Absence Of Differentiation Research Articles

Incomplete accumulation of perilesional reactive astrocytes exacerbates wound healing after closed-head injury by increasing inflammation and BBB disruption

Wound healing after closed-head injury is a significant medical issue. However, conventional models of focal traumatic brain injury, such as fluid percussion injury and controlled cortical impact, employ mechanical impacts on the exposed cerebral cortex after craniotomy. These animal models are inappropriate for studying gliosis, as craniotomy itself induces gliosis. To address this, we developed a closed-head injury model and named “photo injury”, which employs intense light illumination through a thinned-skull cranial window. Our prior work demonstrated that the gliosis of focal cerebral lesion after the photo injury does not encompass artificial gliosis and comprises two distinct reactive astrocyte subpopulations. The reactive astrocytes accumulated in the perilesional recovery area actively proliferate and express Nestin, a neural stem cell marker, while those in distal regions do not exhibit these traits. The present study investigated the role of perilesional reactive astrocytes (PRAs) in wound healing using the ablation of reactive astrocytes by the conditional knockout of Stat3. The extensive and non-selective ablation of reactive astrocytes in Nestin-Cre:Stat3f/f mice resulted in an exacerbation of injury, marked by increased inflammation and BBB disruption. On the other hand, GFAP-CreERT2:Stat3f/f mice exhibited the partial and selective ablation of the PRAs, while their exacerbation of injury was at the same extent as in Nestin-Cre:Stat3f/f mice. The comparison of these two mouse strains indicates that the PRAs are an essential astrocyte component for wound healing after closed-head injury, and their anti-inflammatory and regenerative functions are significantly affected even by incomplete accumulation. In addition, the reporter gene expression in the PRAs by GFAP-CreERT2 indicated a substantial elimination of these cells and an absence of differentiation into other cell types, despite Nestin expression, after wound healing. Thus, the accumulation and subsequent elimination of PRA are proposed as promising diagnostic and therapeutic avenues to bolster wound healing after closed-head injury.

Are intravitreal hyperreflective particles alike in eyes with acute toxoplasma chorioretinitis and non-infectious uveitis?

BackgroundTo compare distinctive features of hyperreflective particles observed on spectral-domain optical coherence tomography (OCT) sections in eyes with acute toxoplasma chorioretinitis (TC) and non-infectious uveitis (NIU). MethodsMedical records and the spectral-domain OCT images of the patients with TC and NIU were retrospectively reviewed. The TC and NIU groups were compared in terms of age, sex, mean OCT image quality, mean central macular thickness (CMT), presence of intraretinal fluid (IRF), presence of subretinal fluid (SRF), number of hyperreflective particles in the posterior vitreous area and mean particle measurement in the posterior vitreous area. ResultsNon-infectious uveitis group included nine patients (60 %) with Behcet's uveitis, five patients (33.3 %) with idiopathic posterior uveitis or panuveitis, and the remaining patient (6.7 %) with HLA-B27 associated uveitis. Comparison of the mean age, sex distribution, mean OCT image quality, mean CMT, presence of IRF, presence of SRF and the mean number of hyperreflective particles in the posterior vitreous area between the two groups showed no statistically significant differences (p = 0.085, p = 0.051, p = 0.748, p = 0.431, p = 0.109, p = 0.080 and p = 0.152, respectively). However, the mean length of the hyperreflective particles in the posterior vitreous area was 27.22 ± 8.60 μm in the TC group, and 21.91 ± 3.58 μm in the NIU group, with a significant difference between the two groups (p = 0.036). ConclusionThis pilot study aimed to assess the hyperreflective particles in the posterior vitreous area using spectral-domain OCT images and image processing software. Despite its limitations, such as the small sample size, limited understanding of the nature of hyperreflective particles, and the absence of differentiation between acute and chronic uveitis, our study points out the potential role of the measurement of the hyperreflective particle length located in the posterior vitreous in differentiating the acute infectious versus non-infectious uveitis as the hyperreflective particles tend to be larger in infectious cases.

Implementation Classification Of Hospital Class And Humanist Standard Inpatient Class In Purwakarta

The government has established provisions for classification of hospital classes and standard class inpatient care in 2020. With these provisions, all hospitals are required to immediately implement and adjust the infrastructure they have. However, not all hospitals have adjusted according to the stipulated provisions. For this reason, readiness research needs to be carried out from each hospital in Purwakarta , regarding the implementation of hospital class classification and the implementation of standard class inpatient care. Method research carried out , use type Study Quantitative Descriptive of 4 hospitals in Purwakarta regarding the inpatient facilities they have. Implementation of Hospital class classification for research objects in Purwakarta is 75% underway. Meanwhile, the implementation of standard class inpatient care is still not fully implemented. Because there is no clarity on implementation and there are no strict sanctions for these regulations. The role of the Government through the Health Service is very much needed to enforce the implementation of the regulations, so that sanctions against hospitals will run well and the review process for determining hospital classes can be carried out. The government's regulatory function must be carried out by preparing clear and specific derivative regulations to guard the regulatory mandate. So that the benefits of health services for the community can be felt and the elements of justice and the absence of differentiation in services will be enjoyed by all people.

118 Variance Components for Age at First Calving and Yearling Weight When Accounting for Age Differences at Fixed Breeding Dates in a Contemporary Group

Abstract The ability of a heifer to calve earlier in a breeding season has implications on the economic success of heifers in a production system. Heifers that calve earlier in a calving season have increased calf performance, improved subsequent fertility, and a longer productive life in the herd. Production systems typically breed heifers during fixed breeding dates, with heifers of variable ages in the same contemporary group. The objective of this study was to determine if heifer yearling weight (YW) or age differences going into a fixed breeding period influenced the additive genetic variance of age at first calving (AFC) explained in a multi-breed population. Heifer fertility data were obtained from International Genetic Solutions. Females with exposure and calf production records were used to identify individuals calving between 630 and 810 days of age. Females with embryo transfer, multiple birth progeny, and an age differential (DIFF) greater than 100 days were excluded. Age differential was defined as the difference in days between an individual’s birth date and the earliest birth date of an animal in a defined contemporary group. Contemporary group was defined as; breeder, herd, year born, birth and yearling group. After data filtering, there were 149,350 calving records. A 3-generation pedigree file was used containing 365,637 animals, with 37,420 unique sires and 219,533 unique dams. Two bivariate multi-trait animal models for AFC and YW with random additive genetic and residual effects and fixed effects of contemporary group, breed proportion, and % retained hybrid vigor were used. The first model consisted of the aforementioned effects while the second model included DIFF as an additional fixed effect. Analyses were performed using ASReml 3.0. When DIFF was not included as a fixed effect, the additive, residual and phenotypic variances for AFC were 126.1, 456.8, and 582.9 d2, respectively, and the genetic correlation between AFC and YW was 0.36 ± 0.02. When DIFF was included as a fixed effect, the additive, residual, and phenotypic variances for AFC were 10.0, 326.0, and 336.0 d2, respectively. The genetic correlation between AFC and YW was 0.19 ± 0.04. In the absence of DIFF, the heritability estimates for AFC and YW were 0.22 ± 0.01 and 0.44 ± 0.01, respectively but were 0.03 ± 0.003 and 0.44 ± 0.01 respectively, when DIFF was included. Age differential was a significant effect on AFC at –0.86 (P < 0.0001). The low additive variance of AFC when accounting for DIFF suggests that the influence of a female's age going into a fixed breeding date explains much of the variation in AFC. The low heritability estimate for AFC and genetic correlation with YW suggests that selection for improved AFC will be difficult using this method and that producers should instead focus on improved management practices to ensure females calve earlier in a calving season.

Determinants of risk readiness as a resource in women’s entrepreneurship

The growth of the scale of women’s entrepreneurship highlights the interest in studying both the specifics of the phenomenon itself and the resource potential of its main subject – women entrepreneurs. Entrepreneurship is built on risk, and the readiness for risk largely determines the success and stability of a business. The aim of the analysis in this article is to determine how the sufficiency/insufficiency of the resource of risk readiness in women’s entrepreneurship is linked to a range of individually subjectively evaluated dispositions in one or another coordinate system. The task was to assess the productivity of introducing the concept of disposition (status) in risk-related research and to determine the presence or absence of differentiation among holders and those in need of risk readiness as a resource in women’s entrepreneurship. The empirical basis of the analysis is the data from the “Russian Longitudinal Monitoring Survey of HSE (RLMS-HSE)”. The methodology of target group analysis is applied. The results of the exploratory study revealed differentiation in several indicators of emotional status, socialpsychological attitudes, financial status, value profile, and decision-making subjectivity in risk and uncertainty situations. Such results allow for considering them with a reasonable degree of certainty as interconnected with risk readiness. The methodological approach of considering dispositions as existing statuses of individuals in specific coordinate systems proved to be productive. A promising task in this regard is a deeper methodological and conceptual elaboration of the concept in connection with risk-related issues.

Galen's Ampulla Aneurysm: A Case Report

Introduction: Galen's vein aneurysm is a rare complex intracranial arteriovenous malformation, associating pseudo-aneurysmal dilation of Galen's ampulla with one or more arteriovenous fistulas. The prognosis is often poor, with high mortality and a risk of neurological sequelae. Objective: To support the role of imaging in the diagnosis, with illustration by two observations collected within our Radiopediatrics department of the CHU Mohammed VI of Marrakech, having benefited from a cerebral angio-scanner. Case Report: 1st case:is an 18-month-old infant with no particular history presenting macrocrania with generalized seizures.2nd case:is also a 2-year-old infant, with the appearance of a vein in the suborbital groove for 6 months, with no other associated signs.3rd patientis a 1-year-old infant with macrocrania with signs of HTIC. 4th case6-month-old boy, presents with HTIC syndrome. Objective cerebral CT in the first three patients: a rounded median mass, in the pineal region behind the 3rd ventricle, slightly hyperdense in spontaneous contrast; CT angiography proves the vascular nature of the lesion by showing intense and homogeneous enhancement after injection of PDC, associated with dilation of the venous sinuses, and moderate passive triventricular hydrocephalus by compression of the aqueduct of Sylvius. The fourth patient benefited from a transfontanellar ultrasound which objectified an anechoic interhemispheric fusiform structure presenting a vascular flow to the color Doppler. Conclusion: The aneurysmal malformation of the Vein of Galen (AVGM) is a rare vascular malformation, specific to children, discovered ante or post natally, in fact only corresponds to a venous dilation draining an arterio-venous malformation, whose system afferent arterial comes from the carotid system or the vertebro-basilar axis; it results from the absence of differentiation in the mature arterio-venous system, between 7 and 12 SA, of a primitive, median embryonic vein which ......

Unusual CD34 positivity in acute myeloid leukaemia with myelodysplasia-related changes with megakaryoblastic differentiation.

Acute megakaryoblastic leukaemia is a rare entity with distinct immunophenotype profile and cytogenetic lesions. Herein, we report a case of acute myeloid leukaemia with myelodysplastic‐related changes with megakaryoblastic differentiation in absence of recurrent genomic lesions such as t(1;22), inv(3) and t(3;3).One of the peculiarities of this case is the positivity of CD34+ within the abnormal megakaryoblasts; CD61 immunohistochemistry highlights the heavily infiltration of bone marrow from abnormal megakaryoblasts.

Analysis of the use of the Redis in the distributed order processing system in the restaurant network

The object of research is a distributed order processing system for a restaurant chain. The subject of the research is the analysis of the use of Redis for managing event queues in distributed systems. When implementing a distributed order processing system in a restaurant chain with a possible load of up to 20,000 users per day, the Redis system was used. Management of 9 distributed subsystems was organized through Redis. This solution showed an increase in the performance of the system under heavy load (from 50 transactions per second), but the response time of the system in some cases of its operation was longer than without using Redis. When working systems using Redis, it is necessary to take into account the amount of data with which Redis will work, since it does not exceed the amount of RAM, the absence of differentiation into users and groups, and the absence of a query language, which is replaced by a key-value scheme. This research is aimed at analyzing the operation of the system during trial operation under real load. We compared the operation of a configured system with Redis enabled and disabled. The main indicators for the analysis were the system response time and the maximum request execution time. The research was carried out for 2 weeks, the first week using the system settings with disabled Redis, the second – with enabled Redis. We selected 2 days with a similar load on the system to each other. Especially indicative are the results of comparing the durations of the longest queries, which show an almost constant value of the duration for the system in the mode of enabled Redis. The hypothesis of an increase in the system response time at low loads was confirmed, but this value not only leveled off at a load of 500 unique users but also became less at loads of 1000 unique users.

Value of the ultrasound research in the diagnostic of acute strangulated small bowel obstruction

Purpose. To identify and evaluate the effectiveness of sonographic signs of intestinal ischemia in patients with strangulated small bowel obstruction.Materials and methods. For the period 2017–2019, 115 patients with SIO were treated at the N.V. Sklifosovsky Federal Research Institute of Emergency Medicine. There were 64 women (55.6%) and 51 men (44.4%). The mean age was 62 ± 15 years. In all patients, the diagnosis was verified intraoperatively. All patients underwent ultrasound examination of the abdominal cavity in B-mode with the assessment of blood flow of the intestinal wall in the mode of CDI. Patients were divided on the basis of intraoperative data into 2 groups. The first group: 63 (54.8%) patients with signs of ischemia of the strangulated loop of the intestine. The second group consisted of 21 (18.1%) patients in whom intestinal necrosis was detected. The comparison group included 31 (26.7%) patients with adhesive small bowel obstruction without intestinal strangulation.Results. The most informative signs of ischemia of the strangulated intestine of the loop are infiltrative changes of its mesentery. In the second and third groups 9 (14.3%) and 12 (57.1%) participants, respectively, showed severity of intestinal ischemia, compared with 1 participant (3.2%) in the first group. The next informative criterion is the thickening of more than 0.4 cm and edema of the intestinal wall. In the second and third groups 30 (47.6%) and 14 (66.6%), in the comparison group 4 (12.9%), akinesis of the strangulated loop and paresis of the entire small intestine also directly correlated with intestinal ischemia. The absence of differentiation of intestinal wall layers occurs in (23.8%), the absence of blood flow in the intestinal wall in the CDI mode (19%), gas inclusions in the intestinal wall (4.3%).Conclusion. The assessment of sonographic symptoms allows to diagnose the presence of ischemic changes in the intestinal wall and perform surgery before the development of necrosis in the early period. In cases of late admission of the patient to the hospital, with the onset of intestinal necrosis and the associated erased clinical picture, ultrasound allows to establish indications for surgery before the development of peritonitis.

Interferon regulatory factor 4 controls effector functions of CD8+ memory T cells

The transcription factor IRF4 is required for CD8+ T cell activation, proliferation, and differentiation to effector cells and thus is essential for robust CD8+ T cell responses. The function of IRF4 in memory CD8+ T cells yet needs to be explored. To investigate the role of IRF4 for maintaining differentiation state and survival of CD8+ memory T cells, we used a mouse model with tamoxifen-inducible Irf4 knockout to preclude effects due to inefficient memory cell differentiation in absence of IRF4. We infected mice with ovalbumin-recombinant listeria and induced Irf4 knockout after clearance of the pathogen. Loss of IRF4 resulted in phenotypical changes of CD8+ memory T cells but did not cause a reduction of the total memory T cell population. However, upon reencounter of the pathogen, CD8+ memory T cells showed impaired expansion and acquisition of effector functions. When compared to CD8+ effector memory T cells, CD8+ tissue-resident memory T cells (TRM cells) expressed higher IRF4 levels. Mice with constitutive Irf4 knockout had diminished CD8+ TRM-cell populations, and tamoxifen-induced Irf4 deletion caused a reduction of this cell population. In conclusion, our results demonstrate that IRF4 is required for effective reactivation but not for general survival of CD8+ memory T cells. Formation and maintenance of CD8+ TRM cells, in contrast, appear to depend on IRF4.

Contribution of a DNA barcode to an assessment of the specificity of ant taxa (Hymenoptera: Formicidae) on Corsica

We used the COI marker, the most popular DNA barcode for the animal kingdom, to assess the taxonomic status of Corsican populations of eight groups of species of ants that occur both on Corsica and the European mainland. (i) In two groups, we detected no genetic differentiation between Corsica and the continent. Absence of differentiation across varieties of Aphaenogaster spinosa within Corsica confirm current synonymies. (ii) In four groups, we detected strong genetic differentiation between Corsica and the continent, confirming recent taxonomic studies based on morphology for three of these groups. For the fourth group, we propose that the status of Corsican populations be raised from sub-species to species: Temnothorax cordieri stat. rev. (iii) In one group, the genetic differentiation and morphological differences do not support splitting and as a consequence we propose to accept the previous synonymy Temnothorax tuberum = Temnothorax melanocephalus. (iv) In Myrmica scabrinodis and Myrmica spinosior, COI sequence information is largely inconsistent with morphology and geography, not only on Corsica but also on the mainland, and should not be used to support taxonomic decisions. Although the use of COI has drawbacks, it is globally consistent with morphology and can be used to complement morphological ant taxonomy. We provide an updated checklist of ants of Corsica.

Lens fiber cell differentiation occurs independently of fibroblast growth factor receptor signaling in the absence of Pten

Fibroblast growth factor receptor (FGFR) signaling patterns multiple tissues in both vertebrates and invertebrates, largely through the activation of intracellular kinases. Recent studies have demonstrated that the phosphatase, PTEN negatively regulates FGFR signaling, such that the loss of PTEN can compensate for reduced FGFR signaling to rescue aspects of normal development. In the developing mouse lens, FGFR signaling promotes cell survival and fiber cell differentiation, and the loss of Pten largely compensates for the loss of Fgfr2 during lens development. To explore this regulatory relationship further, we focused on the phenotypic consequences of Pten loss on lens development and fiber cell differentiation in the absence of all FGFR signaling, both in vivo and in lens epithelial explants. Pten deletion partially rescues primary fiber cell elongation and γ−crystallin accumulation in FGFR-deficient lenses in vivo but fails to rescue cell survival or proliferation. However, in lens epithelial explants, where cells survive without FGFR signaling, Pten deletion rescues vitreous humor-induced lens fiber cell differentiation in the combined absence of Fgfr1, Fgfr2 and Fgfr3. This represents the first evidence that vitreous-initiated signaling cascades, independent of FGFR signaling, can drive mammalian lens fiber cell differentiation, when freed from repression by PTEN.

In Situ Elemental and Sr Isotope Characteristics of Magmatic to Hydrothermal Minerals from the Black Mountain Porphyry Deposit, Baguio District, Philippines

AbstractAt the Black Mountain porphyry Cu-Au deposit in the Baguio district, Northern Luzon (Philippines), pre- and synmineralized rocks preserve magmatic and hydrothermal minerals (e.g., plagioclase, amphibole, titanite, and epidote) spanning the complete paragenesis of the deposit. Strontium isotope values in early crystallized plagioclase phenocrysts from all felsic porphyries can be divided into two types. The type-I plagioclase crystals show relatively homogeneous Sr isotope values (0.7035–0.7038, 1σ <0.0001), indicating crystallization from a relatively stable and long-lived felsic magma chamber. The type-II plagioclase grains have a wider range of Sr isotope compositions (0.7032–0.7039, 1σ <0.0001), indicating mafic and/or felsic magma recharge. In magmatic titanite, Nb/Ta values are higher than those in the whole rock, while Zr/Hf and Y/Ho values are lower. In hydrothermal titanite and epidote, the ratios are similar to those in the whole rock. These patterns reflect crystallization effects imposed during the magmatic stage but an absence of differentiation during the hydrothermal stage. The consistent gradual decrease in total rare earth element, Y, Zr, and U contents in both hydrothermal titanite and epidote from early to late stages indicates the effect of hydrothermal fluid evolution with decreasing temperature. The variation of 87Sr/86Sr values in magmatic amphibole, plagioclase, and hydrothermal epidote in felsic and mafic rocks indicates the addition of mafic magma-derived fluid into the felsic magma-derived fluid. One extra source of fluid (probably derived from wall-rock limestone) was required to generate the highly radiogenic 87Sr/86Sr values of some epidote (0.7038–0.7053). Thus, in situ elemental and Sr isotope variation in minerals from different paragenetic stages can be used to interpret formation process and source for both magmas and hydrothermal fluids.

HNGF Peptides Elicit the NGF-TrkA Signalling Pathway in Cholinergic Neurons and Retain Full Neurotrophic Activity in the DRG Assay.

In the last decade, Nerve Growth Factor (NGF)-based clinical approaches have lacked specific and efficient Tyrosine Kinase A (TrkA) agonists for brain delivery. Nowadays, the characterization of novel small peptidomimetic is taking centre stage in preclinical studies, in order to overcome the main size-related limitation in brain delivery of NGF holoprotein for Central Nervous System (CNS) pathologies. Here we investigated the NGF mimetic properties of the human NGF 1–14 sequence (hNGF1–14) and its derivatives, by resorting to primary cholinergic and dorsal root ganglia (DRG) neurons. Briefly, we observed that: 1) hNGF1–14 peptides engage the NGF pathway through TrkA phosphorylation at tyrosine 490 (Y490), and activation of ShcC/PI3K and Plc-γ/MAPK signalling, promoting AKT-dependent survival and CREB-driven neuronal activity, as seen by levels of the immediate early gene c-Fos, of the cholinergic marker Choline Acetyltransferase (ChAT), and of Brain Derived Neurotrophic Factor (BDNF); 2) their NGF mimetic activity is lost upon selective TrkA inhibition by means of GW441756; 3) hNGF1–14 peptides are able to sustain DRG survival and differentiation in absence of NGF. Furthermore, the acetylated derivative Ac-hNGF1–14 demonstrated an optimal NGF mimetic activity in both neuronal paradigms and an electrophysiological profile similar to NGF in cholinergic neurons. Cumulatively, the findings here reported pinpoint the hNGF1–14 peptide, and in particular its acetylated derivative, as novel, specific and low molecular weight TrkA specific agonists in both CNS and PNS primary neurons.

Ofrendas en el Inframundo: el Libro de las Doce Cavernas en el Osireion de Abidos

The Book of the Twelve Caverns consists of a litany of deities who inhabited these mythical regions of the Beyond. The versatility of its cosmographic nature enabled its use and adaptation to different contexts. It was used in certain liturgical ceremonies in temples and also in a funerary sphere related to the burial equipment of certain deceased individuals in order to help them in their journey through the caverns of the Duat. The version of the composition inscribed in the south chamber of the Osireion in Abydos is, beyond any doubt, the most completed copy hitherto preserved. It can be dated to the reign of Merenptah (c. 1213-1203 BC). The aim of this paper is to present the main features of this example of the book. Its specific features will be highlighted, as well as its textual and iconographic adaptation to the cultic sphere. The absence of differentiation in some aspects to the funerary versions of the book will also be underlined. The composition will be analysed in the architectonical context of the chamber and, at a more general level, in the iconographic programme of the Osirian underground complex. Finally, the relationship with some other sources throughout the history of the book’s transmission will be detailed

Structured Decentralized Control of Positive Systems With Applications to Combination Drug Therapy and Leader Selection in Directed Networks

We study a class of structured optimal control problems in which the main diagonal of the dynamic matrix is a linear function of the design variable. While such problems are in general challenging and nonconvex, for positive systems we prove convexity of the $H_2$ and $H_\infty$ optimal control formulations which allow for arbitrary convex constraints and regularization of the control input. Moreover, we establish differentiability of the $H_\infty$ norm when the graph associated with the dynamical generator is weakly connected and develop a customized algorithm for computing the optimal solution even in the absence of differentiability. We apply our results to the problems of leader selection in directed consensus networks and combination drug therapy for HIV treatment. In the context of leader selection, we address the combinatorial challenge by deriving upper and lower bounds on optimal performance. For combination drug therapy, we develop a customized subgradient method for efficient treatment of diseases whose mutation patterns are not connected.

Mast Cells Regulate CD4+ T Cell Differentiation in Absence of Antigen Presentation

Given their unique capacity for antigen uptake, processing, and presentation, antigen presenting cells (APCs) are critical for initiating and regulating innate and adaptive immune responses. Using bone marrow-derived mast cells and mast cell (MC) deficient mice, our in vivo and in vitro findings indicate that following NAD+ administration MCs, exclusively, promote CD4+ T-cell differentiation, both in absence of antigen and independently of major APCs. Moreover, we found that MCs mediated CD4+ T-cell differentiation independently of MHC-II and TCR signaling machinery. Although treatment with NAD+ resulted in a decreased MHC-II expression on CD11c+ cells, MC-mediated CD4+ T-cell differentiation rendered mice resistant to lethal doses of Listeria monocytogenes. Collectively, our study unravels a novel cellular and molecular pathway that regulates innate and adaptive immunity via MCs and may pave the way for novel therapeutic approaches in the context of immunodeficiencies and antimicrobial resistance.

Israel’s Mediterranean Gas Governance: Evolution of Domestic Regulations and Emerging Regional Issues

:In recent years, Israel has discovered commercially viable natural gas deposits in what the state considers its exclusive economic zone (EEZ) in the Eastern Mediterranean. While these gas discoveries constitute less than 2% of the world’s proven gas reserves, they have the potential to not only meet Israel’s energy needs for several years to come but also enable Israel to export some amount of gas to neighboring countries as well as transregionally, to Europe. While these maritime gas fields have transformed Israel – from energy deficient to energy surplus country – Israeli policymakers are confronted with three main challenges – the revamping of taxation rules, allocation of an export quota for export, and the introduction of competition in the energy sector. The potential for export of gas presents Israel with both opportunities and challenges. While the possibilities include export to Egypt, Turkey and Europe, earning a significant monetary dividend for Israel, problems include territorial disputes and contesting claims over resources among regional countries. The gas supply to Jordanian companies is the only favorable trade deal yet for Israeli field developers. In the absence of differentiation of the exclusive economic zones in the Eastern Mediterranean region, given the political disputes between Turkey and Cyprus and Israel and Lebanon, Israeli gas export ideas may not materialize anytime soon.

GOSH: derivative-free global optimization using multi-dimensional space-filling curves

Global optimization is a field of mathematical programming dealing with finding global (absolute) minima of multi-dimensional multiextremal functions. Problems of this kind where the objective function is non-differentiable, satisfies the Lipschitz condition with an unknown Lipschitz constant, and is given as a “black-box” are very often encountered in engineering optimization applications. Due to the presence of multiple local minima and the absence of differentiability, traditional optimization techniques using gradients and working with problems having only one minimum cannot be applied in this case. These real-life applied problems are attacked here by employing one of the mostly abstract mathematical objects—space-filling curves. A practical derivative-free deterministic method reducing the dimensionality of the problem by using space-filling curves and working simultaneously with all possible estimates of Lipschitz and Holder constants is proposed. A smart adaptive balancing of local and global information collected during the search is performed at each iteration. Conditions ensuring convergence of the new method to the global minima are established. Results of numerical experiments on 1000 randomly generated test functions show a clear superiority of the new method w.r.t. the popular method DIRECT and other competitors.

IRAGu: A Novel Inducible and Reversible Mouse Model for Ubiquitous Recombinase Activity.

Developing lymphocytes express the recombination activating genes (RAGs) 1 and 2 products that form a site specific recombinase complex (RAG), introducing double strand DNA breaks (DSBs) at recombination signal sequences (RSSs) flanking the V, D, and J gene segments in the antigen receptor loci. The subsequent steps in the reaction consist in the ligation of DSBs by ubiquitous enzymes of the non-homologous end joining DNA repair pathway. This mutagenesis process is responsible for the generation of the very large clonal diversity of T and B lymphocytes, itself allowing the recognition of a virtually open-ended antigenic universe. Sequences resembling RSS are found at high frequency all over the genome, and involved in RAG mediated illegitimate recombination and translocations. Hence, natural and induced ectopic activity of RAG is a threat to the genome only recently underscored. Here, we report and characterize a novel mouse transgenic system for which ubiquitous expression of the recombinase is inducible. In this system, the RAG1 protein is constitutively expressed and functional, while the RAG2 protein, coupled to the estrogen receptor, becomes functionally active upon 4-hydroxytamoxifen (TAM) administration. We describe two transgenic lines. The first one, when introgressed into an endogenous Rag2−/− genetic background is faithfully recapitulating lymphocyte development, repertoire dynamics and cryptic rearrangements, in a TAM-dependent manner. In this model, deprivation of TAM is followed by lymphocyte development arrest, evidencing the reversibility of the system. The second transgenic line is leaky, as the transgenes promote lymphocyte differentiation in absence of TAM treatment. Upon TAM-induction defects in lymphocytes composition and global health reveals the deleterious effect of uncontrolled RAG activity. Overall, this novel transgenic model provides a tool where RAG activity can be specifically manipulated to assess the dynamics of lymphocyte differentiation and the challenges imposed by the recombinase on the vertebrate genome.