Multi-product inventory managmement model with a multiple periodicity

Inventory management is of great interest to various spheres of activity. This theory is a new industry that arose in connection with the need of optimal regulation of reserves. Over the past decades, significant progress has been made in the development of various mathematical models for managing commodity and noncommodity inventories. Despite the fact that this topic is quite popular in the literature, the question of purchasing resources in conditions of their deficit remains topical. The study is devoted to the development of a multi-product inventory management model with a multiple periodicity

Simvastatin Reduces Endotoxin-Induced Acute Lung Injury by Decreasing Neutrophil Recruitment and Radical Formation

Treatment of acute lung injury (ALI) remains an unsolved problem in intensive care medicine. As simvastatin exerts protective effects in inflammatory diseases we explored its effects on development of ALI and due to the importance of neutrophils in ALI also on neutrophil effector functions. C57Bl/6 mice were exposed to aerosolized LPS (500 µg/ml) for 30 min. The count of alveolar, interstitial, and intravasal neutrophils were assessed 4 h later by flow cytometry. Lung permeability changes were assessed by FITC-dextran clearance and albumin content in the BAL fluid. In vitro, we analyzed the effect of simvastatin on neutrophil adhesion, degranulation, apoptosis, and formation of reactive oxygen species. To monitor effects of simvastatin on bacterial clearance we performed phagocytosis and bacterial killing studies in vitro as well as sepsis experiments in mice. Simvastatin treatment before and after onset of ALI reduces neutrophil influx into the lung as well as lung permeability indicating the protective role of simvastatin in ALI. Moreover, simvastatin reduces the formation of ROS species and adhesion of neutrophils without affecting apoptosis, bacterial phagocytosis and bacterial clearance. Simvastatin reduces recruitment and activation of neutrophils hereby protecting from LPS-induced ALI. Our results imply a potential role for statins in the management of ALI

IL-4 receptor alpha signaling through macrophages differentially regulates liver fibrosis progression and reversal

Chronic hepatitis leads to liver fibrosis and cirrhosis. Cirrhosis is a major cause ofworldwide morbidity and mortality. Macrophages play a key role in fibrosis progression and reversal. However, the signals that determine fibrogenic vs fibrolytic macrophage function remain ill defined. We studied the role of interleukin-4 receptor α (IL-4Rα), a potential central switch of macrophage polarization, in liver fibrosis progression and reversal. We demonstrate that inflammatory monocyte infiltration and liver fibrogenesis were suppressed in general IL-4Rα−/− aswell as in macrophage-specific IL-4Rα−/− (IL-4RαΔLysM) mice. However,with deletion of IL-4RαΔLysM spontaneous fibrosis reversal was retarded. Results were replicated by pharmacological intervention using IL-4Rα-specific antisense oligonucleotides. Retarded resolution was linked to the loss of M2-type resident macrophages, which secreted MMP-12 through IL-4 and IL-13-mediated phospho-STAT6 activation. We conclude that IL-4Rα signaling regulates macrophage functional polarization in a context-dependent manner. Pharmacological targeting of macrophage polarization therefore requires disease stage-specific treatment strategies. Research in Context: Alternative (M2-type) macrophage activation through IL-4Rα promotes liver Inflammation and fibrosis progression but speeds up fibrosis reversal. This demonstrates context dependent, opposing roles of M2-type macrophages. During reversal IL-4Rα induces fibrolytic MMPs, especially MMP-12, through STAT6. Liver-specific antisense oligonucleotides efficiently block IL-4Rα expression and attenuate fibrosis progression

COSMOS-Web: Intrinsically Luminous z≳\gtrsim10 Galaxy Candidates Test Early Stellar Mass Assembly

We report the discovery of 15 exceptionally luminous $10\lesssim z\lesssim14$ candidate galaxies discovered in the first 0.28 deg$^2$ of JWST/NIRCam imaging from the COSMOS-Web Survey. These sources span rest-frame UV magnitudes of $-20.5>M_{\rm UV}>-22$, and thus constitute the most intrinsically luminous $z\gtrsim10$ candidates identified by JWST to-date. Selected via NIRCam imaging with Hubble ACS/F814W, deep ground-based observations corroborate their detection and help significantly constrain their photometric redshifts. We analyze their spectral energy distributions using multiple open-source codes and evaluate the probability of low-redshift solutions; we conclude that 12/15 (80%) are likely genuine $z\gtrsim10$ sources and 3/15 (20%) likely low-redshift contaminants. Three of our $z\sim12$ candidates push the limits of early stellar mass assembly: they have estimated stellar masses $\sim5\times10^{9}\,M_\odot$, implying an effective stellar baryon fraction of $\epsilon_{\star}\sim0.2-0.5$, where $\epsilon_{\star}\equiv M_{\star}/(f_{b}M_{halo})$. The assembly of such stellar reservoirs is made possible due to rapid, burst-driven star formation on timescales $<$100\,Myr where the star-formation rate may far outpace the growth of the underlying dark matter halos. This is supported by the similar volume densities inferred for $M_\star\sim10^{10}\,M_\odot$ galaxies relative to $M_\star\sim10^{9}\,M_\odot$ -- both about $10^{-6}$ Mpc$^{-3}$ -- implying they live in halos of comparable mass. At such high redshifts, the duty cycle for starbursts would be of order unity, which could cause the observed change in the shape of the UVLF from a double powerlaw to Schechter at $z\approx8$. Spectroscopic redshift confirmation and ensuing constraints of their masses will be critical to understanding how, and if, such early massive galaxies push the limits of galaxy formation in $\Lambda$CDM.Comment: 30 pages, 9 figures; ApJ submitte

Unveiling the distant Universe: Characterizing z≥9z\ge9 Galaxies in the first epoch of COSMOS-Web

We report the identification of 15 galaxy candidates at $z\ge9$ using the initial COSMOS-Web JWST observations over 77 arcmin$^2$ through four NIRCam filters (F115W, F150W, F277W, F444W) with an overlap with MIRI (F770W) of 8.7 arcmin$^2$. We fit the sample using several publicly-available SED fitting and photometric redshift codes and determine their redshifts between $z=9.3$ and $z=10.9$ ($\langle z\rangle=10.0$), UV-magnitudes between M$_{\rm UV}$ = $-$21.2 and $-$19.5 (with $\langle$M$_{\rm UV}\rangle=-20.2$) and rest-frame UV slopes ($\langle \beta\rangle=-2.4$). These galaxies are, on average, more luminous than most $z\ge9$ candidates discovered by JWST so far in the literature, while exhibiting similar blue colors in their rest-frame UV. The rest-frame UV slopes derived from SED-fitting are blue ($\beta\sim$[$-$2.0, $-$2.7]) without reaching extremely blue values as reported in other recent studies at these redshifts. The blue color is consistent with models that suggest the underlying stellar population is not yet fully enriched in metals like similarly luminous galaxies in the lower redshift Universe. The derived stellar masses with $\langle \log_{\rm 10} ($M$_\star/$M$_\odot)\rangle\approx8-9$ are not in tension with the standard $\Lambda$CDM model and our measurement of the volume density of such UV luminous galaxies aligns well with previously measured values presented in the literature at $z\sim9-10$. Our sample of galaxies, although compact, are significantly resolved.Comment: Submitted to Ap

The development and validation of a scoring tool to predict the operative duration of elective laparoscopic cholecystectomy

Background: The ability to accurately predict operative duration has the potential to optimise theatre efficiency and utilisation, thus reducing costs and increasing staff and patient satisfaction. With laparoscopic cholecystectomy being one of the most commonly performed procedures worldwide, a tool to predict operative duration could be extremely beneficial to healthcare organisations. Methods: Data collected from the CholeS study on patients undergoing cholecystectomy in UK and Irish hospitals between 04/2014 and 05/2014 were used to study operative duration. A multivariable binary logistic regression model was produced in order to identify significant independent predictors of long (> 90 min) operations. The resulting model was converted to a risk score, which was subsequently validated on second cohort of patients using ROC curves. Results: After exclusions, data were available for 7227 patients in the derivation (CholeS) cohort. The median operative duration was 60 min (interquartile range 45–85), with 17.7% of operations lasting longer than 90 min. Ten factors were found to be significant independent predictors of operative durations > 90 min, including ASA, age, previous surgical admissions, BMI, gallbladder wall thickness and CBD diameter. A risk score was then produced from these factors, and applied to a cohort of 2405 patients from a tertiary centre for external validation. This returned an area under the ROC curve of 0.708 (SE = 0.013, p  90 min increasing more than eightfold from 5.1 to 41.8% in the extremes of the score. Conclusion: The scoring tool produced in this study was found to be significantly predictive of long operative durations on validation in an external cohort. As such, the tool may have the potential to enable organisations to better organise theatre lists and deliver greater efficiencies in care

Unveiling the Distant Universe: Characterizing z ≥ 9 Galaxies in the First Epoch of COSMOS-Web

We report the identification of 15 galaxy candidates at z ≥ 9 using the initial COSMOS-Web JWST observations over 77 arcmin2 through four Near Infrared Camera filters (F115W, F150W, F277W, and F444W) with an overlap with the Mid-Infrared Imager (F770W) of 8.7 arcmin2. We fit the sample using several publicly available spectral energy distribution (SED) fitting and photometric redshift codes and determine their redshifts between z = 9.3 and z = 10.9 (〈z〉 = 10.0), UV magnitudes between M UV = −21.2 and −19.5 (with 〈M UV〉 = −20.2), and rest-frame UV slopes (〈β〉 = −2.4). These galaxies are, on average, more luminous than most z ≥ 9 candidates discovered by JWST so far in the literature, while exhibiting similar blue colors in their rest-frame UV. The rest-frame UV slopes derived from SED fitting are blue (β ∼ [−2.0, −2.7]) without reaching extremely blue values as reported in other recent studies at these redshifts. The blue color is consistent with models that suggest the underlying stellar population is not yet fully enriched in metals like similarly luminous galaxies in the lower-redshift Universe. The derived stellar masses with 〈log10( M ⋆/M ⊙)〉 ≈ 8–9 are not in tension with the standard Lambda cold dark matter (ΛCDM) model, and our measurement of the volume density of such UV-luminous galaxies aligns well with previously measured values presented in the literature at z ∼ 9–10. Our sample of galaxies, although compact, is significantly resolved

Complement C5a receptor and polymorphonuclear neutrophils- accomplices in atherosclerotic lesion formation

This study focuses on understanding the role of complement C5a receptors (C5aR and C5L2), release of neutrophil extracellular traps (NETs) and the role of neutrophil granule protein (CRAMP in mouse) in atherosclerosis. Atherosclerosis is agreed to be a chronic inflammatory disease of the arterial vessel wall involving both innate and adaptive immunity. Despite considerable progress in the field of medicine, cardiovascular diseases are a major cause of death world-wide. The complement system is involved in every stage of atherosclerosis, from the onset till the development of acute thrombotic events. C5a anaphylatoxin interacts with its two functional receptors C5aR and C5L2. Receptor C5L2 has recently been identified and its role in atherosclerosis is unknown. C5aR was detected at every stage of atherosclerotic plaque with its receptor expression increasing with increasing complexity of the plaque. The pattern observed was similar with mRNA and it correlates with the receptor expression. The C5L2 receptor expression increased substantially in the late stages of atherosclerosis and then there is a gradual increase in its protein levels. The present study reveals that C5aR is expressed initially on the luminal side of the atherosclerotic vessel and C5L2 is expressed in the areas of inflammatory cell infiltrates. Also, the cells that co-express both the receptors (C5aR and C5L2) and positive for oxLDL are phagocytic in origin. Neutrophils are the first phagocytic cells that reach the injured tissue. Neutrophils on engulfing oxLDL have increased expression of C5L2. Following this, internally present C5L2 on neutrophils and is expressed on their surface. Neutrophils have been identified recently to be very important in early atherosclerosis. The mechanistic insight into neutrophil-dependent pro-atherogenic mechanism like release of NETs in atherosclerosis is unveiled in the second part of this thesis. Cytokine stimulation in murine models showed release of NETs from the neutrophils. NETs were luminally present in murine and human atherosclerosis. Atherosclerosis related compound such as oxLDL stimulates neutrophils to release NETs along with granule proteins, such as LL37 (CRAMP in mouse), bound to the released NETs. In the final part of the project the role of cathelicidin (LL37) in atherosclerosis was explored. Lack of cathelicidin reduced the accumulation of lipids in the aorta and reduced the lesion sizes with decrease in cellularity. Compared to the control (Apoe-/-), the knockout (Cramp-/-Apoe-/-) mice showed no difference in cholesterol triglyceride levels, circulating leukocyte count and apoptotic cell count. Data from single cell suspensions of aorta for CRAMP in Cramp-/-Apoe-/- and Apoe-/- mice reveal that cellular expression of CRAMP is confined to neutrophils and the activated neutrophils release CRAMP and immobilize on the endothelium. In vivo adhesion of leukocytes of the carotid artery reveals that LL37 induced adhesion of classical monocytes and neutrophils and blocking the formyl-peptide receptors with an antagonist significantly reduced the adhesion of classical monocytes and neutrophils. Thus summarizing the studies of this thesis-OxLDL stimulates neutrophils leading to the endogenous production of C5a. C5a then binds to C5aR expressed on the membrane of neutrophils. This C5a-C5aR complex exteriorizes the internally present C5L2. Moreover, increase of oxLDL stimulates the neutrophils to releases NETs via NETosis with LL37 adhering to them. The presence of NETs and granule proteins increase the inflammatory cell environment and recruit other immune cells, aiding in the progression of atherosclerosis and resulting in advanced stage plaques

Complement C5a receptor and polymorphonuclear neutrophils- accomplices in atherosclerotic lesion formation

This study focuses on understanding the role of complement C5a receptors (C5aR and C5L2), release of neutrophil extracellular traps (NETs) and the role of neutrophil granule protein (CRAMP in mouse) in atherosclerosis. Atherosclerosis is agreed to be a chronic inflammatory disease of the arterial vessel wall involving both innate and adaptive immunity. Despite considerable progress in the field of medicine, cardiovascular diseases are a major cause of death world-wide. The complement system is involved in every stage of atherosclerosis, from the onset till the development of acute thrombotic events. C5a anaphylatoxin interacts with its two functional receptors C5aR and C5L2. Receptor C5L2 has recently been identified and its role in atherosclerosis is unknown. C5aR was detected at every stage of atherosclerotic plaque with its receptor expression increasing with increasing complexity of the plaque. The pattern observed was similar with mRNA and it correlates with the receptor expression. The C5L2 receptor expression increased substantially in the late stages of atherosclerosis and then there is a gradual increase in its protein levels. The present study reveals that C5aR is expressed initially on the luminal side of the atherosclerotic vessel and C5L2 is expressed in the areas of inflammatory cell infiltrates. Also, the cells that co-express both the receptors (C5aR and C5L2) and positive for oxLDL are phagocytic in origin. Neutrophils are the first phagocytic cells that reach the injured tissue. Neutrophils on engulfing oxLDL have increased expression of C5L2. Following this, internally present C5L2 on neutrophils and is expressed on their surface. Neutrophils have been identified recently to be very important in early atherosclerosis. The mechanistic insight into neutrophil-dependent pro-atherogenic mechanism like release of NETs in atherosclerosis is unveiled in the second part of this thesis. Cytokine stimulation in murine models showed release of NETs from the neutrophils. NETs were luminally present in murine and human atherosclerosis. Atherosclerosis related compound such as oxLDL stimulates neutrophils to release NETs along with granule proteins, such as LL37 (CRAMP in mouse), bound to the released NETs. In the final part of the project the role of cathelicidin (LL37) in atherosclerosis was explored. Lack of cathelicidin reduced the accumulation of lipids in the aorta and reduced the lesion sizes with decrease in cellularity. Compared to the control (Apoe-/-), the knockout (Cramp-/-Apoe-/-) mice showed no difference in cholesterol triglyceride levels, circulating leukocyte count and apoptotic cell count. Data from single cell suspensions of aorta for CRAMP in Cramp-/-Apoe-/- and Apoe-/- mice reveal that cellular expression of CRAMP is confined to neutrophils and the activated neutrophils release CRAMP and immobilize on the endothelium. In vivo adhesion of leukocytes of the carotid artery reveals that LL37 induced adhesion of classical monocytes and neutrophils and blocking the formyl-peptide receptors with an antagonist significantly reduced the adhesion of classical monocytes and neutrophils. Thus summarizing the studies of this thesis-OxLDL stimulates neutrophils leading to the endogenous production of C5a. C5a then binds to C5aR expressed on the membrane of neutrophils. This C5a-C5aR complex exteriorizes the internally present C5L2. Moreover, increase of oxLDL stimulates the neutrophils to releases NETs via NETosis with LL37 adhering to them. The presence of NETs and granule proteins increase the inflammatory cell environment and recruit other immune cells, aiding in the progression of atherosclerosis and resulting in advanced stage plaques