Miracle-dz/UniFAR-FTUs huggingface dataset:
TOR complex 1 regulates the yeast plasma membrane proton pump and pH and potassium homeostasis

We have identified in yeast a connection between two master regulators of cell growth: a biochemical connection involving the TORC1 protein kinase (which activates protein synthesis, nutrient uptake, and anabolism) and a biophysical connection involving the plasma membrane proton‐pumping H+‐ATPase Pma1 (which drives nutrient and K+ uptake and regulates pH homeostasis). Raising the temperature to nonpermissive values in a TOR thermosensitive mutant decreases Pma1 activity. Rapamycin, a TORC1 inhibitor, inhibits Pma1 dependent on its receptor Fpr1 and on the protein phosphatase Sit4, a TORC1 effector. Mutation of either Sit4 or Tco89, a nonessential subunit of TORC1, decreases proton efflux, K+ uptake, intracellular pH, cell growth, and tolerance to weak organic acids. Tco89 does not affect Pma1 activity but activates K+ transport.
Interspecies hormonal control of host root morphology by parasitic plants

Significance Parasitic plants are pests of many plants, including major crop species. An important step toward creating resistance to parasitic plants is gaining a better understanding of how these pathogens control the physiology and development of their hosts. We combined genetic, cell-biological, and biochemical methods to identify the plant hormone cytokinin as a mobile signal between the hemiparasitic plant Phtheirospermum japonicum and the host Arabidopsis thaliana. Transport of parasite-derived cytokinins induced morphological changes in host roots, revealing insights into how parasitic plants manipulate host development and laying the foundation for future explorations for bioactive molecule transfer from parasitic plants to hosts. Parasitic plants share a common anatomical feature, the haustorium. Haustoria enable both infection and nutrient transfer, which often leads to growth penalties for host plants and yield reduction in crop species. Haustoria also reciprocally transfer substances, such as RNA and proteins, from parasite to host, but the biological relevance for such movement remains unknown. Here, we studied such interspecies transport by using the hemiparasitic plant Phtheirospermum japonicum during infection of Arabidopsis thaliana. Tracer experiments revealed a rapid and efficient transfer of carboxyfluorescein diacetate (CFDA) from host to parasite upon formation of vascular connections. In addition, Phtheirospermum induced hypertrophy in host roots at the site of infection, a form of enhanced secondary growth that is commonly observed during various parasitic plant–host interactions. The plant hormone cytokinin is important for secondary growth, and we observed increases in cytokinin and its response during infection in both host and parasite. Phtheirospermum-induced host hypertrophy required cytokinin signaling genes (AHK3,4) but not cytokinin biosynthesis genes (IPT1,3,5,7) in the host. Furthermore, expression of a cytokinin-degrading enzyme in Phtheirospermum prevented host hypertrophy. Wild-type hosts with hypertrophy were smaller than ahk3,4 mutant hosts resistant to hypertrophy, suggesting hypertrophy improves the efficiency of parasitism. Taken together, these results demonstrate that the interspecies movement of a parasite-derived hormone modified both host root morphology and fitness. Several microbial and animal plant pathogens use cytokinins during infections, highlighting the central role of this growth hormone during the establishment of plant diseases and revealing a common strategy for parasite infections of plants.
Does electronic medication reconciliation at hospital discharge decrease prescription medication errors?

PURPOSE Medication errors are an important patient safety issue. Electronic medication reconciliation is a system designed to correct medication discrepancies at transitions in healthcare. The purpose of this paper is to measure types and prevalence of intravenous antibiotic errors at hospital discharge before and after the addition of an electronic discharge medication reconciliation tool (EDMRT). DESIGN/METHODOLOGY/APPROACH A retrospective study was conducted at a tertiary hospital where house officers order discharge medications. In total, 100 pre-EDMRT and 100 post-EDMRT subjects were randomly recruited from the study center's clinical Outpatient Parenteral Antimicrobial Therapy (OPAT) program. Using infectious disease consultant recommendations as gold standard, each antibiotic listed in these consultant notes was compared to the hospital discharge orders to ascertain the primary outcome: presence of an intravenous antibiotic error in the discharge orders. The primary covariate of interest was pre- vs post-EDMRT group. After generating the crude prevalence of antibiotic errors, logistic regression accounted for potential confounding: discharge day (weekend vs weekday), average years of practice by prescribing physician, inpatient service (medicine vs surgery) and number of discharge mediations per patient. FINDINGS Prevalence of medication errors decreased from 30 percent (30/100) among pre-EDMRT subjects to 15 percent (15/100) errors among post-EDMRT subjects. Dosage errors were the most common type of medication error. The adjusted odds ratio of discharge with intravenous antibiotic error in the post-EDMRT era was 0.39 (0.18, 0.87) compared to the pre-EDMRT era. In the adjusted model, the total number of discharge medications was associated with increased OR of discharge error. ORIGINALITY/VALUE To the authors' knowledge, no other study has examined the impact of reconciliation on types and prevalence of medication errors at hospital discharge. The focus on intravenous antibiotics as a class of high-stakes medications with serious risks to patient safety during error events highlights the clinical importance of the findings. Electronic medication reconciliation may be an important tool in efforts to improve patient safety.
Quantitative assessment of HLA-DQ gene polymorphisms with the development of hepatitis B virus infection, clearance, liver cirrhosis, and hepatocellular carcinoma

Hepatitis B is one of the most common infectious diseases, which leads to public health problems in the world, especially in Asian counties. In recent years, extensive human genetic association studies have been carried out to identify susceptible genes and genetic polymorphisms to understand the genetic contributions to the disease progression of HBV infection. HLA-DQ gene variations have been reported to be associated with HBV infection/clearance, disease progression and the development of hepatitis B-related complications, including liver cirrhosis (LC) and hepatocellular carcinoma (HCC). However, the results are either inconclusive or controversial. Therefore, to derive a more precise estimation of the association, a meta-analysis was performed. Our data revealed that the HLA-DQ alleles rs2856718-G, rs7453920-A and rs9275319-G were significantly associated with decreased risk of HBV infection and HBV natural clearance. Logistic regression analyses showed that HLA-DQ alleles rs9275572-A significantly increased HBV infection clearance, and decreased HBV natural clearance. However, rs2856718-G and rs9275572-A were not associated with development of cirrhosis. The HLA-DQ polymorphisms (rs2856718 and rs9275572) were associated with a decreased HBV-related HCC risk in all genetic models, but rs9272105-A increased the risk of HBV-related HCC. In addition, no significant association was observed between HLA-DQ rs9275319-G polymorphism and HBV-related HCC. These stratified analyses were limited due to relatively modest size of correlational studies. In future, further investigation on a large population and different ethnicities are warranted. Our findings contribute to the personalized care and prognosis in hepatitis B.
Preclinical efficacy and biological effects of the oral proteasome inhibitor ixazomib in diffuse large B-cell lymphoma

Despite advances in deciphering the molecular pathogenesis of diffuse large B-cell lymphoma (DLBCL), patients with relapsed/refractory disease, particularly those with adverse genetic features (e.g., mutated p53 or double hit lymphoma (DHL)) have very poor prognoses, and effective therapies are lacking. In this study we examined the preclinical efficacy and associated biological effects of the first oral proteasome inhibitor, ixazomib, in DLBCL in vitro and in vivo models. We demonstrated that ixazomib exhibited anti-tumor activities in 28 representative DLBCL cell lines, 10 primary DLBCL samples, and a DHL xenotransplant mouse model, at clinically achievable drug concentrations. Ixazomib sensitivity in DLBCL cells is correlated with immunoproteasomal activity; stimulating lymphoma cells with interferon gamma induced immunoproteasome activity and sensitized these cells to ixazomib. In addition, we showed that ixazomib induces apoptosis and the DNA damage response pathway, through activation of the checkpoint kinase 2 (CHK2). Hence, pharmacological inhibition of CHK2 enhances the anti-tumor activity of ixazomib in DLBCL cells. Our results indicate that ixazomib is an effective proteasome inhibitor active in DLBCL, including DHL, and its combination with a CHK2 inhibitor offers a potentially more robust therapeutic regimen for treatment-resistant DLBCL.
20-Hz Flicker Stimulus Can Isolate the Cone Function in Rat Retina

Cone electroretinograms (ERGs) are typically isolated in humans by flicker stimuli against rod-desensitizing adapting fields. To investigate the manner in which adapting-field luminance affects the cone ERGs, we recorded ERGs in normal albino Sprague-Dawley rats with flicker stimuli presented against adapting fields that ranged in luminance from –∞ to 1.75 log cd/m2. A flicker rate of 20 Hz was used to isolate the cone ERGs under all adaptation conditions. We found the amplitudes of cone ERGs to increase with increasing adapting-field luminance. These response characteristics are similar to human ERGs using 30-Hz flicker stimuli, which suggests that flicker stimuli are a useful technique to isolate the cone function in rats.
Anxiety Comorbidity in Referred Children and Adolescents with Dysthymic Disorder

Anxiety disorders are common in patients with depressive disorders. This preliminary study investigated some clinical correlates of comorbidity between dysthymic disorder (DD) and generalized anxiety disorder (GAD) in a clinically referred sample of children and adolescents. After psychiatric evaluation, including a diagnostic clinical interview (DICA-R), 51 patients (25 males and 26 females, mean age 13.1 years) with an index diagnosis of DD associated with GAD were compared with 22 patients (13 males and 9 females, mean age 12.9 years) diagnosed as having pure DD. The comparison between subjects (DD with or without GAD) regarding the number of depressive symptoms did not show a significant main effect of group. Suicidal ideation was significantly more frequent in the group with comorbid GAD. Internalizing disorders were more frequent in the group of DD with GAD, while externalizing disorders were more frequent in the group without GAD. Functional impairment, assessed with the Children’s Global Assessment Scale, did not show significant differences between the two groups. Data are discussed in the light of conceptualizations about the relationship between chronic anxiety and depressive disorders.
Development of a Rapid Fluorescence-Based High-Throughput Screening Assay to Identify Novel Kynurenine 3-Monooxygenase Inhibitor Scaffolds

Kynurenine 3-monooxygenase (KMO) is a well-validated therapeutic target for the treatment of neurodegenerative diseases, including Alzheimer’s disease (AD) and Huntington’s disease (HD). This work reports a facile fluorescence-based KMO assay optimized for high-throughput screening (HTS) that achieves a throughput approximately 20-fold higher than the fastest KMO assay currently reported. The screen was run with excellent performance (average Z′ value of 0.80) from 110,000 compounds across 341 plates and exceeded all statistical parameters used to describe a robust HTS assay. A subset of molecules was selected for validation by ultra-high-performance liquid chromatography, resulting in the confirmation of a novel hit with an IC50 comparable to that of the well-described KMO inhibitor Ro-61-8048. A medicinal chemistry program is currently underway to further develop our novel KMO inhibitor scaffolds.
Selective Oestrogen Receptor Modulators Differentially Potentiate Brain Mitochondrial Function

The mitochondrial energy‐transducing capacity of the brain is important for long‐term neurological health and is influenced by endocrine hormone responsiveness. The present study aimed to determine the role of oestrogen receptor (ER) subtypes in regulating mitochondrial function using selective agonists for ERα (propylpyrazoletriol; PPT) and ERβ (diarylpropionitrile; DPN). Ovariectomised female rats were treated with 17β‐oestradiol (E2), PPT, DPN or vehicle control. Both ER selective agonists significantly increased the mitochondrial respiratory control ratio and cytochrome oxidase (COX) activity relative to vehicle. Western blots of purified whole brain mitochondria detected ERα and, to a greater extent, ERβ localisation. Pre‐treatment with DPN, an ERβ agonist, significantly increased ERβ association with mitochondria. In the hippocampus, DPN activated mitochondrial DNA‐encoded COX I expression, whereas PPT was ineffective, indicating that mechanistically ERβ, and not ERα, activated mitochondrial transcriptional machinery. Both selective ER agonists increased protein expression of nuclear DNA‐encoded COX IV, suggesting that activation of ERβ or ERα is sufficient. Selective ER agonists up‐regulated a panel of bioenergetic enzymes and antioxidant defence proteins. Up‐regulated proteins included pyruvate dehydrogenase, ATP synthase, manganese superoxide dismutase and peroxiredoxin V. In vitro, whole cell metabolism was assessed in live primary cultured hippocampal neurones and mixed glia. The results of analyses conducted in vitro were consistent with data obtained in vivo. Furthermore, lipid peroxides, accumulated as a result of hormone deprivation, were significantly reduced by E2, PPT and DPN. These findings suggest that the activation of both ERα and ERβ is differentially required to potentiate mitochondrial function in brain. As active components in hormone therapy, synthetically designed oestrogens as well as natural phyto‐oestrogen cocktails can be tailored to improve brain mitochondrial endpoints.
Lethal Infection of K18-hACE2 Mice Infected with Severe Acute Respiratory Syndrome Coronavirus

ABSTRACT The severe acute respiratory syndrome (SARS), caused by a novel coronavirus (SARS-CoV), resulted in substantial morbidity, mortality, and economic losses during the 2003 epidemic. While SARS-CoV infection has not recurred to a significant extent since 2003, it still remains a potential threat. Understanding of SARS and development of therapeutic approaches have been hampered by the absence of an animal model that mimics the human disease and is reproducible. Here we show that transgenic mice that express the SARS-CoV receptor (human angiotensin-converting enzyme 2 [hACE2]) in airway and other epithelia develop a rapidly lethal infection after intranasal inoculation with a human strain of the virus. Infection begins in airway epithelia, with subsequent alveolar involvement and extrapulmonary virus spread to the brain. Infection results in macrophage and lymphocyte infiltration in the lungs and upregulation of proinflammatory cytokines and chemokines in both the lung and the brain. This model of lethal infection with SARS-CoV should be useful for studies of pathogenesis and for the development of antiviral therapies.
Pure Sensory Syndromes in Thalamic Stroke

We studied 25 patients with an acute thalamic stroke (infarct or hemorrhage) on CT or MRI scan and sensory dysfunction, among the 3,628 patients with first-time stroke included in the Lausanne Stroke Registry. Twelve patients had a right-sided infarct, 11 a left-sided infarct, and 2 a left-sided thalamic hemorrhage. Sensory symptoms or signs were the only clinical abnormality. The presumed causes of stroke were small artery disease in 21 patients including both cases of hemorrhage, emboligenic heart disease in 2, while the etiology of ischemic stroke was undetermined in 2 patients. Nine patients had a loss of all modalities of sensation with faciobrachiocrural distribution, 5 patients suffered dissociated sensory loss with faciobrachiocrural distribution and 11 patients showed a dissociated involvement of sensation with a partial distribution pattern. The inferolateral region (thalamogeniculate arteries) was involved in all patients. Six patients complained of pain and/or dysesthesias during the stroke; 5 of them had involvement of the nucleus ventrocaudalis (in 3 with damage to the nucleus ventro-oralis intermedius, and in one to the pulvinar) and 1 patient had involvement of the nucleus ventro-oralis intermedius. Eighteen patients complained of paresthesias in the contralateral part of the body; 16 of them had involvement of the nucleus ventrocaudalis (in 4 with damage to the nucleus ventro-oralis intermedius, in 1 with damage to the nucleus ventro-oralis intermedius, and nucleus ventro-oralis externus, and in one with damage to the nucleus parvocellularis and pulvinar). Four patients developed delayed pain and/or dysesthesias; all of them had involvement of the nucleus ventrocaudalis (in 1 with damage to the nucleus parvocellularis and pulvinar). Time lag from stroke onset to developing pain ranged from 2 to 15 days (mean 10.5 days). One patient with dissociated involvement of sensation with a partial distribution pattern had paresthesias and dissociated hemisensory loss involving position sense without pain and temperature sensations. This patient had involvement of the posterolateral part of the nucleus ventrocaudalis. In conclusion, sensory dysfunction and delayed pain are more often found in thalamic lesions that involve the nucleus ventrocaudalis, and nucleus ventro-oralis intermedius. Restricted sensory abnormalities correlate with very small lesions located in critical areas within these nuclei.
Idiopathic membranous nephropathy in patients with diabetes mellitus: a diagnostic and therapeutic quandary!

Abstract Background Proteinuria and renal dysfunction is common in diabetic patients and may occur due to variety of causes. Nondiabetic renal diseases (NDRD) account for 30% of the renal biopsies, and idiopathic membranous nephropathy (iMN) is a common non diabetic glomerular disease that can exist alone or in combination with diabetic nephropathy (DN). Immunosuppressants used in iMN may be associated with complications of worsening glycemic control and recurrent infections. There is a paucity of literature on the clinical course, outcomes and treatment adverse effects of patients with iMN and diabetes. Methods We retrospectively analyzed the data of all diabetics, evaluated for NDRD and found to have iMN, between January 2000 and June 2015 in our institute. Results A total of 134 patients with diabetes were biopsied for NDRD and 16 patients had iMN. Mean ± standard deviation age was 54 ± 11.77 years and the median duration of diabetes was 9.4 years. Twelve patients had isolated iMN and four patients had iMN coexisting with DN. Response rates of 18%, 35.71% and 63.63% were seen with Modified Ponticelli (MP) regimen, tacrolimus and mycophenolate mofetil (MMF), respectively. Five patients developed treatment-related adverse effects significant enough to necessitate a treatment change. Worsening glycemic control was the most common side effect. Adverse effects were less with the MMF compared with the MP regimen and tacrolimus. Conclusion Patients with iMN coexisting with diabetes exhibit a poor response to the MP regimen. Treatment-related toxicity is less common with MMF in comparison with the MP regimen and tacrolimus-based regimen. An almost similar response was noted with MMF and tacrolimus-based regimen but there was more withdrawal from treatment due to toxicities observed in the latter.
On the assembly of dwarf galaxies in clusters and their efficient formation of globular clusters

Galaxy clusters contain a large population of low mass dwarf elliptical galaxies whose exact origin is unclear: their colors, structural properties and kinematics differ substantially from those of dwarf irregulars in the field. We use the Illustris cosmological simulation to study differences in the assembly paths of dwarf galaxies (3e8 < M_*/M_sun < 1e10) according to their environment. We find that cluster dwarfs achieve their maximum total and stellar mass on average ~ 8 and ~ 4.5 Gyr ago (or redshifts z = 1.0 and z = 0.4, respectively), around the time of infall into the clusters. In contrast, field dwarfs not subjected to environmental stripping, reach their maximum mass at redshift z = 0. This different assembly history naturally produces a color bimodality, with blue isolated dwarfs and redder cluster dwarfs exhibiting negligible star-formation today. The cessation of star formation happens over median times 3.5-5 Gyr depending on stellar mass, and shows a large scatter (~ 1-8 Gyr), with the lower values associated with starburst events that occur at infall through the virial radius or pericentric passages. We argue that such starbursts together with the early assembly of cluster dwarfs can provide a natural explanation for the higher specific frequency of globular clusters (GCs) in cluster dwarfs, as found observationally. We present a simple model for the formation and stripping of GCs that supports this interpretation. The origin of dwarf ellipticals in clusters is, therefore, consistent with an environmentally-driven evolution of field dwarf irregulars. However the z = 0 field analogs of cluster dwarf progenitors have today stellar masses a factor ~ 3 larger --a difference arising from the early truncation of star formation in cluster dwarfs.
Somatostatin analogs in the treatment of neuroendocrine tumors: current and emerging aspects

ABSTRACT Introduction: Neuroendocrine tumors (NETs) harbor somatostatin receptors and there is a strong rationale for using somatostatin analogs (SSAs) for treatment of NETs. Areas covered: This article discusses i) pharmacology of somatostatin and its analogs; ii) antisecretory and anti-proliferative effects of SSAs in NETs; iii) efficacy and safety of emerging therapeutic regimens with first generation SSAs administered at either high doses or in combination with antineoplastic drugs; iv) efficacy and safety of pasireotide and chimeric molecules; v) efficacy of radionuclide therapy of NETs using SSAs. Expert opinion: SSAs are the first-line medical therapy for functioning and non-functioning well-differentiated NETs. In patients not responder to first generation SSAs, the increase of drug dose over the conventional regimens, the combination of SSAs with other biotherapies or molecular targeted therapies, the switch to pasireotide or the use of SSAs in radionuclide therapy may improve the therapeutic success.