PaMILO: A Solver for Multi-Objective Mixed Integer Linear Optimization and Beyond

In multi-objective optimization, several potentially conflicting objective functions need to be optimized. Instead of one optimal solution, we look for the set of so called non-dominated solutions. An important subset is the set of non-dominated extreme points. Finding it is a computationally hard problem in general. While solvers for similar problems exist, there are none known for multi-objective mixed integer linear programs (MOMILPs) or multi-objective mixed integer quadratically constrained quadratic programs (MOMIQCQPs). We present PaMILO, the first solver for finding non-dominated extreme points of MOMILPs and MOMIQCQPs. PaMILO provides an easy to use interface and is implemented in C++17. It solves occurring subproblems employing either CPLEX or Gurobi. PaMILO adapts the dual-benson algorithm for multi-objective linear programming (MOLP). As it was previously only defined for MOLPs, we describe how it can be adapted for MOMILPs, MOMIQCQPs and even more problem classes in the future

EGFL7 loss correlates with increased VEGF-D expression, upregulating hippocampal adult neurogenesis and improving spatial learning and memory

Correction: Volume: 80 Issue: 8 DOI: 10.1007/s00018-023-04835-3 Article Number: 201 Published: AUG 2023Neural stem cells reside in the subgranular zone, a specialized neurogenic niche of the hippocampus. Throughout adulthood, these cells give rise to neurons in the dentate gyrus, playing an important role in learning and memory. Given that these core cognitive processes are disrupted in numerous disease states, understanding the underlying mechanisms of neural stem cell proliferation in the subgranular zone is of direct practical interest. Here, we report that mature neurons, neural stem cells and neural precursor cells each secrete the neurovascular protein epidermal growth factor-like protein 7 (EGFL7) to shape this hippocampal niche. We further demonstrate that EGFL7 knock-out in a Nestin-CreERT2-based mouse model produces a pronounced upregulation of neurogenesis within the subgranular zone. RNA sequencing identified that the increased expression of the cytokine VEGF-D correlates significantly with the ablation of EGFL7. We substantiate this finding with intraventricular infusion of VEGF-D upregulating neurogenesis in vivo and further show that VEGF-D knock-out produces a downregulation of neurogenesis. Finally, behavioral studies in EGFL7 knock-out mice demonstrate greater maintenance of spatial memory and improved memory consolidation in the hippocampus by modulation of pattern separation. Taken together, our findings demonstrate that both EGFL7 and VEGF-D affect neurogenesis in the adult hippocampus, with the ablation of EGFL7 upregulating neurogenesis, increasing spatial learning and memory, and correlating with increased VEGF-D expression.Peer reviewe

The geodynamic and limnological evolution of Balkan Lake Ohrid, possibly the oldest extant lake in Europe

Studies of the upper 447 m of the DEEP site sediment succession from central Lake Ohrid, Balkan Peninsula, North Macedonia and Albania provided important insights into the regional climate history and evolutionary dynamics since permanent lacustrine conditions established at 1.36 million years ago (Ma). This paper focuses on the entire 584-m-long DEEP sediment succession and a comparison to a 197-m-long sediment succession from the Pestani site ~5 km to the east in the lake, where drilling ended close to the bedrock, to unravel the earliest history of Lake Ohrid and its basin development. 26Al/10Be dating of clasts from the base of the DEEP sediment succession implies that the sedimentation in the modern basin started at c. 2 Ma. Geophysical, sedimentological and micropalaeontological data allow for chronological information to be transposed from the DEEP to the Pestani succession. Fluvial conditions, slack water conditions, peat formation and/or complete desiccation prevailed at the DEEP and Pestani sites until 1.36 and 1.21 Ma, respectively, before a larger lake extended over both sites. Activation of karst aquifers to the east probably by tectonic activity and a potential existence of neighbouring Lake Prespa supported filling of Lake Ohrid. The lake deepened gradually, with a relatively constant vertical displacement rate of ~0.2 mm a−1 between the central and the eastern lateral basin and with greater water depth presumably during interglacial periods. Although the dynamic environment characterized by local processes and the fragmentary chronology of the basal sediment successions from both sites hamper palaeoclimatic significance prior to the existence of a larger lake, the new data provide an unprecedented and detailed picture of the geodynamic evolution of the basin and lake that is Europe’s presumed oldest extant freshwater lake

Role of Ox-PAPCs in the Differentiation of Mesenchymal Stem Cells (MSCs) and Runx2 and PPARγ2 Expression in MSCs-Like of Osteoporotic Patients

BACKGROUND: Mesenchymal stem cells (MSCs) can differentiate into osteoblasts and adipocytes and conditions causing bone loss may induce a switch from the osteoblast to adipocyte lineage. In addition, the expression of Runx2 and the PPARγ2 transcription factor genes is essential for cellular commitment to an osteogenic and adipogenic differentiation, respectively. Modified lipoproteins derived from the oxidation of arachidonate-containing phospholipids (ox-PAPCs: POVPC, PGPC and PEIPC) are considered important factors in atherogenesis. METHODOLOGY: We investigated the effect of ox-PAPCs on osteogenesis and adipogenesis in human mesenchymal stem cells (hMSCs). In particular, we analyzed the transcription factor Runx2 and the PPARγ2 gene expression during osteogenic and adipogenic differentiation in absence and in presence of ox-PAPCs. We also analyzed gene expression level in a panel of osteoblastic and adipogenic differentiation markers. In addition, as circulating blood cells can be used as a "sentinel" that responds to changes in the macro- or micro-environment, we analyzed the Runx2 and the PPARγ2 gene expression in MSCs-like and ox-PAPC levels in serum of osteoporotic patients (OPs). Finally, we examined the effects of sera obtained from OPs in hMSCs comparing the results with age-matched normal donors (NDs). PRINCIPAL FINDINGS: Quantitative RT-PCR demonstrated that ox-PAPCs enhanced PPARγ2 and adipogenic gene expression and reduced Runx2 and osteoblast differentiation marker gene expression in differentiating hMSCs. In OPs, ox-PAPC levels and PPARγ2 expression were higher than in NDs, whereas Runx2 was lower than in ND circulant MSCs-like. CONCLUSIONS: Ox-PAPCs affect the osteogenic differentiation by promoting adipogenic differentiation and this effect may appear involved in bone loss in OPs

The geodynamic and limnological evolution of Balkan Lake Ohrid, possibly the oldest extant lake in Europe

Studies of the upper 447 m of the DEEP site sediment succession from central Lake Ohrid, Balkan Peninsula, North Macedonia and Albania provided important insights into the regional climate history and evolutionary dynamics since permanent lacustrine conditions established at 1.36 million years ago (Ma). This paper focuses on the entire 584-m-long DEEP sediment succession and a comparison to a 197-m-long sediment succession from the Pestani site ~5 km to the east in the lake, where drilling ended close to the bedrock, to unravel the earliest history of Lake Ohrid and its basin development. 26Al/10Be dating of clasts from the base of the DEEP sediment succession implies that the sedimentation in the modern basin started at c. 2 Ma. Geophysical, sedimentological and micropalaeontological data allow for chronological information to be transposed from the DEEP to the Pestani succession. Fluvial conditions, slack water conditions, peat formation and/or complete desiccation prevailed at the DEEP and Pestani sites until 1.36 and 1.21 Ma, respectively, before a larger lake extended over both sites. Activation of karst aquifers to the east probably by tectonic activity and a potential existence of neighbouring Lake Prespa supported filling of Lake Ohrid. The lake deepened gradually, with a relatively constant vertical displacement rate of ~0.2 mm a−1 between the central and the eastern lateral basin and with greater water depth presumably during interglacial periods. Although the dynamic environment characterized by local processes and the fragmentary chronology of the basal sediment successions from both sites hamper palaeoclimatic significance prior to the existence of a larger lake, the new data provide an unprecedented and detailed picture of the geodynamic evolution of the basin and lake that is Europe’s presumed oldest extant freshwater lake

Hard color-singlet exchange in dijet events in proton-proton collisions at root s=13 TeV

Events where the two leading jets are separated by a pseudorapidity interval devoid of particle activity, known as jet-gap-jet events, are studied in proton-proton collisions at root s = 13 TeV. The signature is expected from hard color-singlet exchange. Each of the highest transverse momentum (p(T)) jets must have p(T)(jet) > 40 GeV and pseudorapidity 1.4 0.2 GeV in the interval vertical bar eta vertical bar < 1 between the jets are observed in excess of calculations that assume only color-exchange. The fraction of events produced via color-singlet exchange, f(CSE), is measured as a function of p(T)(jet2), the pseudorapidity difference between the two leading jets, and the azimuthal angular separation between the two leading jets. The fraction f(CSE) has values of 0.4-1.0%. The results are compared with previous measurements and with predictions from perturbative quantum chromodynamics. In addition, the first study of jet-gap-jet events detected in association with an intact proton using a subsample of events with an integrated luminosity of 0.40 pb(-1) is presented. The intact protons are detected with the Roman pot detectors of the TOTEM experiment. The f(CSE) in this sample is 2.91 +/- 0.70(stat)(-1.01)(+1.08)(syst) times larger than that for inclusive dijet production in dijets with similar kinematics.Peer reviewe

Human Cytomegalovirus Fcγ Binding Proteins gp34 and gp68 Antagonize Fcγ Receptors I, II and III

Human cytomegalovirus (HCMV) establishes lifelong infection with recurrent episodes of virus production and shedding despite the presence of adaptive immunological memory responses including HCMV immune immunoglobulin G (IgG). Very little is known how HCMV evades from humoral and cellular IgG-dependent immune responses, the latter being executed by cells expressing surface receptors for the Fc domain of IgG (FcγRs). Remarkably, HCMV expresses the RL11-encoded gp34 and UL119-118-encoded gp68 type I transmembrane glycoproteins which bind Fcγ with nanomolar affinity. Using a newly developed FcγR activation assay, we tested if the HCMV-encoded Fcγ binding proteins (HCMV FcγRs) interfere with individual host FcγRs. In absence of gp34 or/and gp68, HCMV elicited a much stronger activation of FcγRIIIA/CD16, FcγRIIA/CD32A and FcγRI/CD64 by polyclonal HCMV-immune IgG as compared to wildtype HCMV. gp34 and gp68 co-expression culminates in the late phase of HCMV replication coinciding with the emergence of surface HCMV antigens triggering FcγRIII/CD16 responses by polyclonal HCMV-immune IgG. The gp34- and gp68-dependent inhibition of HCMV immune IgG was fully reproduced when testing the activation of primary human NK cells. Their broad antagonistic function towards FcγRIIIA, FcγRIIA and FcγRI activation was also recapitulated in a gain-of-function approach based on humanized monoclonal antibodies (trastuzumab, rituximab) and isotypes of different IgG subclasses. Surface immune-precipitation showed that both HCMV-encoded Fcγ binding proteins have the capacity to bind trastuzumab antibody-HER2 antigen complexes demonstrating simultaneous linkage of immune IgG with antigen and the HCMV inhibitors on the plasma membrane. Our studies reveal a novel strategy by which viral FcγRs can compete for immune complexes against various Fc receptors on immune cells, dampening their activation and antiviral immunity.DFG grant He 2526/6-2.European Commission grants QLRT-2001-01112 and MRTN-CT-2005-019248.Helmholtz Association through VISTRIE VH-VI-242.UCR::Vicerrectoría de Docencia::Salud::Facultad de Microbiologí