Estimating the demand parameters for single period problem, Markov-modulated Poisson demand, large lot size, and unobserved lost sales

We consider a single-period single-item problem when the demand is a Markov-modulated Poisson process with hidden states, unknown intensities and continuous batch size distribution. The number of customers and lot size are assumed to be large enough. The estimators of demand mean and standard deviation for unobservable lost sales in the steady state are considered. The procedures are based on two censored samples: observed selling durations and the demands over the period. Numerical results are given

The protective effect of the spleen in sickle cell patients. A comparative study between patients with asplenia/hyposplenism and hypersplenism

Sickle cell disease (SCD) is caused by a point mutation in the beta-globin gene. SCD is characterized by chronic hemolytic anemia, vaso-occlusive events leading to tissue ischemia, and progressive organ failure. Chronic inflammatory state is part of the pathophysiology of SCD. Patients with SCD have extremely variable phenotypes, from mild disease to severe complications including early age death. The spleen is commonly injured in SCD. Early splenic dysfunction and progressive spleen atrophy are common. Splenomegaly and hypersplenism can also occur with the loss of the crucial splenic function. Acute, life-threatening spleen-related complications in SCD are well studied. The association of laboratory parameters with the spleen status including hyposplenism, asplenia, and splenomegaly/hypersplenism, and their implication in vaso-occlusive crisis and long-term complications in SCD remain to be determined. We evaluated the association between the spleen status with clinical and laboratory parameters in 31 SCD patients: Group a) Patients with asplenia/hyposplenism (N = 22) (including auto-splenectomy and splenectomized patients) vs. Group b) patients with splenomegaly and or hypersplenism (N = 9). Laboratory studies included: Complete Blood Count, reticulocyte count, iron metabolism parameters, C Reactive Protein (CRP), Hb variant distribution, and D-dimer. Metabolic and morphological red blood cell (RBC) studies included: density gradient (by Percoll), glucose consumption, lactate release, and K$^{+}$ leakage, fetal RBC (F-Cells) and F-Reticulocytes, annexinV+, CD71$^{+}$, oxidative stress measured by GSH presence in RBC and finally Howell Jolly Bodies count were all analyzed by Flow Cytometry. Scanning electron microscopy analysis of RBC was also performed. Patients with asplenia/hyposplenism showed significantly higher WBC, platelet, Hematocrit, hemoglobin S, CRP, D-dimer, Gamma Glutamyl Transferase (GGT), cholesterol, transferrin, annexin V+ RBCs, CD71$^{+}$ RBCs, together with a markedly lower F Reticulocyte levels in comparison with splenomegaly/hypersplenism patients. In summary, important differences were also found between the groups in the studied RBCs parameters. Further studies are required to elucidate the effect of the spleen including hyper and hypo-splenia on laboratory parameters and in clinical manifestations, vascular pathology, and long-term complications of SCD. The benefits and risks of splenectomy compared to chronic transfusion need to be evaluated in clinical trials and the standard approach managing hypersplenism in SCD patients should be re-evaluated

Back to the "Gold Standard": How Precise is Hematocrit Detection Today?

Introduction: The commonly used method for hematocrit detection, by visual examination of microcapillary tube, known as "micro-HCT", is subjective but remains one of the key sources for fast hematocrit evaluation. Analytical automation techniques have increased the standardization of RBC index detection; however, indirect hematocrit measurements by blood analyzer, the automated HCT, do not correlate well with "micro-HCT" results in patients with hematological pathologies. We aimed to overcome those disadvantages in "micro-HCT" analysis using "ImageJ" processing software. Methods: 223 blood samples from the "general population" and 19 from sickle cell disease patients were examined in parallel for hematocrit values using the automated HCT, standard "micro-HCT," and "ImageJ" micro-HCT methods. Results: For the "general population" samples, the "ImageJ" values were significantly higher than the corresponding values evaluated by standard "micro-HCT" and automated HCT, except for the 0 to 2 month old newborns, in which the automated HCT results were similar to the "ImageJ" evaluated HCT. Similar to the "general population" cohort, we found significantly higher values measured by "ImageJ" compared to either "micro-HCT" or the automated HCT in SCD patients. Correspondent differences for the MCV and MCHC were also found. Discussion: This study introduces the "micro-HCT" assessment technique using the image-analysis module of "ImageJ" software. This procedure allows overcoming most of the data errors associated with the standard "micro-HCT" evaluation and can replace the use of complicated and expensive automated equipment. The presented results may also be used to develop new standards for calculating hematocrit and associated parameters for routine clinical practice. Keywords: Image analysis; Microcapillary hematocrit; RBC indices

The Impact of Ca2+ on Intracellular Distribution of Hemoglobin in Human Erythrocytes

The membrane-bound hemoglobin (Hb) fraction impacts red blood cell (RBC) rheology and metabolism. Therefore, Hb–RBC membrane interactions are precisely controlled. For instance, the signaling function of membrane-bound deoxy-Hb and the structure of the docking sites in the cytosolic domain of the anion exchanger 1 (AE-1) protein are well documented; however, much less is known about the interaction of Hb variants with the erythrocyte’s membrane. Here, we identified factors other than O2 availability that control Hb abundance in the membrane-bound fraction and the possible variant-specific binding selectivity of Hb to the membrane. We show that depletion of extracellular Ca2+ by chelators, or its omission from the extracellular medium, leads to membrane-bound Hb release into the cytosol. The removal of extracellular Ca2+ further triggers the redistribution of HbA0 and HbA2 variants between the membrane and the cytosol in favor of membrane-bound HbA2. Both effects are reversible and are no longer observed upon reintroduction of Ca2+ into the extracellular medium. Fluctuations of cytosolic Ca2+ also impact the pre-membrane Hb pool, resulting in the massive transfer of Hb to the cellular cytosol. We hypothesize that AE-1 is the specific membrane target and discuss the physiological outcomes and possible clinical implications of the Ca2+ regulation of the intracellular Hb distribution

A conserved function of Human DLC3 and Drosophila Cv-c in testis development

The identification of genes affecting gonad development is essential to understand the mechanisms causing Variations/Differences in Sex Development (DSD). Recently, a DLC3 mutation was associated with male gonadal dysgenesis in 46,XY DSD patients. We have studied the requirement of Cv-c, the Drosophila ortholog of DLC3, in Drosophila gonad development, as well as the functional capacity of DLC3 human variants to rescue cv-c gonad defects. We show that Cv-c is required to maintain testis integrity during fly development. We find that Cv-c and human DLC3 can perform the same function in fly embryos, as flies carrying wild type but not patient DLC3 variations can rescue gonadal dysgenesis, suggesting functional conservation. We also demonstrate that the StART domain mediates Cv-c's function in the male gonad independently from the GAP domain's activity. This work demonstrates a role for DLC3/Cv-c in male gonadogenesis and highlights a novel StART domain mediated function required to organize the gonadal mesoderm and maintain its interaction with the germ cells during testis development.This work was supported by María de Maeztu Unit excellence grants MDM-2016-0687 and CEX2020-001088 M and a Ministerio de Ciencia e Innovación grant PID2019-104656GB-I00 cofunded by the European Regional Development Fund (FEDER) to JC-GH. SV acknowledges support from the Swiss National Science Foundation (PP00P3_194807). This work was also supported by grants from the Swiss National Supercomputing Centre under project ID s1132 and has received funding from the European Research Council under the European Union’s Horizon 2020 research and innovation program (grant agreement no. 803952). AL-B acknowledges support from the Swiss National Science Foundation’s Grant 320030-184807. LL acknowledges support from the Swiss National Science Foundation (grant number SCOPES IZ73Z0_152347/1) and National Academy of Sciences of Ukraine, project 'Molecular-Genetic Mechanisms of Human Disorders of Sexual Development' [0121U110054]: With funding from the Spanish government through the ‘Severo Ochoa Centre of Excellence’ accreditation (referencia del instituto). Por ejemplo: With funding from the Spanish government through the ‘Severo Ochoa Centre of Excellence’ accreditation (CEX2020-001088)

Advances in Molecular Quantum Chemistry Contained in the Q-Chem 4 Program Package

A summary of the technical advances that are incorporated in the fourth major release of the Q-Chem quantum chemistry program is provided, covering approximately the last seven years. These include developments in density functional theory methods and algorithms, nuclear magnetic resonance (NMR) property evaluation, coupled cluster and perturbation theories, methods for electronically excited and open-shell species, tools for treating extended environments, algorithms for walking on potential surfaces, analysis tools, energy and electron transfer modelling, parallel computing capabilities, and graphical user interfaces. In addition, a selection of example case studies that illustrate these capabilities is given. These include extensive benchmarks of the comparative accuracy of modern density functionals for bonded and non-bonded interactions, tests of attenuated second order Møller–Plesset (MP2) methods for intermolecular interactions, a variety of parallel performance benchmarks, and tests of the accuracy of implicit solvation models. Some specific chemical examples include calculations on the strongly correlated Cr2 dimer, exploring zeolite-catalysed ethane dehydrogenation, energy decomposition analysis of a charged ter-molecular complex arising from glycerol photoionisation, and natural transition orbitals for a Frenkel exciton state in a nine-unit model of a self-assembling nanotube

Role of Non-Steroidal Anti-Inflammatory Drugs in Gynecology

This review summarizes the current use of non-steroidal anti-inflammatory drugs (NSAIDs) in obstetrics, gynecology and infertility. These medications are commonly used in different fields of reproductive medicine, for pain management after operative procedures and to relieve dysmenorrhea. In addition to their analgesic effect, NSAIDs are helpful in the management of menorrhagia by decreasing menstrual blood loss. NSAIDs alleviate pain associated with medical abortion, assist in undertaking natural cycle in-vitro fertilization by preventing follicular rupture and reducing premature ovulation, and serve as tocolytics in preterm labor. New NSAIDs may have a growing role in management of women's health

Discrimination between G/C Binding Sites by Olivomycin A Is Determined by Kinetics of the Drug-DNA Interaction

Olivomycin A (OA) exerts its cytotoxic potency due to binding to the minor groove of the G/C-rich DNA and interfering with replication and transcription. Screening of the complete set of tetranucleotide G/C sites by electrophoretic mobility gel shift assay (EMSA) revealed that the sites containing central GC or GG dinucleotides were able to bind OA, whereas the sites with the central CG dinucleotide were not. However, studies of equilibrium OA binding in solution by fluorescence, circular dichroism and isothermal titration calorimetry failed to confirm the sequence preference of OA, indicating instead a similar type of complex and comparable affinity of OA to all G/C binding sites. This discrepancy was resolved by kinetics analysis of the drug–DNA interaction: the dissociation rate significantly differed between SGCS, SGGS and SCGS sites (S stands for G or C), thereby explaining the disintegration of the complexes during EMSA. The functional relevance of the revealed differential kinetics of OA–DNA interaction was demonstrated in an in vitro transcription assay. These findings emphasize the crucial role of kinetics in the mechanism of OA action and provide an important approach to the screening of new drug candidates

Disordering of human telomeric G-quadruplex with novel antiproliferative anthrathiophenedione.

Linear heteroareneanthracenediones have been shown to interfere with DNA functions, thereby causing death of human tumor cells and their drug resistant counterparts. Here we report the interaction of our novel antiproliferative agent 4,11-bis[(2-{[acetimido]amino}ethyl)amino]anthra[2,3-b]thiophene-5,10-dione with telomeric DNA structures studied by isothermal titration calorimetry, circular dichroism and UV absorption spectroscopy. New compound demonstrated a high affinity (K(ass)∼10⁶ M⁻¹) for human telomeric antiparallel quadruplex d(TTAGGG)₄ and duplex d(TTAGGG)₄∶d(CCCTAA)₄. Importantly, a ∼100-fold higher affinity was determined for the ligand binding to an unordered oligonucleotide d(TTAGGG TTAGAG TTAGGG TTAGGG unable to form quadruplex structures. Moreover, in the presence of Na+ the compound caused dramatic conformational perturbation of the telomeric G-quadruplex, namely, almost complete disordering of G-quartets. Disorganization of a portion of G-quartets in the presence of K+ was also detected. Molecular dynamics simulations were performed to illustrate how the binding of one molecule of the ligand might disrupt the G-quartet adjacent to the diagonal loop of telomeric G-quadruplex. Our results provide evidence for a non-trivial mode of alteration of G-quadruplex structure by tentative antiproliferative drugs