Miracle-dz/UniFAR-FTUs huggingface dataset:
The PI3K and MAPK/p38 pathways control stress granule assembly in a hierarchical manner

PI3K and p38 act in a hierarchical manner to enhance mTORC1 activity and stress granule formation; although PI3K is the main driver, the impact of p38 gets apparent as PI3K activity declines. All cells and organisms exhibit stress-coping mechanisms to ensure survival. Cytoplasmic protein-RNA assemblies termed stress granules are increasingly recognized to promote cellular survival under stress. Thus, they might represent tumor vulnerabilities that are currently poorly explored. The translation-inhibitory eIF2α kinases are established as main drivers of stress granule assembly. Using a systems approach, we identify the translation enhancers PI3K and MAPK/p38 as pro-stress-granule-kinases. They act through the metabolic master regulator mammalian target of rapamycin complex 1 (mTORC1) to promote stress granule assembly. When highly active, PI3K is the main driver of stress granules; however, the impact of p38 becomes apparent as PI3K activity declines. PI3K and p38 thus act in a hierarchical manner to drive mTORC1 activity and stress granule assembly. Of note, this signaling hierarchy is also present in human breast cancer tissue. Importantly, only the recognition of the PI3K-p38 hierarchy under stress enabled the discovery of p38’s role in stress granule formation. In summary, we assign a new pro-survival function to the key oncogenic kinases PI3K and p38, as they hierarchically promote stress granule formation.
Muon Tracker for the Second Pathfinder of the Pacific Ocean Neutrino Explorer

This Bachelor thesis reports on the development of a devise to track muons. As part of STRAW-b (STRings for Absorption length in Water part b), it will be deployed in the North Pacific several hundred miles away from Vancouver Island in Canada. After a feasibility study of the expected muon flux, energy loss in scintillators, coincidental events and reconstruction of the incident angle of the muon, calculations of the light detection efficiency with silicon photomultiplier (SiPM) arrays will be presented. The design of the final muon tracker module is based on those studies and the given parameters by the glass sphere it will be deployed in. How the design is further influenced by measurements of the reflectivity and the transmission of teflon samples and reflective foil will be explained in this thesis. The main focus will be on the characterisation measurements of the SiPM arrays when illuminated with the same light pulse. The linear increase of the gain with increasing supply voltage and decreasing temperature will be derived, experimentally. Eventually, the proof of concept will be given with first results of the muon detection in the laboratory.
AGROFORESTRY: A MANAGEMENT STRATEGY FOR IMPROVING SOIL HEALTH

Soil health is one of the most important resources for sustainable agriculture, improving agro-ecosystems and environmental sustainability. Improving soil health is the only key factor for safeguarding our future food grain production. Since time immemorial everyone is busy for the production of food only without taking care of the soil. Nowadays people are more aware of good soil health after the introduction of the concept ‘sustainable agriculture’. With sustainable agriculture, one will be producing foods without compromising future production. There are certain management practices for improving soil health. Among all agroforestry system is one of the most important that can improve the soil health with safeguarding the future production. With the introduction of agroforestry, different soil physical, chemical and biological properties increase with improving the farm incomes. Agroforestry is the combined venture of forestry, horticulture, agriculture and vetenarary. With the inclusion of tree species with crops the production increases with increasing soil health. Biomass returns of both surface and sub-surface increases with adoption of agroforestry through leaf litter and root, respectively. With increase biomass return to soil, the soil organic matter (SOM) concentration increases which is the most important source of food to the beneficial microorganisms present in soil. With increase in population of microorganisms in soil the decomposition process as well as transformation of different nutrients in soil increases. The biomass returns also acts as mulching materials to soil reducing the impact of rain drops, which is the basic principle of conservation agriculture. With the adoption of different agroforestry systems with proper selection of tree species, certain important soil health attributes (physical, chemical and biological) increases. In short, with the adoption of agroforestry system soil health can be improved which will safeguard the sustainable food production.
Effects of Hydroxychloroquine on Proteinuria in IgA Nephropathy: A Randomized Controlled Trial.

RATIONALE & OBJECTIVE Despite optimization of renin-angiotensin-aldosterone system (RAAS) inhibition, patients with immunoglobulin A nephropathy (IgAN) and persistent proteinuria remain at risk for kidney failure. We evaluated the efficacy and safety of hydroxychloroquine (HCQ), an immunomodulator, when added to the treatment regimen of patients with IgAN. STUDY DESIGN Double-blind, randomized, placebo-controlled, phase 2 clinical trial. SETTING & PARTICIPANTS Participants had IgAN (proteinuria with protein excretion of 0.75-3.5g/d and estimated glomerular filtration rate>30mL/min/1.73m2) and were receiving optimized RAAS inhibitor therapy. INTERVENTIONS Patients were randomly assigned 1:1 to receive daily oral HCQ or a placebo for 6 months. OUTCOMES The primary outcome was percentage change in proteinuria between baseline and 6 months. RESULTS 60 participants (mean estimated glomerular filtration rate, 53.8mL/min/1.73m2; median urine protein excretion, 1.7g/d) were recruited and randomly assigned to receive HCQ (n=30) or placebo (n=30). Percentage change in proteinuria at 6 months was significantly different between the HCQ group and the placebo group (-48.4% [IQR, -64.2%, -30.5%] vs 10.0% [IQR, -38.7%, 30.6%]; P<0.001, respectively). At 6 months, median proteinuria level was significantly lower in the HCQ group than in the placebo group (0.9 [IQR, 0.6, 1.0] g/d vs 1.9 [IQR, 0.9, 2.6] g/d; P=0.002, respectively). No serious adverse events were recorded during the study in either study group. LIMITATIONS The short treatment period and lack of postwithdrawal observations limit conclusions about long-term renoprotective efficacy and safety. CONCLUSIONS HCQ in addition to optimized RAAS inhibition significantly reduced proteinuria in patients with IgAN over 6 months without evidence of adverse events. These findings require confirmation in larger treatment trials. FUNDING This study was supported by grants from a government entity, the Capital of Clinical Characteristics, and the Applied Research Fund. TRIAL REGISTRATION Registered at ClinicalTrials.gov with study number NCT02942381.
An innovative approach to screening and chemoprophylaxis among contacts of leprosy patients in low endemic settings: experiences from Cambodia

Leprosy is endemic in numerous poverty-affected communities. Many years usually pass between an infection with Mycobacterium leprae and the onset of clinical signs of leprosy. The inconspicuous first symptoms and slow progress of the disease often result in considerable delay until the diagnosis is established and treatment initiated [1]. Contributing to this delay are the generally weak health systems in areas where leprosy is endemic. Additionally, health personnel are often unfamiliar with the cardinal signs of leprosy, which can lead to misdiagnoses [2]. The introduction of multi-drug therapy (MDT) in the 1980s has resulted in a massive reduction of the number of registered leprosy patients [3, 4]. MDT drugs were first donated by the Nippon Foundation (1995–1999) and since 2000 by Novartis. Following the global achievement of “leprosy elimination as a public health problem” in 2000, the efforts to actively identify leprosy patients have been drastically scaled back in most countries. Instead, passive case detection and integration of leprosy services into the general health system have become standard [5]. Unfortunately, achieving elimination as a public health problem has not halted leprosy transmission [4, 5]. Close and long-term contact with an untreated leprosy patient is considered to be a major risk factor for infection [6]. The administration of a single dose of rifampicin (SDR) as postexposure prophylaxis (PEP) to leprosy negative contacts of recently diagnosed patients has been shown to reduce their risk of developing leprosy over the following years [7, 8]. The feasibility and impact of a combination of contact tracing, screening, and PEP with SDR is currently being evaluated in eight countries in the frame of the Leprosy Post-Exposure Prophylaxis (LPEP) program [9, 10]. Cambodia declared leprosy elimination as a public health problem in 1998. Following this milestone, leprosy control was largely halted, and the National Leprosy Elimination Program (NLEP) atrophied. One decade later, a build-up of undiagnosed leprosy patients was observed, and the concept of retrospective active case finding (RACF) campaigns or “drives” was developed. At its core, a drive is carried out by a mobile team of specifically trained leprosy experts who systematically trace the leprosy patients diagnosed in an operational district (OD) and screen their contacts. From 2011 until 2015, the contacts of all leprosy patients diagnosed across Cambodia between 2001 and 2010 were screened in the frame of 11 drives [11].
RevAMP(K)ing Mitochondria for Sarcoglycanopathy Therapeutics.

Muscular dystrophies (MDs) are a class of genetic diseases characterized by progressive weakness, degeneration, and loss of skeletal muscle. MDs vary widely in age of onset, disease severity, rate of progression, and even muscles involved, depending on the gene affected and the type of mutation that occurs in the gene. Because skeletal muscle fibers and cardiomyocytes share many of the same proteins, a large proportion of MD patients develop cardiomyopathy, which also widely ranges in severity and onset and typically progresses towards dilated cardiomyopathy (DCM). Most MD cases result from mutations of genes associated with the DGC (dystrophin-glycoprotein complex), a large protein complex that stabilizes muscle membrane integrity during contraction. This includes the most prevalent and severe MD, Duchenne muscular dystrophy (DMD), which is caused by loss of dystrophin. Additional MDs associated with this complex include limb-girdle MD 2C, 2D, 2E, and 2F, corresponding mutations in γ-, α-, β-, and δsarcoglycan glycoproteins, respectively (collectively known as sarcoglycanopathies). Limb-girdle MD 2F/δ-sarcoglycanopathy, in particular, is associated with severe DCM,1,2 and translational efforts to investigate potential therapies for this form of MD are aided by rodent models that also exhibit aggressive DCM development.3 In an age where the treatment of monogenetic diseases, including many MDs, via gene therapy is inching towards reality, the continued identification and development of effective small molecule primary and adjunct therapeutics for MDs remains a critical need for patient populations, particularly considering many gene therapeutic strategies (1) aim to only lessen disease severity, (2) face cases of autosomal-dominant (ie, dominant-negative forming) mutations, and (3) will only be effective or feasible in younger patients. In the current issue of Circulation: Heart Failure, Kanamori et al4 evaluate the efficacy of metformin, a common antidiabetic medication, as a DCM therapeutic in the Sgcd-null mouse model of limb-girdle MD2F. Incredibly, a 4-week trial of metformin in DCM-exhibiting mice reverses left ventricular dilation and functional defects to wild-type values. The authors also find metformin to reduce myocardial fibrosis and cardiomyocyte hypertrophy, as well as improve histopathology of the skeletal muscle component of the disease. These improvements in clinically meaningful end points agree with other reports of cardioprotective5 and MD-therapeutic effects6 of metformin and suggest a common mechanism may be shared to improve outcome measures in these diseases. Cellular protein and organelle quality-control mechanisms, such as the ubiquitinproteasome system and autophagy, play a major role in maintenance of homeostasis through facilitating the removal of damaged or dysfunctional molecules from the cell. The importance of these cellular disposal mechanisms is highlighted by their impairments leading to striated muscle pathology.7–9 The beneficial metaEDITORIAL
Structural effects of Diamond nanoparticles and Paclitaxel combination on calf thymus DNA

Abstract The combination effects of nanodiamonds (NDs) and Paclitaxel (PTX) on the DNA structure were examined. The UV-Visible, steady-state and time-resolved fluorescence spectroscopy, CD, viscosity and zeta potential results showed that PTX + NDs could form a complex via groove binding mechanism. The values of binding constants, ΔG° and ΔH° and ΔS° values showed that PTX + NDs interact strongly with DNA and the hydrophobic force plays main role in this interaction. The and Tm study indicated the instability of DNA in presence of PTX + NDs. This study demonstrated that NDs could enhance the effect of PTX on DNA structure as well as its affinity and binding to DNA.
Zoonotic Potential of Currently Circulating Avian Influenza Viruses

Over the past and the current centuries, human influenza pandemics have been attributable to viruses with an avian ancestry. Birds are the main source of influenza A viruses and harbour a variety of antigenic subtypes. Certain avian influenza viruses are capable for cross-species transmission including human infections. Although sustained intrehuman transmission of such viruses has not been documented so far, each human infection with avian influenza viruses provides chances for the virus adaptation towards efficient transmission within human population. Here are reviewed currently circulating avian influenza viruses that are of major significance for public
Behavioral and Structural Effects of Single and Repeat Closed-Head Injury

BACKGROUND AND PURPOSE: The effects of multiple head impacts, even without detectable primary injury, on subsequent behavioral impairment and structural abnormality is yet well explored. Our aim was to uncover the dynamic changes and long-term effects of single and repetitive head injury without focal contusion on tissue microstructure and macrostructure. MATERIALS AND METHODS: We introduced a repetitive closed-head injury rodent model (n = 70) without parenchymal lesions. We performed a longitudinal MR imaging study during a 50-day study period (T2-weighted imaging, susceptibility-weighted imaging, and diffusion tensor imaging) as well as sequential behavioral assessment. Immunohistochemical staining for astrogliosis was examined in a subgroup of animals. Paired and independent t tests were used to evaluate the outcome change after injury and the cumulative effects of impact load, respectively. RESULTS: There was no gross morphologic evidence for head injury such as skull fracture, contusion, or hemorrhage on micro-CT and MR imaging. A significant decrease of white matter fractional anisotropy from day 21 on and an increase of gray matter fractional anisotropy from day 35 on were observed. Smaller mean cortical volume in the double-injury group was shown at day 50 compared with sham and single injury (P < .05). Behavioral deficits (P < .05) in neurologic outcome, balance, and locomotor activity were also aggravated after double injury. Histologic analysis showed astrogliosis 24 hours after injury, which persisted throughout the study period. CONCLUSIONS: There are measurable and dynamic changes in microstructure, cortical volume, behavior, and histopathology after both single and double injury, with more severe effects seen after double injury. This work bridges cross-sectional evidence from human subject and pathologic studies using animal models with a multi-time point, longitudinal research paradigm.
In patients with idiopathic pulmonary fibrosis the presence of hiatus hernia is associated with disease progression and mortality

In idiopathic pulmonary fibrosis (IPF), the role of gastro-oesophageal reflux (GOR) and its treatment remain unclear [1]. Both acid and non-acid components of GOR contribute to lung inflammation and fibrosis [2, 3]. There are conflicting data on the use of proton pump inhibitors (PPIs) in IPF, which do not act on the non-acid component of GOR and may be associated with higher rates of respiratory infection [4, 5]. Hiatus hernia (HH) is strongly linked to GOR [6] and is common in IPF patients [7]. One previous study pre-dating the era of anti-fibrotic therapy found an association between HH and increased mortality in IPF [8]. However, it did not control for immunosuppressive therapy, at that time routinely used in IPF treatment but now recognised as harmful, thereby limiting the applicability to patients with IPF today. Furthermore, the impact of HH on lung function in IPF has not been reported in any study to date. The WRAP-IPF study, which randomised patients to fundoplication or medical therapy, has generated interest in the role of surgical GOR interventions [9]. Patient selection for WRAP-IPF was dependent on a positive DeMeester score, a measure of acid reflux that has not been examined in relation to IPF outcomes. We aimed to assess the impact of HH and acid reflux as measured by DeMeester score in IPF, hypothesising that HH, which is associated with both acid and non-acid GOR, may be an important contributor to IPF progression. For IPF patients, the presence of hiatus hernia is associated with lung function decline and increased mortality. This observation supports the view that hiatus hernia may influence pathogenic mechanisms involved in IPF disease progression. http://ow.ly/hPAY30omE9o
Radiation Dose Practice Audit of 6,234 Fluoroscopically-Guided Spinal Injections.

BACKGROUND Fluoroscopic imaging guidance is frequently used in performing spinal interventional techniques. Reference level standards are a quality improvement tool to help reduce radiation dose and serve as benchmarks for physicians and their technologists to achieve reasonable radiation exposure while performing fluoroscopically-guided spinal procedures. There are limited data describing radiation dose for musculoskeletal injections - in particular, spinal injections without any published reference standards. OBJECTIVE The purpose of this study is to perform a practice audit of radiation doses of fluoroscopically-guided spinal injections to establish preliminary reference levels as a quality improvement tool for potential use in future radiation reduction measures. STUDY DESIGN Retrospective, observational study. SETTINGS An academic-based subspecialty, high volume pain medicine practice. METHODS A retrospective analysis of 6,234 spinal injections of 9 different types performed by experienced practitioners between January and December 2012 was conducted under an institutional review board's approval with HIPAA compliance and waiver of informed consent. Cumulative radiation dose (in mGy) and exposure time (in seconds) distributions (percentiles) as displayed on the C-arm were calculated per injection for each type of fluoroscopically-guided spinal injection. Confidence intervals for the dose distributions were determined by using bootstrap resampling and were used to determine preliminary reference levels. RESULTS Proposed preliminary reference levels of cumulative radiation dose (in mGy) and exposure time (in seconds) for fluoroscopically-guided spinal interventional procedures are provided for lumbar transforaminal (13 mGy, 30 s), cervical transforaminal (6 mGy, 49 s), caudal epidural (12 mGy, 23s), cervical facet injection (3 mGy, 36 s), lumbar facet injection (9 mGy, 20s), interlaminar (13mGy, 39s), lumbar radiofrequency denervation (7 mGy, 17s), lumbar sympathetic block (21 mGy, 39s), cervical medial branch block (2 mGy, 25 s), lumbar medial branch block (4 mGy, 12s) and sacroiliac joint injections (18 mGy, 37s). LIMITATIONS Study performed at a single subspecialty institution using only one type of C-arm which limits generalizability. CONCLUSIONS Radiation doses and preliminary reference levels of fluoroscopically-guided interventional spine procedures performed by experienced practitioners are made available without correction for body habitus or field of view, magnification or subtraction techniques or continuous vs pulsed mode. A registry of radiation-dose data for fluoroscopically-guided interventional spine procedures would be the next step to refine this data. KEY WORDS Spinal procedures, radiation dose, patient safety.
Evaluating the effects of honey bee (Apis mellifera L.) venom on the expression of insulin sensitivity and inflammation‐related genes in co‐culture of adipocytes and macrophages

Obese adipose tissue is characterized by adipocyte hypertrophy and a massive macrophage infiltration. The interaction between macrophages with mature adipocytes releases pro‐inflammatory cytokines. This chronic inflammatory state can contribute to obesity‐related complications, such as insulin resistance, type 2 diabetes and cardiovascular disease. Therefore, we can attempt to prevent and treat obesity‐related diseases by inhibiting macrophage infiltration and blocking their interaction with adipocytes. Honey bee (Apis mellifera) venom (BV) has been reported to have anti‐inflammatory effects. Although BV is used to treat chronic inflammatory diseases, few studies have addressed its use in obesity‐associated inflammation. This study examines the inhibitory effects of BV on lipid accumulation in differentiating preadipocytes, inflammation, and insulin resistance in macrophages and adipocyte‐macrophage co‐culture system. We treated 3 T3‐L1 preadipocytes with BV during differentiation. We later measured lipid accumulation and gene expression of master adipogenic transcription factors. After RAW264.7 and 3 T3‐L1 cells were pretreated with BV, RAW264.7 cells were activated with LPS or co‐cultured with pretreated 3 T3‐L1 cells. Gene expression of pro‐inflammatory cytokines and insulin sensitizing genes was measured in these cells. BV inhibited lipid accumulation and C/EBPα and PPARγ gene expression during intermediate and late 3 T3‐L1 cell differentiation. BV also suppressed gene expression of pro‐inflammatory cytokines (COX‐2, iNOS, MCP‐1, TNF‐α, IL‐1β and IL‐6) in LPS‐stimulated macrophages, and in co‐culture of 3 T3‐L1 adipocytes and RAW264.7 macrophages. However, adiponectin and GLUT‐4 expression were both significantly increased by BV in co‐culture. These findings demonstrate that BV attenuates adipocyte hypertrophy and improves obesity‐related inflammation and insulin resistance in obese adipose tissue.
A XP e o Itaú Unibanco: dos Produtos de Investimento a Desbancarização

This teaching case presents the narrative of the acquisition of XP Investimentos by Itau Unibanco. The bank offered to buy XP Investimentos. This movement occurred shortly before the broker asked to register for its IPO (Initial Offering of Shares, acronym in English) on the Brazilian stock exchange (B3). The objective of the study is to encourage discussions of the acquisition operation for the themes of governance structure and the theory of transaction costs amid technological innovation in the Brazilian financial market. On the XP side, the plan was clear: in one stroke, stay with the asset and eliminate a competitor, and now you can not only dream of being the largest investment group in Brazil. For Itau Unibanco - the largest player in the market - it now has the XP portfolio ready and eliminates a competitor that took its market share. The case indicates discussions about the logic behind Itau Unibanco’s acquisition of XP. Still, it allows asking whether the largest bank in Brazil would not be able to develop such capacities acquired from the broker, in addition to questioning whether XP’s internalized capacities are so valuable to the point of such investment.