordings, it was clear that some afferent neurons respond uniquely and others to stimuli of multiple qualities. There is frequently a "best stimulus" for a given neuron, leading to the suggestion that taste exhibits "labeled line coding. " In the extreme, a strict "labeled line" requires neurons and pathways dedicated to single qualities (e.g., sweet, bitter, etc.). At the other end of the spectrum, "across-fiber," "combinatorial," or "ensemble" coding requires minimal specific information to be imparted by a single neuron. Instead, taste quality information is encoded by simultaneous activity in ensembles of afferent fibers. Further, "temporal coding" models have proposed that certain features of taste quality may be embedded in the cadence of impulse activity. Taste receptor proteins are often expressed in nonoverlapping sets of cells in taste buds apparently supporting "labeled lines. " Yet, taste buds include both narrowly and broadly tuned cells. As gustatory signals proceed to the hindbrain and on to higher centers, coding becomes more distributed and temporal patterns of activity become important. Here, we present the conundrum of taste coding in the light of current electrophysiological and imaging techniques at several levels of the gustatory processing pathway.
Exaggerated mechanoreflex in early-stage type 1 diabetic rats: role of Piezo channels.

Recent findings have shown that muscle contraction evokes an exaggerated pressor response in type 1 diabetes mellitus (T1DM) rats; however, it is not known whether the mechanoreflex, which is commonly stimulated by stretching the Achilles tendon, contributes to this abnormal response. Furthermore, the role of mechano-gated Piezo channels, found on thin-fiber afferent endings, in evoking the mechanoreflex in T1DM is also unknown. Therefore, in male and female streptozotocin (STZ, 50 mg/kg)-induced T1DM and healthy control (CTL) rats, we examined the pressor and cardioaccelerator responses to tendon stretch during the early stage of the disease. To determine the role of Piezo channels, GsMTx-4, a selective Piezo channel inhibitor, was injected into the arterial supply of the hindlimb. At 1 wk after STZ injection in anesthetized, decerebrate rats, we stretched the Achilles tendon for 30 s and measured pressor and cardioaccelerator responses. We then compared pressor and cardioaccelerator responses to tendon stretch before and after GsMTx-4 injection (10 µg/100 ml). We found that the pressor (change in mean arterial pressure) response [41 ± 5 mmHg (n = 15) for STZ and 18 ± 3 mmHg (n = 11) for CTL (P < 0.01)] and cardioaccelerator (change in heart rate) response [18 ± 4 beats/min for STZ (n = 15) and 8 ± 2 beats/min (n = 11) for CTL (P < 0.05)] to tendon stretch were exaggerated in STZ rats. Local injection of GsMTx-4 attenuated the pressor [55 ± 7 mmHg (n = 6) before and 27 ± 9 mmHg (n = 6) after GsMTx-4 (P < 0.01)], but not the cardioaccelerator, response to tendon stretch in STZ rats and had no effect on either response in CTL rats. These data suggest that T1DM exaggerates the mechanoreflex response to tendon stretch and that Piezo channels play a role in this exaggeration.
Prediction of apoptosis protein subcellular localization via heterogeneous features and hierarchical extreme learning machine

ABSTRACT Apoptosis is a fundamental process controlling normal tissue homeostasis by regulating a balance between cell proliferation and death. Predicting the subcellular location of apoptosis proteins is very helpful for understanding the mechanism of programmed cell death. Predicting protein subcellular localization with bioinformatic techniques provides quite a few opportunities in related fields. In this work, we propose the use of a hierarchical extreme learning machine (H-ELM) to make a classification of high-dimensional input data without demanding a dimension reduction process, which yields acceptable results. An attempt is made to extract features from different perspectives, and a feature fusion process is accomplished. Regarding the position-specific scoring matrix, the first type depicts the correlation within the sequence with the autocorrelation function for relatively random sections from the sequence; and the second type is the Kullback-Leibler (K-L) divergence of the two distributions formed by the amino acids’ constitutuent proportions. It is illustrated in an experiment with features from different sources mixed by simple concatenation yielding a poor result, but the synthetical feature fused with stochastic nonlinear embedding (t-SNE) greatly improved the classification. Finally, the highest overall accuracy of ZD98 is 87.5% by adjusting the hyper-parameters of H-ELM, and of CL317 is 92.4%.
Oxidative Stress and Dysfunctional Intracellular Traffic Linked to an Unhealthy Diet Results in Impaired Cargo Transport in the Retinal Pigment Epithelium (RPE).

SCOPE Oxidative stress and dysregulated intracellular trafficking are associated with an unhealthy diet which underlies pathology. Here, these effects on photoreceptor outer segment (POS) trafficking in the retinal pigment epithelium (RPE), a major pathway of disease underlying irreversible sight-loss, are studied. METHODS AND RESULTS POS trafficking is studied in ARPE-19 cells using an algorithm-based quantification of confocal-immunofluorescence data supported by ultrastructural studies. It is shown that although POS are tightly regulated and trafficked via Rab5, Rab7 vesicles, LAMP1/2 lysosomes and LC3b-autophagosomes, there is also a considerable degree of variation and flexibility in this process. Treatment with H2 O2 and bafilomycin A1 reveals that oxidative stress and dysregulated autophagy target intracellular compartments and trafficking in strikingly different ways. These effects appear limited to POS-containing vesicles, suggesting a cargo-specific effect. CONCLUSION The findings offer insights into how RPE cells cope with stress, and how mechanisms influencing POS transport/degradation can have different outcomes in the senescent retina. These shed new light on cellular processes underlying retinopathies such as age-related macular degeneration. The discoveries reveal how diet and nutrition can cause fundamental alterations at a cellular level, thus contributing to a better understanding of the diet-disease axis.
The diversion of stimulant medications among a convenience sample of college students with current prescriptions.

Diversion is defined as the unlawful channeling of regulated pharmaceuticals from legal sources to the illicit marketplace. Persons with legal prescriptions often give away or sell their medications to others. The misuse of prescription stimulant medications continues to be a problem on college campuses and a need to understand how students are obtaining stimulant medications exists. The object of the study was to identify the prevalence, correlates, and motivations associated with diversion of prescription stimulants among current prescription holders. A large sample of undergraduates (n = 1,022) between the ages of 18 and 24 enrolled at a large public university in the southeastern United States completed an in class questionnaire. Among those respondents, we identified 151 current stimulant prescription holders and analyzed the prevalence, motivations, and correlates associated with lifetime and current diversion. Overall, 58.9% of current prescription holders had given away or sold their stimulant medication during their lifetime. Those with a history of nonmedical use of prescription stimulants were almost 5 times more likely to divert their medication during their lifetime. The majority of those engaging in lifetime and current diversion medication did so infrequently. The most common motivations reported for both lifetime and current diversion were "to make extra money" and to "help during a time of high academic stress. " Students who reported a history of prescription misuse were also more likely to engage in current diversion. Diversion-related behaviors should be explored further and programs aimed at the reducing these behaviors should be considered.
Effects of the antioxidant drug tempol on renal oxygenation in mice with reduced renal mass.

We tested the hypothesis that reactive oxygen species (ROS) contributed to renal hypoxia in C57BL/6 mice with ⅚ surgical reduction of renal mass (RRM). ROS can activate the mitochondrial uncoupling protein 2 (UCP-2) and increase O(2) usage. However, UCP-2 can be inactivated by glutathionylation. Mice were fed normal (NS)- or high-salt (HS) diets, and HS mice received the antioxidant drug tempol or vehicle for 3 mo. Since salt intake did not affect the tubular Na(+) transport per O(2) consumed (T(Na/)Q(O2)), further studies were confined to HS mice. RRM mice had increased excretion of 8-isoprostane F(2α) and H(2)O(2), renal expression of UCP-2 and renal O(2) extraction, and reduced T(Na/)Q(O2) (sham: 20 ± 2 vs. RRM: 10 ± 1 μmol/μmol; P < 0.05) and cortical Po(2) (sham: 43 ± 2, RRM: 29 ± 2 mmHg; P < 0.02). Tempol normalized all these parameters while further increasing compensatory renal growth and glomerular volume. RRM mice had preserved blood pressure, glomeruli, and patchy tubulointerstitial fibrosis. The patterns of protein expression in the renal cortex suggested that RRM kidneys had increased ROS from upregulated p22(phox), NOX-2, and -4 and that ROS-dependent increases in UCP-2 led to hypoxia that activated transforming growth factor-β whereas erythroid-related factor 2 (Nrf-2), glutathione peroxidase-1, and glutathione-S-transferase mu-1 were upregulated independently of ROS. We conclude that RRM activated distinct processes: a ROS-dependent activation of UCP-2 leading to inefficient renal O(2) usage and cortical hypoxia that was offset by Nrf-2-dependent glutathionylation. Thus hypoxia in RRM may be the outcome of NADPH oxidase-initiated ROS generation, leading to mitochondrial uncoupling counteracted by defense pathways coordinated by Nrf-2.
Dysbiosis of the Gut Microbiota on the Inflammatory Background due to Lack of Suppressor of Cytokine Signalling-1 in Mice

Background: Both environmental and genetic factors have been implicated in the induction of autoimmune disease. Therefore, it is important to understand the pathophysiological significance of the gut microbiota and host genetic background that contribute to an autoimmune disease such as inflammatory bowel disease (IBD). We have previously reported that mice deficient for suppressor of cytokine signaling-1 (SOCS1), in which SOCS1 expression was restored in T and B cells on an SOCS1–/– background (SOCS1–/–Tg mice), developed systemic autoimmune diseases accompanied by spontaneous colitis. Methods: To investigate whether the proinflammatory genetic background affects the gut microbiota, we used SOCS1–/–Tg mice as a model of spontaneous chronic colitis. Fecal samples were collected from SOCS1–/–Tg mice and SOCS1+/+Tg (control) mice at 1 and 6 months of age, and the fecal bacterial 16S ribosomal RNA genes were sequenced using the Illumina MiSeq platform. Results: Gut microbial diversity was significantly reduced and the intestinal bacterial community composition changed in SOCS1–/–Tg mice in comparison with the control mice. Interestingly, the population of Prevotella species, which is known to be elevated in ulcerative colitis and colorectal cancer patients, was significantly increased in SOCS1–/–Tg mice regardless of age. Conclusion: Taken together, these results suggest that the proinflammatory genetic background owing to SOCS1 deficiency causes dysbiosis of the gut microbiota, which in turn generates a procolitogenic environment.
Styryl Quinazolinones as Potential Inducers of Myeloid Differentiation via Upregulation of C/EBPα

The CCAAT enhancer-binding protein α (C/EBPα) plays an important role in myeloid cell differentiation and in the enhancement of C/EBPα expression/activity, which can lead to granulocytic differentiation in acute myeloid leukemia (AML) cells. We found that styryl quinazolinones induce upregulation of C/EBPα expression, and thereby induce myeloid differentiation in human myeloid leukemia cell lines. We screened a series of active styryl quinazolinones and evaluated the structure–activity relationship (SAR) of these small molecules in inducing C/EBPα expression—thereby prompting the leukemic cells to differentiate. We observed that compound 78 causes differentiation at 3 μM concentration, while 1 induces differentiation at 10 μM concentration. We also observed an increase in the expression of neutrophil differentiation marker CD11b upon treatment with 78. Both the C/EBPα and C/EBPε levels were found to be upregulated by treatment with 78. These SAR findings are inspiration to develop further modified styryl quinazolinones, in the path of this novel differentiation therapy, which can contribute to the care of patients with AML.
Phylogeny and taxonomy of three new Ctenomyces (Arthrodermataceae, Onygenales) species from China

Abstract Twelve Ctenomyces (Arthrodermataceae, Onygenales) strains were obtained and identified during a survey of keratinophilic fungi in soils from China. We used molecular identification combined with morphological evidence to delimit species, circumscribing five species in the genus. Three new species are herein described: C.albussp. nov., C.obovatussp. nov. and C.peltricolorsp. nov. We also described, illustrated and compared the novel species with related species in the morphology.
Impaired αVβ8 and TGFβ signaling lead to microglial dysmaturation and neuromotor dysfunction

Microglia play a pivotal role in the coordination of brain development and have emerged as a critical determinant in the progression of neurodegenerative diseases; however, the role of microglia in the onset and progression of neurodevelopmental disorders is less clear. Here we show that conditional deletion of &agr;V&bgr;8 from the central nervous system (Itgb8&Dgr;CNS mice) blocks microglia in their normal stepwise development from immature precursors to mature microglia. These “dysmature” microglia appear to result from reduced TGF&bgr; signaling during a critical perinatal window, are distinct from microglia with induced reduction in TGF&bgr; signaling during adulthood, and directly cause a unique neurodevelopmental syndrome characterized by oligodendrocyte maturational arrest, interneuron loss, and spastic neuromotor dysfunction. Consistent with this, early (but not late) microglia depletion completely reverses this phenotype. Together, these data identify novel roles for &agr;V&bgr;8 and TGF&bgr; signaling in coordinating microgliogenesis with brain development and implicate abnormally programmed microglia or their products in human neurodevelopmental disorders that share this neuropathology.
A Postharvest Fruit Rot in d'Anjou Pears Caused by Sphaeropsis pyriputrescens sp. nov.

During a survey of postharvest diseases in stored pears conducted in the 2001-02 storage season, a new postharvest fruit rot in d'Anjou pears was discovered in Washington State. Symptoms of this disease were stem-end rot, calyx-end rot, and wound-associated rot, which presumably originated from infections of stem, calyx, and wounds on the fruit surfaces, respectively. The decayed area on the fruit was firm or spongy and appeared brown. During the late storage period from March to May 2002, this disease was observed in 19 of 39 lots and accounted for 2 to 21% of all decayed fruit. The causal agent, Sphaeropsis sp. , was consistently recovered from decayed fruit with the symptoms described above. Two isolates of the fungus were used for pathogenicity tests on pear fruit. Decay symptoms developed on fruit inoculated with spore suspensions of the fungus on the stem, calyx, and wounds on the fruit surface. The fungus was reisolated from these decayed fruit. The fungus, Sphaeropsis pyriputrescens sp. nov., was characterized and described. On potato dextrose agar (PDA), oatmeal agar, and pear juice agar at 20°C, the fungus grew at mean rates of 21, 15, and 24 mm day-1 in colony diameter, respectively. On PDA, the fungus formed a circular colony with dense, hyaline hyphae and a few or some aerial mycelia. Colonies appeared light yellow to yellow on 2-week-old PDA cultures. The fungus grew at temperatures from 0 to 25°C, with optimum growth between 15 and 20°C, little or no growth at 30°C, and no growth at 35°C. This is a low-temperature species.
Consensus-based recommendations for the management of juvenile localised scleroderma

In 2012, a European initiative called Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) was launched to optimise and disseminate diagnostic and management regimens in Europe for children and young adults with rheumatic diseases. Juvenile localised scleroderma (JLS) is a rare disease within the group of paediatric rheumatic diseases (PRD) and can lead to significant morbidity. Evidence-based guidelines are sparse and management is mostly based on physicians’ experience. This study aims to provide recommendations for assessment and treatment of JLS. Recommendations were developed by an evidence-informed consensus process using the European League Against Rheumatism standard operating procedures. A committee was formed, mainly from Europe, and consisted of 15 experienced paediatric rheumatologists and two young fellows. Recommendations derived from a validated systematic literature review were evaluated by an online survey and subsequently discussed at two consensus meetings using a nominal group technique. Recommendations were accepted if ≥80% agreement was reached. In total, 1 overarching principle, 10 recommendations on assessment and 6 recommendations on therapy were accepted with ≥80% agreement among experts. Topics covered include assessment of skin and extracutaneous involvement and suggested treatment pathways. The SHARE initiative aims to identify best practices for treatment of patients suffering from PRDs. Within this remit, recommendations for the assessment and treatment of JLS have been formulated by an evidence-informed consensus process to produce a standard of care for patients with JLS throughout Europe.