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IL-6 plays a fundamental role in T cell differentiation and is strictly controlled by surface expression and shedding of IL-6R. IL-6 also acts on other cells that might affect T cell maturation. To study the impact of cell-autonomous and uncontrolled IL-6 signaling in T cells, we generated mice with a constitutively active IL-6R gp130 chain (Lgp130) expressed either in all T cells (Lgp130 × CD4Cre mice) or inducible in CD4+ T cells (Lgp130 × CD4CreERT2 mice). Lgp130 × CD4Cre mice accumulated activated T cells, including TH17 cells, in the lung, resulting in severe inflammation. Tamoxifen treatment of Lgp130 × CD4CreERT2 mice caused Lgp130 expression in 40–50% of CD4+ T cells, but mice developed lung disease only after several months. Lgp130+ CD4+ T cells were also enriched for TH17 cells; however, there was concomitant expansion of Lgp130− regulatory T cells, which likely restricted pathologic Lgp130+ T cells. In vitro, constitutive gp130 signaling in T cells enhanced but was not sufficient for TH17 cell differentiation. Augmented TH17 cell development of Lgp130+ T cells was also observed in Lgp130 × CD4CreERT2 mice infected with Staphylococcus aureus, but gp130 activation did not interfere with formation of TH1 cells against Listeria monocytogenes. Lgp130+ CD4+ T cells acquired a memory T cell phenotype and persisted in high numbers as a polyclonal T cell population in lymphoid and peripheral tissues, but we did not observe T cell lymphoma formation. In conclusion, cell-autonomous gp130 signaling alters T cell differentiation. Although gp130 signaling is not sufficient for TH17 cell differentiation, it still promotes accumulation of activated T cells in the lung that cause tissue inflammation.

Protein-ligand binding free-energy calculations using molecular dynamics (MD) simulations have emerged as a powerful tool for in silico drug design. Here, we present results obtained with the ARROW force field (FF)─a multipolar polarizable and physics-based model with all parameters fitted entirely to high-level ab initio quantum mechanical (QM) calculations. ARROW has already proven its ability to determine solvation free energy of arbitrary neutral compounds with unprecedented accuracy. The ARROW FF parameterization is now extended to include coverage of all amino acids including charged groups, allowing molecular simulations of a series of protein-ligand systems and prediction of their relative binding free energies. We ensure adequate sampling by applying a novel technique that is based on coupling the Hamiltonian Replica exchange (HREX) with a conformation reservoir generated via potential softening and nonequilibrium MD. ARROW provides predictions with near chemical accuracy (mean absolute error of ∼0.5 kcal/mol) for two of the three protein systems studied here (MCL1 and Thrombin). The third protein system (CDK2) reveals the difficulty in accurately describing dimer interaction energies involving polar and charged species. Overall, for all of the three protein systems studied here, ARROW FF predicts relative binding free energies of ligands with a similar accuracy level as leading nonpolarizable force fields.

Sir Roger Scruton nie aprobował zmian w przestrzeni miast, które zapoczątkowane zostały w XX wieku przez modernizm. W swych pismach z zakresu estetyki, w publicystyce i działalności społecznej konsekwentnie upominał się o przywrócenie „prawdziwego” miasta, w którym decyduje wspólnota mieszkańców. Celem tekstu jest prześledzenie jeo argumentacji i wykorzystanie jej do wyjaśnienia chaosu przestrzennego w Polsce. Z wielowątkowej twórczości Scrutona ograniczyłem się do trzech elementów związanych z krytyką modernizmu, rolą architekta i problemem tożsamości miasta i jego mieszkańców. Miało to doprowadzić do pokazania konserwatywnej recepty na odmianę sytuacji w mieście. Polega ona na oddaniu miasta wspólnocie mieszkańców, odbudowie przestrzeni publicznej (traktowanej jako dobro wspólne) i upomnienie się o pewne normy, które w interesie wspólnoty ograniczą leseferystyczne podejście do przestrzeni – to zasadnicze kwestie, których realizacja może wpłynąć na odmianę polskiej przestrzeni.

Background Factor XIa (FXIa) is an emerging therapeutic target, and FXIa inhibition is a promising mechanism to improve therapeutic index over current anticoagulants. Milvexian (BMS-986177/JNJ-70033093) is an oral small-molecule FXIa inhibitor. Objective Milvexian's antithrombotic efficacy was characterized in a rabbit arteriovenous (AV) shunt model of venous thrombosis and compared with the factor Xa inhibitor apixaban and the direct thrombin inhibitor dabigatran. Methods The AV shunt model of thrombosis was conducted in anesthetized rabbits. Vehicle or drugs were administered as intravenous bolus plus a continuous infusion. Thrombus weight was the primary efficacy endpoint. Ex vivo activated partial thromboplastin time (aPTT), prothrombin time (PT), and thrombin time (TT) were measured as the pharmacodynamic responses. Results Milvexian dose dependently reduced thrombus weights by 34.3 ± 7.9, 51.6 ± 6.8 (p Conclusion Results demonstrate that milvexian is an effective anticoagulant for prevention of venous thrombosis in the rabbit model, which supports the utility of milvexian in venous thrombosis, as seen in the phase 2 clinical study.

Although cisplatin remains a backbone of standard-of-care chemotherapy regimens for a variety of malignancies, its use is often associated with severe dose-limiting toxicities (DLT). Notably, 30%–40% of patients treated with cisplatin-based regimens are forced to discontinue treatment after experiencing nephrotoxicity as a DLT. New approaches that simultaneously prevent renal toxicity while improving therapeutic response have the potential to make a major clinical impact for patients with multiple forms of cancer. Here, we report that pevonedistat (MLN4924), a first-in-class NEDDylation inhibitor, alleviates nephrotoxicity and synergistically enhances the efficacy of cisplatin in head and neck squamous cell carcinoma (HNSCC) models. We demonstrate that pevonedistat protects normal kidney cells from injury while enhancing the anticancer activity of cisplatin through a thioredoxin-interacting protein (TXNIP)-mediated mechanism. Cotreatment with pevonedistat and cisplatin yielded dramatic HNSCC tumor regression and long-term animal survival in 100% of treated mice. Importantly, the combination decreased nephrotoxicity induced by cisplatin monotherapy as evidenced by the blockade of kidney injury molecule-1 (KIM-1) and TXNIP expression, a reduction in collapsed glomeruli and necrotic cast formation, and inhibition of cisplatin-mediated animal weight loss. Inhibition of NEDDylation represents a novel strategy to prevent cisplatin-induced nephrotoxicity while simultaneously enhancing its anticancer activity through a redox-mediated mechanism. Significance: Cisplatin therapy is associated with significant nephrotoxicity, which limits its clinical use. Here we demonstrate that NEDDylation inhibition with pevonedistat is a novel approach to selectively prevent cisplatin-induced oxidative damage to the kidneys while simultaneously enhancing its anticancer efficacy. Clinical evaluation of the combination of pevonedistat and cisplatin is warranted.

(1) Background: It was suspected that the COVID-19 pandemic would negatively affect health care, including cancer treatment. The aim of the study was to assess the impact of the COVID-19 pandemic on the number of radiotherapy procedures and patients treated with radical and palliative radiotherapy in Poland. (2) Methods: The study was carried out in Warmia and Masuria voivodeship. The number of procedures and treated patients one year before and in the first year of the COVID-19 pandemic were compared. (3) Results: In the first year of the COVID-19 pandemic, the number of radiotherapy procedures and cancer patients treated with radiotherapy in Warmia and Masuria voivodeship in Poland was stable compared to the period before the pandemic. The COVID-19 pandemic has not affected the ratio of palliative to radical procedures. The percentage of ambulatory and hostel procedures significantly increased with the reduction of inpatient care in the first year of the COVID-19 pandemic. (4) Conclusion: No significant decrease in patients treated with radiotherapy during the first year of the pandemic in Warmia and Masuria voivodeship in Poland could indicate the rapid adaptation of radiotherapy centers to the pandemic situation. Future studies should be carried out to monitor the situation because the adverse effects of the pandemic may be delayed.

Despite the widespread effectiveness of pneumococcal conjugate vaccines on the overall incidence of invasive pneumococcal disease, the global epidemiological landscape continues to be transformed by residual disease from non-vaccine serotypes, thus highlighting the need for vaccines with expanded disease coverage. To address these needs, we have developed V116,an investigational 21-valent non-adjuvanted pneumococcal conjugate vaccine (PCV),containingpneumococcal polysaccharides (PnPs) 3, 6A, 7F, 8, 9N, 10A, 11A,12F, 15A, 16F, 17F, 19A, 20, 22F, 23A, 23B, 24F, 31, 33F, 35B, anda de-O-acetylated 15B(deOAc15B) individually conjugated to the nontoxic diphtheria toxoid CRM197 carrier protein. Preclinical studies evaluated the immunogenicity of V116 inadult monkeys, rabbits, and mice. Following one dose, V116 was found to be immunogenic in preclinical animal species and induced functional antibodies for all serotypes included in the vaccine, in addition to cross-reactive functional antibodies to serotypes 6C and 15B. In these preclinical animal studies, the increased valency of V116 did not result in serotype-specific antibody suppression when compared to lower valent vaccines V114 or PCV13. In addition, when compared with naïve controls, splenocytes from V116 to immunized animals demonstrated significant induction of CRM197-specific T cells in both IFN-γ and IL-4 ELISPOT assays, as well as Th1 and Th2 cytokine induction through in vitro stimulation assays, thus suggesting the ability of V116 to engage T cell dependent immune response pathways to aid in development of memory B cells. V116 also demonstrated significant protection in mice from intratracheal challenge with serotype 24F, a novel serotype not contained in any currently licensed vaccine.

Purpose: To report vitrectomy with the inverted internal limiting membrane (ILM) flap technique in a patient with a full-thickness macular hole (FTMH) and Coats disease. Methods: A case and its long-term findings were analyzed. Results: A 27-year-old patient with Coats disease who was treated 5 years earlier with laser photocoagulation presented with an FTMH. Vitrectomy with the temporal inverted ILM flap technique was performed. The macular hole decreased in size on serial OCT scans but did completely close until 18 months postoperatively. The final visual acuity was 20/40 (0.3 logMAR). The patient’s vision remained stable for the next 5 years. Conclusions: Although the healing process after vitrectomy with ILM peeling and the inverted flap technique in an FTMH coexisting with Coats disease is prolonged compared with an idiopathic FTMH, it is still possible to obtain satisfactory anatomic and functional results.

Salmonella enterica and Escherichia coli are two pathogenic bacteria of worldwide importance that can infect the gastrointestinal tract. Contamination in the food supply chain is an area of concern. Animal feed may be supplemented with essential trace elements, which function as nutritional additives to promote growth & health and optimize production. Bacteria have acquired many metal resistance genes to adapt to the exposure of metals. In this study, our objectives were to evaluate in S. enterica and E. coli, the correlation between the resistance genotype and phenotype to certain heavy metals, and the ability of conjugative plasmids to transfer antimicrobial resistance genes (AMRGs) and heavy metal resistance genes (HMRGs). A total of 10 strains, five S. enterica and five E. coli, were used for this study. Minimal inhibitory concentrations (MICs) were determined for heavy metals: copper, silver, arsenic, and tellurite. The tested isolates showed resistance to copper (5/10; 50%), arsenic (7/10; 70%), and silver (9/10; 90%). Cohen’s Kappa statistics were used to analyze genotype to phenotype agreements. Among the 10 strains sampled, the accordance between geno- and phenotypic heavy metal resistance was fair for copper (kappa = 0.4), none to slight for arsenic (kappa = 0.19) and tellurite (kappa = 0), and no agreement for silver (kappa = -0.19). The transfer of HMRGs was determined in a conjugation experiment performed for all five Salmonella strains as donors using mixed broth cultures. Transconjugants were obtained only from the genotypically tellurite-resistant strain PSU-3260, which yielded a transfer frequency of 10⁻³ transconjugants per donor. In such strain, the tellurite-resistant genes reside on an IncHI2-type plasmid that shares high DNA sequence identity with known HMRG-disseminating Salmonella plasmids. Our results indicated no considerable correlation between the geno- and phenotypic resistance towards heavy metals in the sampled S. enterica and E. coli. The necessity of research in this area is supported by the lack of standardized protocols and MIC clinical breakpoints for heavy metals. KEYWORDS: Heavy metal; resistance; Salmonella; E. coli; agriculture; genotype; phenotype; MIC

Zusammenfassung Hintergrund Analysiert wurden die Patientencharakteristika und Krankheitsverläufe aller Patienten, die mit COVID-19 in der 1. und 2. Welle im HELIOS-Klinikum Krefeld behandelt wurden. Methoden Eingeschlossen wurden 84 Patienten aus der 1. Welle (11.03.2020–30.06.2020) und 344 Patienten aus der 2. Welle (01.07.2020–31.01.2021). Ergebnisse Alter, Geschlecht und Komorbiditäten der Patienten waren ähnlich, mit Ausnahme der venösen Thrombose in der Anamnese. Diese lagen in der 1. Welle häufiger vor als in der 2. Welle (6 % vs. 0,3 %, p = 0,001). Bei der Aufnahme gab es keine Unterschiede in den Ergebnissen der initialen Laborwerte (C-reaktives Protein, Leukozyten) und Blutgasanalysen zwischen beiden Gruppen. Die Behandlung unterschied sich in der Anwendung von Dexamethason und Antikoagulation. In der 1. Welle erhielt niemand Dexamethason, in der 2. Welle jedoch 52,6 % der Patienten für eine durchschnittliche Dauer von 3,6 ± 4,1 Tagen. Eine Antikoagulation mit doppelter Standardprophylaxe (2 × 40 mg niedermolekulares Heparin, subkutan) wurde in der 1. Welle bei 7,1 % und in der 2. Welle bei 30,2 % der Patienten (p = 0,002) durchgeführt. In der 1. Welle wurden mehr thromboembolische Ereignisse nach der Aufnahme diagnostiziert (19,0 % gegenüber 7,0 %, p = 0,001). Die Sterblichkeitsrate im Krankenhaus lag in der 1. Welle bei 26,2 % und in der zweiten Welle bei 15,4 % (p = 0,0234). Die meisten Todesfälle waren auf das akute Atemnotsyndrom (ARDS) zurückzuführen. Schlussfolgerung Die Patientencharakteristika unterschieden sich in der 1. und 2. COVID-19-Welle nicht, aber Antikoagulation und Dexamethason wurden in der 2. Welle häufiger eingesetzt. Darüber hinaus traten in der 2. Welle weniger thromboembolische Komplikationen auf.

The precise ages of Cenozoic basaltic rocks from 20 localities (24 samples) in south-western Poland were studied by means of the 40Ar/39Ar isotope method. Three phases of volcanic activity were identified in this area. The older, Ruphelian phase took place 31–29 Ma ago and the younger, Aquitanian phase occurred 22–21 Ma ago. Significantly younger ages (4.8–4.6 Ma: Zanclean phase) were obtained for the basalts cropping out in the vicinity of Lądek Zdrój only. Most of the analyzed basalts from the Ruphelian phase are classified as nephelinites. They occur in the area of Lausitz Masif, south of Sudetic Marginal Fault and in the Opole Depression. The volcanic rocks from the Aquitanian phase crop out in the wide area north of the Sudetic Marginal Fault. They are composed of alkali basalts. The youngest phase is represented by the basanites only. The deep discontinuous tectonic structures intersecting the areas of volcanic activity in SW Poland, parallel or oblique to the tectonic stress directions previously reconstructed for the Oligocene and Miocene in the Bohemian Massif, were most probably reactivated by an extension approximately parallel or slightly oblique to them, thus opening pathways for the migration of basaltic magma in the Sudetes and their foreland.

The existence of abnormal cytokine profile in Sjögren’s syndrome (SS) may contribute to find potential SS biomarkers and accompanying comorbidities. We aimed to investigate and compare gene expressions in the labial salivary glands of SS and of healthy subjects (HS) by means of microarray analysis. The study group comprised 8 SS patients and 8 HS in microarray analysis. The relative gene expression changes were validated with real time quantitative polymerase chain reaction in 25 SS and 20 HS. Among the differently expressed genes belonging to the “cellular response to cytokine stimulus”, “cytokine-mediated signaling pathway” and “innate immune response” ontology groups with a fold change >1.5 and with a p value < 0.05, the adiponectin, C1Q and collagen domain containing (ADIPOQ), S100 calcium binding protein A9 (S100A9), leptin receptor (LEPR), and fatty acid binding protein 4 (FABP4) gene expressions in SS group were higher than in HS. Increased expression of the assessed genes are determined by the presence of SS and the accompanying inflammation and may be a valuable diagnostic biomarker of SS. Their selected systemic effects may suggest their role as potential prognostic biomarkers of the risk of accelerated atherosclerosis and cardiovascular complications in SS.

Polyelectrolytes continue to find wide interest and application in science and engineering, including areas such as water purification, drug delivery, and multilayer thin films. We have been interested in the dynamics of small molecules in a variety of polyelectrolyte (PE) environments; in this paper, we report simulations and analysis of the small dye molecule rhodamine B (RB) in several very simple polyelectrolyte solutions. Translational diffusion of the RB zwitterion has been measured in fully atomistic, 2 μs long molecular dynamics simulations in four different polyelectrolyte solutions. Two solutions contain the common polyanion sodium poly(styrene sulfonate) (PSS), one with a 30-mer chain and the other with 10 trimers. The other two solutions contain the common polycation poly(allyldimethylammonium) chloride (PDDA), one with two 15-mers and the other with 10 trimers. RB diffusion was also simulated in several polymer-free solutions to verify its known experimental value for the translational diffusion coefficient

In this note we are going to continue investigation concerning the asymptotic behavior of some Levitan almost periodic functions or almost periodic functions in view of the Lebesgue measure as well as their convolutions with some functions naturally arising in the theory of ordinary linear differential equations. In particular, we obtain some estimations for functions (1), where $$\alpha$$ α is an irrational number of finite irrationality measure or a Liouville number. We also focus on the set of all irrational numbers for which the convolution of function (1) with function (2) exists. In particular, we characterize it from the topological and set-theoretical point of view.

Hemodynamic instability and hemorrhagic shock are frequently encountered by emergency medical services providers managing ill and injured patients during critical care transport. Although many critical care transport services commonly transfuse crystalloids and/or packed red blood cells (PRBCs), the administration of whole blood (WB) in prehospital care is currently limited. WB contains PRBCs, plasma, and platelets in a physiologic ratio to aid in oxygen delivery to tissue as well as hemostasis. This study describes a single critical care transport program's experience using WB for critically ill and injured patients and reports important clinical and safety outcomes.This study was a retrospective review of patients who were transported by a single rotor wing-based critical care transport service to 1 of 2 tertiary care receiving hospitals within a single health system. Patients who were transported between November 1, 2018, and November 30, 2019, and who received at least 1 unit of low-titer group O WB during critical care transport were included. The primary outcomes of interest included 24-hour mortality and the total 24-hour transfusion requirement. The safety outcomes included transfusion reactions, acute lung injury, acute kidney injury, and the incidence of venous thromboembolism.During the study period, there were 3,084 total patients transported by our critical care transport service. There were 71 patients who received prehospital WB, 64 of whom met the inclusion criteria. The top 3 indications for WB administration included blunt trauma (n = 27, 42.2%), gastrointestinal hemorrhage (n = 15, 23.4%), and penetrating trauma (n = 11, 17.2%). The median total number of blood components transfused within 24 hours was 4.0 (interquartile range, 2.0-9.5), and the overall 24-hour mortality rate was 21.9%.The administration of WB by emergency medical services providers to critically ill and injured patients in the prehospital setting is feasible and is associated with low incidences of adverse events and transfusion reactions. Further research is needed to elucidate the benefits of WB relative to current prehospital standards of care.

Introduction: External resorptions often occur as a lesion of inflammatory origin. The origin of the process begins on the side of the root cementum and goes towards the pulp of the tooth. The changes consist of the pathological loss of root cement, dentin, and bone surrounding the tooth. The dynamics of the process are enhanced by inflammatory or necrotic pulp changes. Aims: This study aimed to present contemporary views on the resorption of external tooth roots and the possibility of their treatment. Material and methods: The technique of observation and clinical and radiological diagnostics were used by the case-by-case method Result: Endodontic treatment was undertaken, consisting of chemo-mechanical preparation of the canal system and simultaneous obturation of the gutta percha canals with the AH + sealant and the BL thermal system. Conclusions: The applied treatment inhibited the progression of the resorption and led to the healing of periapical periodontitis.

Quantifying digestive and fermentative processes within the rumen environment has been the subject of decades of research; however, our existing research methodologies preclude time-sensitive and spatially explicit investigation of this system. To better understand the temporal and spatial dynamics of the rumen environment, real-time and in situ monitoring of various chemical and physical parameters in the rumen through implantable microsensor technologies is a practical solution. Moreover, such sensors could contribute to the next generation of precision livestock farming, provided sufficient wireless data networking and computing systems are incorporated. In this review, various microsensor technologies applicable to real-time metabolic monitoring for ruminants are introduced, including the detection of parameters for rumen metabolism, such as and requirements of the sensors are summarized with respect to the selected target parameters. Lastly, future discussed. NIFA (USDA, Washington, DC) [2019-67021- 28991]; NSF -USDA [2018-67007-28452]; NSF CPS program [2018-67007-28439, 2019-67021- 28990] Published version C.S.H. acknowledges support from NIFA (USDA, Washington, DC) through award number 2019-67021- 28991. M.G.K. and S.P. acknowledge support through the NSF -USDA award number 2018-67007-28452. R.W. acknowledges support through the NSF CPS program. U.K., H.B., R.A.N., and R.M.V. acknowledge support through grant nos. 2018-67007-28439 and 2019-67021- 28990. The authors have not stated any other conflicts of interest.

This paper describes a new approach to automatic long-term cloud resource usage planning with a novel hybrid anomaly detection mechanism. It analyzes existing anomaly detection solutions, possible improvements and the impact on the accuracy of resource usage planning. The proposed anomaly detection solution is an important part of the research, since it allows greater accuracy to be achieved in the long term. The proposed approach dynamically adjusts reservation plans in order to reduce the unnecessary load on resources and prevent the cloud from running out of them. The predictions are based on cloud analysis conducted using machine learning algorithms, which made it possible to reduce costs by about 50%. The solution was evaluated on real-life data from over 1700 virtual machines.

Peptide-based analogues of the gut-derived incretin hormone, glucagon-like peptide 1 (GLP1), stimulate insulin secretion in a glucose-dependent manner. Currently marketed GLP1 receptor (GLP1R) agonists are safe and effective in the management of Type 2 diabetes but often offer only modest weight loss. This has prompted the search for safe and effective alternatives to enhance the weight loss component of these treatments. We have demonstrated that concomitant activation GLP1R and the glucagon receptor (GCGR) can improve glucose metabolism and provide superior weight loss when compared to selective GLP1R agonism in preclinical species. This paper will highlight chemistry structure-activity relationship optimization and summarize in vivo efficacy studies toward the discovery of a once daily balanced dual agonist

Current dam discharge patterns in Noxon Rapids Reservoir reduce concentration and exposure times (CET) of herbicides used for aquatic plant management. Herbicide applications during periods of low dam discharge may increase herbicide CETs and improve efficacy. Applications of rhodamine WT dye were monitored under peak (736 to 765 m3 s−1) and minimum (1.4 to 2.8 m3 s−1) dam discharge patterns to quantify water-exchange processes. Whole-plot dye half-life under minimal discharge was 33 h, a 15-fold increase compared with the dye treatment during peak discharge. Triclopyr concentrations measured during minimum discharge within the treated plot ranged from 214 ± 25 to 1,243 ± 36 µg L−1 from 0 to 48 h after treatment (HAT), respectively. Endothall concentrations measured during minimum discharge in the same plot ranged from 164 ± 78 to 2,195 ± 1,043 µg L−1 from 0 to 48 HAT, respectively. Eurasian watermilfoil (Myriophyllum spicatum L.) occurrence in the treatment plot was 66%, 8%, and 14% during pretreatment, 5 wk after treatment (WAT), and 52 WAT, respectively. Myriophyllum spicatum occurrence in the nontreated plot was 68%, 71%, and 83% during pretreatment, 5 WAT, and 52 WAT, respectively. Curlyleaf pondweed (Potamogeton crispus L.) occurrence in the treatment plot was 29%, 0%, and 97% during pretreatment, 5 WAT, and 52 WAT, respectively. Potamogeton crispus increased from 24% to 83% at 0 WAT to 52 WAT, respectively, in the nontreated plot. Native species richness declined from 3.3 species per point to 2.1 in the treatment plot in the year of treatment but returned to pretreatment numbers by 52 WAT. Native species richness did not change during the study in the nontreated reference plot. Herbicide applications during periods of low flow can increase CETs and improve control, whereas applications during times of high-water flow would shorten CETs and could result in reduced treatment efficacy.

Cloud computing is gaining popularity among small and medium-sized enterprises. The cost of cloud resources plays a significant role for these companies and this is why cloud resource optimization has become a very important issue. Numerous methods have been proposed to optimize cloud computing resources according to actual demand and to reduce the cost of cloud services. Such approaches mostly focus on a single factor (i.e. compute power) optimization, but this can yield unsatisfactory results in real-world cloud workloads which are multi-factor, dynamic and irregular. This paper presents a novel approach which uses anomaly detection, machine learning and particle swarm optimization to achieve a cost-optimal cloud resource configuration. It is a complete solution which works in a closed loop without the need for external supervision or initialization, builds knowledge about the usage patterns of the system being optimized and filters out anomalous situations on the fly. Our solution can adapt to changes in both system load and the cloud provider's pricing plan. It was tested in Microsoft's cloud environment Azure using data collected from a real-life system. Experiments demonstrate that over a period of 10 months, a cost reduction of 85% was achieved.

Lung cancer remains the first cause of cancer-related death despite many therapeutic innovations, including immune checkpoint inhibitors (ICI). ICI are now well used in daily practice at late metastatic stages and locally advanced stages after a chemo-radiation. ICI are also emerging in the peri-operative context. However, all patients do not benefit from ICI and even suffer from additional immune side effects. A current challenge remains to identify patients eligible for ICI and benefiting from these drugs. Currently, the prediction of ICI response is only supported by Programmed death-ligand 1 (PD-L1) tumor expression with perfectible results and limitations inherent to tumor-biopsy specimen analysis. Here, we reviewed alternative markers based on liquid biopsy and focused on the most promising biomarkers to modify clinical practice, including non-tumoral blood cell count such as absolute neutrophil counts, platelet to lymphocyte ratio, neutrophil to lymphocyte ratio, and derived neutrophil to lymphocyte ratio. We also discussed soluble-derived immune checkpoint-related products such as sPD-L1, circulating tumor cells (detection, count, and marker expression), and circulating tumor DNA-related products. Finally, we explored perspectives for liquid biopsies in the immune landscape and discussed how they could be implemented into lung cancer management with a potential biological–driven decision.

Arginyl-tRNA-protein transferase 1 (ATE1) is a master regulator of protein homeostasis, stress response, cytoskeleton maintenance, and cell migration. The diverse functions of ATE1 arise from its unique enzymatic activity to covalently attach an arginine onto its protein substrates in a tRNA-dependent manner. However, how ATE1 (and other aminoacyl-tRNA transferases) hijacks tRNA from the highly efficient ribosomal protein synthesis pathways and catalyzes the arginylation reaction remains a mystery. Here, we describe the three-dimensional structures of Saccharomyces cerevisiae ATE1 with and without its tRNA cofactor. Importantly, the putative substrate binding domain of ATE1 adopts a previously uncharacterized fold that contains an atypical zinc-binding site critical for ATE1 stability and function. The unique recognition of tRNAArg by ATE1 is coordinated through interactions with the major groove of the acceptor arm of tRNA. Binding of tRNA induces conformational changes in ATE1 that helps explain the mechanism of substrate arginylation.

24 brick samples for archaeomagnetic studies were taken from teen historical buildings constructed between c.1280 AD and 1630 AD in northern Poland. Eight of them are from the gothic period. The Thellier-Thellier archaeointensity protocol was used in order to determine the ancient intensity and inclination registered by the bricks. 28 representative specimens from 16 bricks gave successful archaeointensity determination with category B of results quality. For 25 of them the corrections for anisotropy of thermoremanent magnetization and cooling rate were introduced. A large number of specimens classified as category C (48%) is due to a high value of relative additivity check error d(AC) caused most probably by the presence of multi-domain magnetite. Corrected data are convergent with the Central European master curve of archaeointensity. The corrections of raw data reduce their dispersion at specimen/sample level in most of sites.

Although cisplatin remains a backbone of standard-of-care chemotherapy regimens for a variety of malignancies, its use is often associated with severe dose-limiting toxicities (DLT). Notably, 30%–40% of patients treated with cisplatin-based regimens are forced to discontinue treatment after experiencing nephrotoxicity as a DLT. New approaches that simultaneously prevent renal toxicity while improving therapeutic response have the potential to make a major clinical impact for patients with multiple forms of cancer. Here, we report that pevonedistat (MLN4924), a first-in-class NEDDylation inhibitor, alleviates nephrotoxicity and synergistically enhances the efficacy of cisplatin in head and neck squamous cell carcinoma (HNSCC) models. We demonstrate that pevonedistat protects normal kidney cells from injury while enhancing the anticancer activity of cisplatin through a thioredoxin-interacting protein (TXNIP)-mediated mechanism. Cotreatment with pevonedistat and cisplatin yielded dramatic HNSCC tumor regression and long-term animal survival in 100% of treated mice. Importantly, the combination decreased nephrotoxicity induced by cisplatin monotherapy as evidenced by the blockade of kidney injury molecule-1 (KIM-1) and TXNIP expression, a reduction in collapsed glomeruli and necrotic cast formation, and inhibition of cisplatin-mediated animal weight loss. Inhibition of NEDDylation represents a novel strategy to prevent cisplatin-induced nephrotoxicity while simultaneously enhancing its anticancer activity through a redox-mediated mechanism.Significance:Cisplatin therapy is associated with significant nephrotoxicity, which limits its clinical use. Here we demonstrate that NEDDylation inhibition with pevonedistat is a novel approach to selectively prevent cisplatin-induced oxidative damage to the kidneys while simultaneously enhancing its anticancer efficacy. Clinical evaluation of the combination of pevonedistat and cisplatin is warranted.

qRT-PCR of selected genes in the oxidoreductase pathway.

Knockdown of NRF2 blunts pevonedistat-mediated protection from cisplatin.

Genes altered by 2 fold change or more by pevonedistat treatment.

Pevonedistat does not alter OCT2 or CTR1 expression.

Pevonedistat stabilizes NRF2 expression in RPTECs.

Combination indices following treatment with pevonedistat and cisplatin.

Median survival time of FaDu tumor bearing mice.

Quantification of IHC staining.

Significantly upregulated oxidative stress response genes by pevonedistat.

PDF file - 117KB, Supplementary figure 5: Rescue of EGFR inhibition by active Src in Fhit siRNA-treated cells. (a) Western blot analysis of phospho-Src, total Src, Fhit and Slug levels in HBE4-E6/E7 cells transduced with control or Src. (b) Analysis by Western blotting and zymography of the effect of Src overexpression on vimentin and MMP-9 levels in Fhit siRNA transfectants treated with DMSO or gefitinib.

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PDF file - 297KB, Supplementary figure 2: Representative fields of cell invasion assays. The invasive capacities of scrambled or Fhit siRNA HBE4-E6/E7 transfectants were tested in a modified Boyden chamber invasion assay either after co-transfection with Slug siRNA 1 (a) or Slug siRNA 2 (b) or in the presence of PD98059 (c), PP1 (d), Gefitinib (e) and anti-EGFR antibody (f). The respective controls for Slug siRNA, inhibitor and neutralizing antibody experiments were scrambled siRNA, DMSO and IgG1. Bar = 100 ?m.

PDF file - 99KB, Supplementary figure 1: Cell invasion induced by Fhit is Slug-dependent. (a) Analysis of the effect of Slug siRNA 2 or a scrambled siRNA on the invasive capacities of HBE4-E6/E7 transfectants in a modified Boyden chamber invasion assay. (b) Western blot and zymography analysis of the effect of Slug siRNA 2 or a scrambled siRNA on Fhit, Slug, vimentin and MMP-9 levels in HBE4-E6/E7 transfectants.

PDF file - 108KB, Supplementary figure 4: Effect of pharmacological inhibitors of various signaling pathways on cell invasion induced by Fhit silencing. HBE4-E6/E7 cells were transfected with scrambled or Fhit siRNA as described in the "Materials and Methods" section. The invasive capacities of the transfectants were tested in a modified Boyden chamber invasion assay in the presence of PD98059 (ERK), PP1 (Src), SB203580 (p38), Y27632 (ROCK), KT5720 (PKA), wortmaninn (PI3K), U73122 (PLC) or SP600125 (JNK) inhibitors. A representative experiment is shown. Data are expressed as fold induction relative to the DMSO control. *P < 0.05.

PDF file, 85KB.