Miracle-dz/UniFAR-FTUs huggingface dataset:
Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS–SOS1 interaction

Significance Mutants of RAS are major oncogenes and occur in many human cancers, but efforts to develop drugs that directly inhibit the corresponding constitutively active RAS proteins have failed so far. We therefore focused on SOS1, the guanine nucleotide exchange factor (GEF) and activator of RAS. A combination of high-throughput and fragment screening resulted in the identification of nanomolar SOS1 inhibitors, which effectively down-regulate active RAS in tumor cells. In cells with wild-type KRAS, we observed complete inhibition of the RAS-RAF-MEK-ERK pathway. In a mutant KRAS cell line, SOS1 inhibition resulted in a reduction of phospho-ERK activity by 50%. Together, the data indicate that inhibition of GEFs may represent a viable approach for targeting RAS-driven tumors. Since the late 1980s, mutations in the RAS genes have been recognized as major oncogenes with a high occurrence rate in human cancers. Such mutations reduce the ability of the small GTPase RAS to hydrolyze GTP, keeping this molecular switch in a constitutively active GTP-bound form that drives, unchecked, oncogenic downstream signaling. One strategy to reduce the levels of active RAS is to target guanine nucleotide exchange factors, which allow RAS to cycle from the inactive GDP-bound state to the active GTP-bound form. Here, we describe the identification of potent and cell-active small-molecule inhibitors which efficiently disrupt the interaction between KRAS and its exchange factor SOS1, a mode of action confirmed by a series of biophysical techniques. The binding sites, mode of action, and selectivity were elucidated using crystal structures of KRASG12C–SOS1, SOS1, and SOS2. By preventing formation of the KRAS–SOS1 complex, these inhibitors block reloading of KRAS with GTP, leading to antiproliferative activity. The final compound 23 (BAY-293) selectively inhibits the KRAS–SOS1 interaction with an IC50 of 21 nM and is a valuable chemical probe for future investigations.
[testicles self examination - knowledge and abilities - survey study].

OBJECTIVE Introduction: Testicle cancer is a common malignant cancer among young men (20 to 44 years). In 90% of cases we can feel nodule or change of consistency, which means during testicles self examination we can quickly discover cancer. The aim: To estimate the level of knowledge about testicles self examination among men and also medical stuff and students. PATIENTS AND METHODS Materials and methods: We gathered the data through the internet questionnaire, which contained of 13 questions. There were 204 respondents (53% women and 47% men). 93% were related with medicine. Average age was 23,5 years old. The participation in the study was voluntary and annonymous. RESULTS Results: Only 41% of our respondents perform self examination. When asked if They every had Their testicles checked by a doctor only 33% responded positively. Most of the respondents almost correctly point out symtpoms and risk factors of testicles cancer. Only 22% of medical related respondents feel confident while performing testicles examination with the patient and just 12% of them had a chance to do it during studies. We also asked our respondents if They have ever seen a social campaign about priopriate testicles self exmiantion and 80% of them respondet negatively. CONCLUSION Conclusions: The level of education about testicles examination is on low level. Men are usually aware of the risk, but They neglect it. In most cases doctors do not examine testicles and are not confident about it. We have to put more concern to that case.
The Effect of Potential on Surface Characteristic and Corrosion Resistance of Anodic Oxide Film Formed on Commercial Pure Titanium at the Potentiodynamic-Aging Mode

Anodic oxidation treatment of commercially pure titanium was carried out at the voltages of 10, 30, 50 V in 0.5 M H2SO4 solution at the potentiodynamic-aging mode so as to obtain the effects of the anodic potential on the surface characteristic and corrosion resistance of the anodic oxide film. The influences of potential on the surface morphology, the roughness, the crystalline behavior, the chemical composition and the corrosion resistance of the anodic oxide films were investigated by using scanning electron microscopy (SEM), atomic force microscope (AFM), Raman spectrum, X-ray diffractometry (XRD), X-ray photoelectron spectroscopy (XPS), potentiodynamic polarization curves and electrode impedance spectroscopy (EIS). The results show that increasing anodic potential at the potentiodynamic-aging mode can significantly enhance thickness, flatness, crystallization, chemical stability, and corrosion resistance of anodic oxide film.
New Rigid Nicotine Analogues, Carrying a Norbornane Moiety, Are Potent Agonists of α7 and α3* Nicotinic Receptors.

A three-dimensional database search has been applied to design a series of endo- and exo-3-(pyridin-3-yl)bicyclo[2.2. 1]heptan-2-amines as nicotinic receptor ligands. The synthesized compounds were tested in radioligand binding assay on rat cortex against [3H]-cytisine and [3H]-methyllycaconitine to measure their affinity for α4β2* and α7* nicotinic receptors. The new derivatives showed some preference for the α4β2* over the α7* subtype, with their affinity being dependent on the endo/exo isomerism and on the methylation degree of the basic nitrogen. The endo primary amines displayed the lowest Ki values on both receptor subtypes. Selected compounds (1a, 2a, 3a, and 6a) were tested on heterologously expressed α4β2, α7, and α3β2 receptors and on SHSY-5Y cells. Compounds 1a and 2a showed α4β2 antagonistic properties while behaved as full agonists on recombinant α7 and on SHSY5Y cells. On the α3β2 subtype, only the chloro derivative 2a showed full agonist activity and submicromolar potency (EC50 = 0.43 μM). The primary amines described here represent new chemotypes for the α7 and α3* receptor subtypes.
The Effect of Dietary Supplementation of Vitamin E, Selenium, Zinc, Folic Acid, and N-3 Polyunsaturated Fatty Acids on Sperm Motility and Membrane Properties in Dogs

Simple Summary Practitioners look for specific treatments to solve sub-fertility, which nowadays represents a common challenge in canine reproduction. In human, as well as in veterinary medicine, several dietary protocols have been developed to relieve poor sperm concentration and function. They both are constraining factors of breeding programs. Particularly, food supplementation should include micronutrients and anti-oxidants in balanced amounts, exploiting their synergistic actions. Thus, the cumulative effect of vitamin E, selenium, zinc, folic acid, and n-3 polyunsaturated fatty acids (PUFA) on sperm motility and membrane properties was investigated in healthy normospermic dogs. Results of a 90-day-long supplementation period were compared to a control group, not receiving any dietary integration. The positive results obtained in healthy subjects on sperm motility and membrane properties lead us to consider the opportunity to further use the dietary strategy to improve seminal parameters in sub-fertile dogs, too, as reported for other species. Food supplementation and a balanced diet can be pointed out as cheap and safe alternatives within an innovative multimodal approach to improve reproductive performances in healthy dogs. Abstract Sub-fertility represents a common challenge in canine reproduction. Different protocols, supplementing daily given quantities of micronutrients, were investigated to improve poor sperm concentration and/or function, which represent breeding major constraining factors in the canine species. Little information is available for dogs concerning the effect of a daily supplementation with a complex of vitamin E, zinc, selenium, folic acid, and n-3 polyunsaturated fatty acids (PUFA) on semen quality. Thus, the present study investigated this effect on semen motility and sperm membrane properties. Serial semen analyses from fourteen healthy normospermic dogs, fed with the same commercial diet, were performed on Days 0 (T0), 30 (T30), 60 (T60), and 90 (T90). Seven dogs were randomly included in the treatment (T) group, receiving a supplementation of vitamin E, zinc, selenium, folic acid, n-3 PUFA; and seven other subjects composed the control (C) group. Total Sperm Count (TSC), Computer-Assisted Sperm Analysis (CASA) indexes, mortality, and functional membrane integrity were assessed. The ANOVA compared results between groups and sampling times (p < 0.05). From T60, the supplementation significantly improved TSC, progressive motility, functional membrane integrity, and decreased mortality. Present results lead us to consider ameliorative effects of a two-month healthy diet supplementation on canine spermatozoa. The positive effects of the described balanced integration of micronutrients on sperm motility and prevention of oxidative stress should be considered, especially when decreased seminal parameters may result from inadequate intake, reduced absorption, increased losses or demand, or to attenuate the impact of age.
Role of CsrA in stress responses and metabolism important for Salmonella virulence revealed by integrated transcriptomics

To cause infection, Salmonella must survive and replicate in host niches that present dramatically different environmental conditions. This requires a flexible metabolism and physiology, responsive to conditions of the local milieu. The sequence specific RNA binding protein CsrA serves as a global regulator that governs gene expression required for pathogenicity, metabolism, biofilm formation, and motility in response to nutritional conditions. Its activity is determined by two noncoding small RNAs (sRNA), CsrB and CsrC, which sequester and antagonize this protein. Here, we used ribosome profiling and RNA-seq analysis to comprehensively examine the effects of CsrA on mRNA occupancy with ribosomes, a measure of translation, transcript stability, and the steady state levels of transcripts under in vitro SPI-1 inducing conditions, to simulate growth in the intestinal lumen, and under in vitro SPI-2-inducing conditions, to simulate growth in the Salmonella containing vacuole (SCV) of the macrophage. Our findings uncovered new roles for CsrA in controlling the expression of structural and regulatory genes involved in stress responses, metabolism, and virulence systems required for infection. We observed substantial variation in the CsrA regulon under the two growth conditions. In addition, CsrB/C sRNA levels were greatly reduced under the simulated intracellular conditions and were responsive to nutritional factors that distinguish the intracellular and luminal environments. Altogether, our results reveal CsrA to be a flexible regulator, which is inferred to be intimately involved in maintaining the distinct gene expression patterns associated with growth in the intestine and the macrophage.
A Short Study Exploring the Effect of the Glycaemic Index of the Diet on Energy intake and Salivary Steroid Hormones

Background: The glycaemic index or load (GI or GL) is a concept for ranking carbohydrate-rich foods based on the postprandial blood glucose response compared with a reference food (glucose). Due to the limited research investigating the effect of the GI or GL of the diet on salivary steroidal hormones, this explorative short study was conducted. Methods: 12 female participants consumed a low GI and a high GI diet for three days each, followed by a washout period between each intervention. Saliva was collected at baseline, and following the low or high GI diets. Cortisol and testosterone concentrations were measured by enzyme-linked immuno-sorbent assay (ELISA). Results: GI and GL were significantly different between the low and high GI diets (p < 0.001). There was a small but significant increase in salivary cortisol after the high GI diet (7.38 to 10.93 ng/mL, p = 0.036). No effect was observed after the low GI diet. Higher levels of testosterone were produced after the low GI diet (83.7 to 125.9 pg/mL, p = 0.002), and no effect was found after the high GI diet. The total intake of calories consumed on the low GI diet was significantly lower compared to the high GI diet (p = 0.019). Conclusions: A low GI diet was associated with a small but significant increase in salivary testosterone, while a high GI diet increased cortisol levels. Altering the GI of the diet may influence overall energy intake and the health and wellbeing of female volunteers.
Characterization of recombinant fructose-1,6-bisphosphatase gene mutations: evidence of inhibition/activation of FBPase protein by gene mutation

Specific residues of the highly regulated fructose-1,6-bisphosphatase (FBPase) enzyme serve as important contributors to the catalytic activity of the enzyme. Previous clinical studies exploring the genetic basis of hypoglycemia revealed two significant mutations in the coding region of the FBPase gene in patients with hypoglycemia, linking the AMP-binding site to the active site of the enzyme. In the present study, a full kinetic analysis of similar mutants was performed. Kinetic results of mutants Y164A and M177A revealed an approximate two to three-fold decrease in inhibitory constants (Ki’s) for natural inhibitors AMP and fructose-2,6-bisphosphate (F2,6-BP) compared with the Wild-type enzyme (WT). A separate mutation (M248D) was performed in the active site of the enzyme to investigate whether the enzyme could be activated. This mutant displayed an approximate seven-fold increase in Ki for F2,6-BP. Interfacial mutants L56A and L73A exhibited an increase in Ki for F2,6-BP by approximately five-fold. Mutations in the AMP-binding site (K112A and Y113A) demonstrated an eight to nine-fold decrease in AMP inhibition. Additionally, mutant M248D displayed a four-fold decrease in its apparent Michelis constant (Km), and a six-fold increase in catalytic efficiency (CE). The importance—and medical relevance—of specific residues for FBPase structural/functional relationships in both the catalytic site and AMP-binding site is discussed.
Influences of light and humidity on carbonyl sulfide-based estimates of photosynthesis

Significance Carbonyl sulfide (COS) measurements enable quantification of terrestrial photosynthesis, which cannot be directly measured at scales greater than the leaf level. The accuracy of COS-based estimates of gross primary production (GPP) depends on how we relate the COS uptake to that of CO2. This study shows that COS-based GPP estimates will be significantly overestimated if the different environmental responses of COS and CO2 uptake are not taken into account. These findings are relevant for studies that rely on COS to quantify ecosystem to regional scale GPP, and support the use of a COS-based approach to constrain ecosystem flux partitioning. Moreover, the strong stomatal control on COS uptake shown in this study makes COS a suitable tracer for stomatal diffusion. Understanding climate controls on gross primary productivity (GPP) is crucial for accurate projections of the future land carbon cycle. Major uncertainties exist due to the challenge in separating GPP and respiration from observations of the carbon dioxide (CO2) flux. Carbonyl sulfide (COS) has a dominant vegetative sink, and plant COS uptake is used to infer GPP through the leaf relative uptake (LRU) ratio of COS to CO2 fluxes. However, little is known about variations of LRU under changing environmental conditions and in different phenological stages. We present COS and CO2 fluxes and LRU of Scots pine branches measured in a boreal forest in Finland during the spring recovery and summer. We find that the diurnal dynamics of COS uptake is mainly controlled by stomatal conductance, but the leaf internal conductance could significantly limit the COS uptake during the daytime and early in the season. LRU varies with light due to the differential light responses of COS and CO2 uptake, and with vapor pressure deficit (VPD) in the peak growing season, indicating a humidity-induced stomatal control. Our COS-based GPP estimates show that it is essential to incorporate the variability of LRU with environmental variables for accurate estimation of GPP on ecosystem, regional, and global scales.
The Oxysterol 25-Hydroxycholesterol Inhibits Replication of Murine Norovirus

Cholesterol, an essential component of mammalian cells, is also an important factor in the replicative-cycles of several human and animal viruses. The oxysterol, 25-hydroxycholesterol, is produced from cholesterol by the enzyme, cholesterol 25-hydroxylase. 25-hydroxycholesterol (25-HC) has been shown to have anti-viral activities against a wide range of viruses, including a range of positive-sense RNA viruses. In this study, we have investigated the role of 25-HC in norovirus replication using murine norovirus (MNV) as a model system. As a control, we employed herpes simplex virus-1 (HSV-1), a pathogen previously shown to be inhibited by 25-HC. Consistent with previous studies, 25-HC inhibited HSV-1 replication in the MNV-susceptible cell line, RAW264.7. Treating RAW264.7 cells with sub-cytotoxic concentrations of 25-HC reduced the MNV titers. However, other sterols such as cholesterol or the oxysterol, 22-S-hydroxycholesterol (22-S-HC), did not inhibit MNV replication. Moreover, treating MNV-infected RAW264.7 cells with 25-HC-stimulated caspase 3/7 activity, which leads to enhanced apoptosis and increased cell death. Our study adds noroviruses to the list of viruses inhibited by 25-HC and begins to offer insights into the mechanism behind this inhibition.
Which osteoarthritic gait features recover following total knee replacement surgery?

Background Gait analysis can be used to measure variations in joint function in patients with knee osteoarthritis (OA), and is useful when observing longitudinal biomechanical changes following Total Knee Replacement (TKR) surgery. The Cardiff Classifier is an objective classification tool applied previously to examine the extent of biomechanical recovery following TKR. In this study, it is further developed to reveal the salient features that contribute to recovery towards healthy function. Methods Gait analysis was performed on 30 patients before and after TKR surgery, and 30 healthy controls. Median TKR follow-up time was 13 months. The combined application of principal component analysis (PCA) and the Cardiff Classifier defined 18 biomechanical features that discriminated OA from healthy gait. Statistical analysis tested whether these features were affected by TKR surgery and, if so, whether they recovered to values found for the controls. Results The Cardiff Classifier successfully discriminated between OA and healthy gait in all 60 cases. Of the 18 discriminatory features, only six (33%) were significantly affected by surgery, including features in all three planes of the ground reaction force (p<0.001), ankle dorsiflexion moment (p<0.001), hip adduction moment (p=0.003), and transverse hip angle (p=0.007). All but two (89%) of these features remained significantly different to those of the control group after surgery. Conclusions This approach was able to discriminate gait biomechanics associated with knee OA. The ground reaction force provided the strongest discriminatory features. Despite increased gait velocity and improvements in self-reported pain and function, which would normally be clinical indicators of recovery, the majority of features were not affected by TKR surgery. This TKR cohort retained pre-operative gait patterns; reduced sagittal hip and knee moments, decreased knee flexion, increased hip flexion, and reduced hip adduction. The changes that were associated with surgery were predominantly found at the ankle and hip, rather than at the knee.
Communication Training

&NA; Needs among oncology nurses across the cancer continuum Figure. No Caption available. BACKGROUND: Oncology nurses are responsible for communication‐aimed prognosis, patient education about cancer care and treatment, survivorship, and care coordination. Communication difficulties and uncomfortable communication topics put nurses at risk for compassion fatigue. OBJECTIVES: Supporting nurse communication skills requires institutional policies and structures to foster patient‐centered communication. This study reports on communication training needs for oncology nurses to inform future development of communication curricula and institutional training. METHODS: A national survey of oncology nurse teams (N = 355) attending one of four communication training courses was used. Surveys were used to evaluate institutions’ current patient‐centered communication practices and to ascertain institutional communication training needs. FINDINGS: Nurses’ role in communicating prognosis remains unclear, and training is needed for discussing survivorship. Curriculum development should be congruent with institutionally defined roles for nurse communication.
The performance of sulphur doped activated carbon supercapacitors prepared from waste tea

ABSTRACT The pore structure, high surface area and good conductivity are the key properties for the electrochemical double layer based supercapacitors. The activated carbons were produced from the waste tea, utilising microwave pretreatment with H3PO4 and activation at 450°C. Sodium thiosulfate pentahydrate (Na2S2O3·5H2O) was used as sulphur doping agent at 800°C to enhance conductivity of the activated carbons. Supercapacitor electrodes were prepared from both the activated carbon (WTAC) and sulphur doped activated carbon (WTAC-S) samples and the electrochemical performances were tested in the presence of 6 M KOH and 1 M H2SO4 as electrolytes. The activated carbon samples were characterised by Brunauer–Emmett–Teller (BET) surface area, Scanning Electron Microscopy/Energy Dispersive X-Ray Spectroscopy (SEM/EDS) and Fourier Transform Infrared Spectroscopy (FTIR) analysis techniques. The electrochemical performance analyses were performed by galvanostatic charge–discharge (GCD), cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) methods. The specific capacitance values of the WTAC and WTAC-S samples under the 1 A g−1 current density were found to be 89.3, 144.7 F g−1 for KOH electrolyte and 73.8 and 101.9 F g−1 for H2SO4 electrolyte, respectively. The results show that the sulphur doping process enhances the electrochemical performance of activated carbon samples. GRAPHICAL ABSTRACT
Application of provincial data in mathematical modelling to inform sub-national tuberculosis program decision-making in South Africa

South Africa has the highest tuberculosis (TB) disease incidence rate in the world, and TB is the leading infectious cause of death. Decisions on, and funding for, TB prevention and care policies are decentralised to the provincial governments and therefore, tools to inform policy need to operate at this level. We describe the use of a mathematical model planning tool at provincial level in a high HIV and TB burden country, to estimate the impact on TB burden of achieving the 90-(90)-90 targets of the Stop TB Partnership Global Plan to End TB. “TIME Impact” is a freely available, user-friendly TB modelling tool. In collaboration with provincial TB programme staff, and the South African National TB Programme, models for three (of nine) provinces were calibrated to TB notifications, incidence, and screening data. Reported levels of TB programme activities were used as baseline inputs into the models, which were used to estimate the impact of scale-up of interventions focusing on screening, linkage to care and treatment success. All baseline models predicted a trend of decreasing TB incidence and mortality, consistent with recent data from South Africa. The projected impacts of the interventions differed by province and were greatly influenced by assumed current coverage levels. The absence of provincial TB burden estimates and uncertainty in current activity coverage levels were key data gaps. A user-friendly modelling tool allows TB burden and intervention impact projection at the sub-national level. Key sub-national data gaps should be addressed to improve the quality of sub-national model predictions.