Miracle-dz/UniFAR-FTUs huggingface dataset:
TLR Signaling Is Activated in Lymph Node-Resident CLL Cells and Is Only Partially Inhibited by Ibrutinib.

Chronic lymphocytic leukemia (CLL) is a malignancy of mature B cells driven by B-cell receptor (BCR) signaling and activated primarily in the lymph node. The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib effectively inhibits BCR-dependent proliferation and survival signals and has emerged as a breakthrough therapy for CLL. However, complete remissions are uncommon and are achieved only after years of continuous therapy. We hypothesized that other signaling pathways that sustain CLL cell survival are only partially inhibited by ibrutinib. In normal B cells, Toll-like receptor (TLR) signaling cooperates with BCR signaling to activate prosurvival NF-κB. Here, we show that an experimentally validated gene signature of TLR activation is overexpressed in lymph node-resident CLL cells compared with cells in the blood. Consistent with TLR activation, we detected phosphorylation of NF-κB, STAT1, and STAT3 in lymph node-resident CLL cells and in cells stimulated with CpG oligonucleotides in vitro. CpG promoted IRAK1 degradation, secretion of IL10, and extended survival of CLL cells in culture. CpG-induced TLR signaling was significantly inhibited by both an IRAK1/4 inhibitor and ibrutinib. Although inhibition of TLR signaling was incomplete with either drug, the combination achieved superior results, including more effective inhibition of TLR-mediated survival signaling. Our data suggest an important role for TLR signaling in CLL pathogenesis and in sustaining the viability of CLL cells during ibrutinib therapy. The combination of ibrutinib with a TLR pathway inhibitor could provide superior antitumor activity and should be investigated in clinical studies. SIGNIFICANCE: CLL relies on the concomitant cooperation of B-cell receptor and Toll-like receptor signaling; inhibition of both pathways is superior to inhibition of either pathway alone. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals. org/content/canres/79/2/360/F1.large. jpg.
Measurement and evaluation of quality of life and well-being in individuals having or having had fertility problems: a systematic review

Abstract Objectives: The aims of this study were: (1) to identify which measurement instruments are used in practice to assess the quality of life or well-being of individuals with and without (sub)fertility; (2) to describe the design and outcomes of studies comparing quality of life or well-being of individuals with and without fertility problems; and (3) to determine which of the outcomes of the identified studies could be used in cost-utility studies.Methods: A systematic literature review was performed of studies published before July 2018, using multiple databases. Included studies investigated (health-related) quality of life or well-being of individuals with fertility problems. The applied instruments were assessed, as were the outcomes and suitability for use in cost-utility studies.Results: Twenty-six studies met the inclusion criteria. Twelve distinct instruments of measurement were applied: two generic quality-of-life instruments, five generic well-being instruments and five disease-specific instruments. Most studies found negative associations in one or more domains assessing fertility problems and quality of life or well-being. However, two studies found the opposite. None of the studies reported outcomes relevant for cost-utility studies.Conclusion: Quality of life and well-being related to having fertility problems are regularly studied. However, the reported information is not suitable for use in cost-utility studies. There is a clear need for studies investigating the impact of fertility problems on quality of life in a way that outcomes can be compared across studies and disease areas.
Gastrointestinal kanama odağının saptanmasında işaretli eritrosit sintigrafisinin rolü

BACKGROUND We aimed to evaluate the role of Tc-99m labeled red blood cell (RBC) scintigraphy for determination of localization of gastrointestinal system (GIS) bleeding. METHODS Fifty-seven cases (27 females, 30 males; mean age 43.9±24; range 1 to 91 years) who referred to our clinic between 1995-2010 were evaluated for determination of localization of GIS bleeding with RBC scintigraphy. Prior to scintigraphy, gastroscopy in 51, colonoscopy in 45, and angiography in 9 patients were performed. RESULTS RBC scintigraphies were positive and negative in 31 and 26 patients, respectively. Positive scintigraphic findings were obtained within the 1st hour of dynamic imaging in 19 patients, within the 1st-4th hour static images in 7, and within the 4th-24th hour images in 5 patients. Fourteen patients underwent surgical exploration. In 13 patients, the surgery confirmed the diagnosis by RBC scintigraphy (accuracy: 92.8%). Of 43 patients without surgical exploration, 12 had anemia due to iron deficiency and their scintigraphic evaluation were negative. Four patients died and in 27 patients, GIS bleeding ceased spontaneously or with conservative measures. CONCLUSION Scintigraphy should be the primary tool for accurate diagnosis of patients with active GIS bleeding. Positive dynamic images obtained within the first hour of imaging may be more accurate for demonstrating bleeding localization and a good predictor of requirement of surgical exploration.
Comprehensive 3D-QSAR Model Predicts Binding Affinity of Structurally Diverse Sigma 1 Receptor Ligands

The Sigma 1 Receptor (S1R) has attracted intense interest as a pharmaceutical target for various therapeutic indications, including the treatment of neuropathic pain and the potentiation of opioid analgesia. Efforts by drug developers to rationally design S1R antagonists have been spurred recently by the 2016 publication of the high-resolution X-ray crystal structure of the ligand-bound human S1R. Until now, however, the absence in the published literature of a single, large-scale, and comprehensive quantitative structure-activity relationship (QSAR) model that encompasses a structurally diverse collection of S1R ligands has impaired rapid progress. To our best knowledge, the present study represents the first report of a statistically robust and highly predictive 3D-QSAR model (R2 = 0.92, Q2 = 0.62, Rpred2 = 0.81) based on the X-ray crystal structure of human S1R and constructed from a pooled compilation of 180 S1R antagonists that encompass five structurally diverse chemical families investigated using identical experimental protocols. Best practices, as recommended by the Organization for Economic Cooperation and Development (OECD: http://www.oecd.org/ ), were adopted for pooling data from disparate sources and for QSAR model development and both internal and external model validation. The practical utility of the final 3D-QSAR model was tested by virtual screening of the DrugBank database of FDA approved drugs supplemented by eight reported S1R antagonists. Among the top-ranked 40 DrugBank hits, four approved drugs which were previously unknown as S1R antagonists were tested using in vitro radiolabeled human S1R binding assays. Of these, two drugs (diphenhydramine and phenyltoloxamine) exhibited potent S1R binding affinity with Ki = 58 nM and 160 nM, respectively. As diphenhydramine is approved as an antiallergic, and phenyltoloxamine as an analgesic and sedative, each of these compounds represents a viable starting point for a drug discovery campaign aimed at the development of novel S1R antagonists for a wide range of therapeutic indications.
Exercise physiology in aged care: Perceptions and acceptability from the perspectives of family members and care staff in the residential aged care environment

As we age, maintaining physical functionality is important with respect to wellbeing and healthy ageing. For older adults with dementia this may be difficult, particularly in the residential aged care environment. This article reports the qualitative examination of an Exercise Physiologist-delivered exercise programme for residents with dementia. Perspectives related to the perceived impact and acceptability of the programme, as well as barriers to implementation, and delivery of exercise to residents, were sought from family members and care staff through semi-structured interviews. Benefits related to physical and social factors were identified, and perceptions related to who might benefit from exercise were changed as a result of observing residents participate in the programme. These findings support the notion that an Exercise Physiologist-delivered exercise programme, with a person-centred approach, can contribute to improved functionality for residents with dementia
IAA producing fungal endophyte Penicillium roqueforti Thom., enhances stress tolerance and nutrients uptake in wheat plants grown on heavy metal contaminated soils

Heavy metals contaminated soil is a serious environmental concern that has a negative impact on agriculture and ecosystem. Economical and efficient ways are needed to address this problem worldwide. In this regard, exploration and application of proficient microbial strains that can help the crop plants to thrive in agricultural soils that are greatly contaminated with heavy metals. The present study mainly focused on the effect of IAA producing endophytic fungi Penicillium ruqueforti Thom. , on wheat plants cultivated in soil rich in heavy metals (Ni, Cd, Cu, Zn, and Pb). P. ruqueforti has induced great resistance in wheat inoculated plants grown in heavy metal contaminated soil. Application of the isolated strain of P. ruqueforti restricted the transfer of heavy metals from soil to the plants by secreting indole acetic acid (IAA). Furthermore, P. ruqueforti inoculated wheat seedlings watered with waste water had higher plant growth, nutrient uptake and low concentrations of heavy metals in shoot and roots. On the contrary, non-inoculated wheat plants under heavy metal stress had stunted growth with symptoms of chlorosis. From the results, it is concluded that P. ruqueforti inoculation can establish a symbiotic relationship with host plants, which is useful for phytostabilization of heavy metals or in other words helping the host crops to flourish through soil that are highly contaminated with heavy metals.
Adaptive coupling influences generalization of sensorimotor learning

Sensorimotor learning typically shows generalization from one context to another. Models of sensorimotor learning characterize this with a fixed generalization function that couples learning between contexts. Here we examine whether such coupling is indeed fixed or changes with experience. We examine the interaction between motor memories for novel dynamics during reciprocating, back and forth reaching movements. Subjects first experienced a force field for one movement direction and we used channel trials to assess generalization on the reciprocal movements. This showed minimal coupling such that errors experienced for one movement direction did not lead to adaptation for the other. However, after subjects had experienced a force field for both movement directions concurrently, a coupling developed between the corresponding motor memories. That is, on re-exposure for one direction there was a significant adaptation for movements in the other direction. The coupling was specific to the errors experienced, with minimal coupling when the errors had the opposite sign to those experienced during adaptation. We developed a state-space model in which the states for the two movement directions are represented by separate, yet potentially coupled learning processes. The coupling in the model controlled the extent to which each learning process was updated by the errors experienced on the other movement direction. We show that the coupling relies on a memory trace of the consecutive errors experienced for both movement directions. Our results suggest that the generalization of motor learning is an adaptive process, reflecting the relation between errors experienced across different movements.
Outcome and complications in goats treated by perineal urethrostomy for obstructive urolithiasis: 25 cases (2010‐2017)

Background Obstructive urolithiasis commonly affects male goats. Perineal urethrostomy (PU) can be a permanent treatment option but is generally considered undesirable because of the risk of stricture of the urethral stoma. Limited information exists regarding long‐term outcome and complications in goats undergoing PU for treatment of obstructive urolithiasis. Objectives To determine short‐term and long‐term outcome and complications in goats undergoing PU for treatment of obstructive urolithiasis. Animals Twenty‐five client‐owned goats. Methods Multi‐institutional retrospective case series. Results Of the 25 goats, 13 (52%) were alive at the time of follow‐up. Mean time from surgery to follow‐up was 34 months (range, 4‐65). Nine goats (36%) died between discharge and follow‐up with a mean survival time of 46 days (range, 5‐120). Cause of death in 7 of 9 (78%) goats was related to urolithiasis. Goats treated by use of a modified proximal perineal urethrostomy (MPPU) were significantly more likely to survive at least 150 days postoperatively (P < .01). The most common postoperative complications were hemorrhage (10/25 [40%]) and surgical site infection (3/25 [12%]). Hemorrhage was significantly associated with MPPU (P < .0001). Stricture of the surgical stoma occurred in 7 of 22 (32%) discharged goats. Mean time to stricture was 65 days (range, 10‐240). Conclusions and Clinical Importance Perineal urethrostomy can provide effective long‐term resolution of obstructive urolithiasis in goats. Re‐obstruction or stricture seems most likely within the 1st 2 months after surgery. MPPU may provide better long‐term results but should be approached cautiously because it can be associated with life‐threatening hemorrhage.
CYP76B74 Catalyzes the 3′′-Hydroxylation of Geranylhydroquinone in Shikonin Biosynthesis1

CYP76B74 encodes geranylhydroquinone 3′′-hydroxylase involved in the shikonin biosynthetic pathway and is necessary for the accumulation of shikonin derivatives in Arnebia euchroma. Shikonin and its derivatives are the most abundant naphthoquinone pigments formed in species of the medicinally and economically valuable Boraginaceae. A key step in the shikonin biosynthetic pathway, namely the C-3′′ hydroxylation of the prenylated phenolic intermediate geranylhydroquinone, is expected to be catalyzed by a cytochrome P450. To identify cytochrome P450 candidates with transcription profiles similar to those of genes known to be involved in shikonin biosynthesis, we carried out coexpression analysis of transcriptome data sets of shikonin-proficient and shikonin-deficient cell lines and examined the spatial expression of candidate genes in different organs of Arnebia euchroma. In biochemical assays using geranylhydroquinone as the substrate, CYP76B74 exhibited geranylhydroquinone 3′′-hydroxylase activity and produced 3′′-hydroxy-geranylhydroquinone. In CYP76B74 RNA interference A. euchroma hairy roots, shikonin derivative accumulation decreased dramatically, which demonstrated that CYP76B74 is required for shikonin biosynthesis in the plant. Phylogenetic analysis confirmed that CYP76B74 belonged to the CYP76B subfamily and was most likely derived from an ancestral geraniol 10-hydroxylase. In a subcellular localization analysis, a GFP-CYP76B74 fusion localized to endoplasmic reticulum membranes. Our results demonstrate that CYP76B74 catalyzes the key hydroxylation step in shikonin biosynthesis with high efficiency. The characterization of the CYP76B74 described here paves the way for further exploration of the ring closure reactions generating the naphthoquinone skeleton as well as for the alternative metabolism of geranylhydroquinone 3′′-hydroxylase to dihydroechinofuran.
Genetic recovery of ErbB4 in adulthood partially restores brain functions in null mice

Significance NRG1–ErbB4 signaling is implicated in GABAergic circuit assembly during development and GABAergic transmission at adulthood. However, it is unclear whether phenotypes in the adult stage in ErbB4 mutant mice result from abnormal neural development. By using two strains of mice with temporal control of ErbB4 deletion and expression, we demonstrate that ErbB4 deletion in adult mice impaired behavior and GABA release, whereas deficits due to ErbB4 null mutation during development were alleviated by restoring ErbB4 expression at the adult stage. Together, our results indicate that NRG1–ErbB4 signaling at adulthood is critical to GABAergic transmission and behavior and suggest that restoring NRG1–ErbB4 signaling at the postdevelopmental stage might benefit relevant brain disorders. Neurotrophic factor NRG1 and its receptor ErbB4 play a role in GABAergic circuit assembly during development. ErbB4 null mice possess fewer interneurons, have decreased GABA release, and show impaired behavior in various paradigms. In addition, NRG1 and ErbB4 have also been implicated in regulating GABAergic transmission and plasticity in matured brains. However, current ErbB4 mutant strains are unable to determine whether phenotypes in adult mutant mice result from abnormal neural development. This important question, a glaring gap in understanding NRG1–ErbB4 function, was addressed by using two strains of mice with temporal control of ErbB4 deletion and expression, respectively. We found that ErbB4 deletion in adult mice impaired behavior and GABA release but had no effect on neuron numbers and morphology. On the other hand, some deficits due to the ErbB4 null mutation during development were alleviated by restoring ErbB4 expression at the adult stage. Together, our results indicate a critical role of NRG1–ErbB4 signaling in GABAergic transmission and behavior in adulthood and suggest that restoring NRG1–ErbB4 signaling at the postdevelopmental stage might benefit relevant brain disorders.
Farewell Letters I: The Dying Process of a Healthy Man

This qualitative case study describes the dying process from a purely psychological perspective. The letters of Count Moltke, who was sentenced to death and executed during the Nazi regime, to his wife were analyzed content analytically. A work program of four self-imposed tasks emerged, namely first to avert the death sentence, second to prepare for the ideological and intellectual battle with the chairman of the court, third to support his wife in her anticipatory mourning, and fourth to achieve willingness for his dying by strangulation and for losing his life. Contrasting these findings with two cases of incurably ill men confirmed work and structure as the overarching way of coping. Religious coping is also of central importance. There was neither a linear trajectory nor a sequence of phases; rather, Moltke’s dying process corresponds to a circular model. A consequence of the findings is outlined.
Long‐Lasting Poloidal ULF Waves Observed by Multiple Satellites and High‐Latitude SuperDARN Radars

Poloidal ultralow frequency (ULF) waves between 5 and 10 mHz were observed by multiple satellites and three high‐latitude Super Dual Auroral Radar Network radars during the recovery phase of a moderate geomagnetic storm on 24–27 January 2016. The long‐lasting ULF waves were observed in the magnetic field and energetic particle flux perturbations during three successive passes by two Geostationary Operational Environmental Satellites through the dayside magnetosphere, during which plasmasphere expansion and refilling were observed by two Time History of Events and Macroscale Interactions during Substorms probes. The radial magnetic field oscillation was in phase (∼180° out of phase) with the northward (southward) moving proton flux oscillation at 95 keV, consistent with high‐energy drift‐bounce resonance signatures of protons with second harmonic poloidal standing Alfvén waves. The longitudinal extent of the waves approached 10 hr in local time on the dayside and gradually decreased with time. High‐time‐resolution (∼6 s) data from three high‐latitude Super Dual Auroral Radar Network radars show that the wave intensification region was localized in latitude with a radial extent of ∼135–225 km in the subauroral ionosphere. No signature of these waves were observed by ground‐based magnetometers colocated with the Geostationary Operational Environmental Satellites suggesting that the poloidal waves were high‐m mode and thus screened by the ionosphere. During this interval one of the Time History of Events and Macroscale Interactions during Substorms probes observed a bump‐on‐tail ion distribution at 1–3 keV, which we suggest is the source of the long‐lasting second harmonic poloidal ULF waves.
The Importance of Early Surgical Decompression for Acute Traumatic Spinal Cord Injury

Background Traumatic spinal cord injury (SCI) is a tragic event that has a major impact on individuals and society as well as the healthcare system. The purpose of this study was to investigate the strength of association between surgical treatment timing and neurological improvement. Methods Fifty-six patients with neurological impairment due to traumatic SCI were included in this study. From January 2013 to June 2017, all their medical records were reviewed. Initially, to identify the factors affecting the recovery of neurological deficit after an acute SCI, we performed univariate logistic regression analyses for various variables. Then, we performed a multivariate logistic regression analysis for variables that showed a p-value of < 0.2 in the univariate analyses. The Hosmer-Lemeshow test was used to determine the goodness of fit for the multivariate logistic regression model. Results In the univariate analysis on the strength of associations between various factors and neurological improvement, the following factors had a p-value of < 0.2: surgical timing (early, < 8 hours; late, 8–24 hours; p = 0.033), completeness of SCI (complete/incomplete; p = 0.033), and smoking (p = 0.095). In the multivariate analysis, only two variables were significant: surgical timing (odds ratio [OR], 0.128; p = 0.004) and completeness of SCI (OR, 9.611; p = 0.009). Conclusions Early surgical decompression within 8 hours after traumatic SCI appeared to improve neurological recovery. Furthermore, incomplete SCI was more closely related to favorable neurological improvement than complete SCI. Therefore, we recommend early decompression as an effective treatment for traumatic SCI.
Coupled simulations of Greenland Ice Sheet and climate change up to A.D. 2300

Recent observations indicate a high sensitivity of the Greenland Ice Sheet (GrIS) to climate change. We examine the coupling between the GrIS surface mass balance, elevation, and dynamical flow with one of the few coupled GrIS and atmosphere‐ocean general circulation models. Bidirectional coupling from the early Holocene reveals a growing present‐day GrIS in the absence of anthropogenic forcing. We identify atmospheric sources of biases in the simulated present‐day GrIS and assess the GrIS sensitivity to future greenhouse gas forcing through three Representative Concentration Pathways and their extensions and to climate variability. The elevation‐surface mass balance feedback contributes to future GrIS mass loss with 8–11% (by 2100), depending on the forcing scenario, and 24–31% (by 2300). Climate variability causes a 2.5 times spread in the magnitude of the simulated present‐day GrIS mass trends in a three‐member ensemble. Our results represent a first step toward more advanced higher resolution coupled modeling of GrIS and climate evolution.