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Treatments to rescue vision are currently limited. Here, the authors identify a cone-driven gain control mechanism that reduces visual function beyond the atrophic area in humans. They also show that activating laterally projecting cells results improved vision in two mouse models of retinal degeneration.

Flooding is a consequence of the prevailing meteorological situation, the intensity and duration of precipitation, geomorphology, human activities over a geographical region and other factors. Floods result in damage and destruction of infrastructure and private property and, in some cases, in fatalities. Flash floods are sudden and quite localized in extend, characterized by excessive amounts of rainfall within a short period of time and are distinguished from other floods by their degree of severity. The broader knowledge concerning flash floods is useful for the better understanding of the underlying thermodynamic and dynamic mechanisms, as well as the associated physical processes. The wider understanding of flashfloods can form part of an integrated system for short and very short forecasting of these events. In the present study, the synoptic, dynamic and thermodynamic conditions during the development of a baroclinic depression which affected the area of Cyprus on 6 November 2005 are studied. The depression was associated with extreme weather phenomena, such as thunderstorms, a water spout and high precipitation accumulations. The results indicate the importance of the dynamic parameters in the system's development and the thermodynamic analysis has shown the convective potential of the atmosphere.

This prospective, case-control study evaluated the impact of obesity on oocyte quality based on mtDNA expression in cumulus cells (CC), and on bone morphogenetic protein 15 (BMP-15) and heparan sulfate proteoglycan 2 (HSPG2) in follicular fluid (FF). It included women 18 to <40 years of age, divided according to BMI < 24.9 (Group 1, n = 28) and BMI > 25 (Group 2, n = 22). Demographics, treatment, and pregnancy outcomes were compared. The mtDNA in CC, BMP-15, HSPG2, the lipid profile, the hormonal profile, and C-reactive protein were evaluated in FF and in blood samples. The BMP-15 levels in FF and the mitochondrial DNA in CC were higher in Group 1 (38.8 ± 32.5 vs. 14.3 ± 10.8 ng/mL; p = 0.001 and 1.10 ± 0.3 vs. 0.87 ± 0.18-fold change; p = 0.016, respectively) than in Group 2. High-density lipoprotein levels in blood and FF were higher in Group 1 (62 ± 18 vs. 50 ± 12 mg/dL; p = 0.015 and 34 ± 26 vs. 20.9 ± 7.2 mg/dL; p = 0.05, respectively). Group 2 had higher blood C-reactive protein (7.1 ± 5.4 vs. 3.4 ± 4.3 mg/L; p = 0.015), FF (5.2 ± 3.8 vs. 1.5 ± 1.6 mg/L; p = 0.002) and low-density lipoprotein levels (91 ± 27 vs. 71 ± 22 mg/dL; p = 0.008) vs. Group 1. Group 1 demonstrated a trend toward a better clinical pregnancy rate (47.8% vs. 28.6%: p = 0.31) and frozen embryo transfer rate (69.2% vs. 53.8; p = 0.69). Higher BMI resulted in lower BMP-15 levels and reduced mtDNA expression, which reflect decreased oocyte quality in overweight women.

This prospective, observational study investigated the incidence of irregular cleavage (IRC) among human embryos and its influence on IVF treatment outcomes. It included 1001 women who underwent 1976 assisted reproduction treatments during 2016-2021 in a single IVF clinic. Embryo morphokinetics were analyzed and evaluated for the association between IRC and women's characteristics, treatment characteristics, and pregnancy outcomes. The incidence of IRC was 17.5% (1689/9632 embryos). Of these, 85% of the embryos had one IRC, 15% had multiple IRC and 35% of IRC events occurred during the embryo's first cell cycle. IRC embryos were found to correlate with male factor ( p = 0.01) and higher ICSI rate ( p = 0.01). Age, BMI, parity, basal FSH level, stimulation protocol, and number of retrieved oocytes did not differ between groups. Embryos with early IRC or more than one IRC had lower blastulation rates ( p = 0.01 for each). Fresh cycles with IRC embryos had a lower clinical pregnancy rate ( p = 0.01) and embryos with early IRC had a lower live birth rate ( p = 0.04) compared to embryos without IRC. Frozen transfer cycles of blastocyst embryos, with or without IRC, had comparable results. In conclusion, the number of abnormal cleavage events and their timing are important factors in the prognosis of the developing human embryo.

Follicular lymphoma (FL) is an indolent disease, characterized by a median life expectancy of 18-20 years and by intermittent periods of relapse and remission. FL frequently transforms into the more aggressive diffuse large B cell lymphoma (t-FL). In previous studies, the analysis of immunoglobulin heavy chain variable region (IgHV) genes in sequential biopsies from the same patient revealed two different patterns of tumor clonal evolution: direct evolution, through acquisition of additional IgHV mutations over time, or divergent evolution, in which lymphoma clones from serial biopsies independently develop from a less-mutated common progenitor cell (CPC). Our goal in this study was to characterize the somatic hypermutation (SHM) patterns of IgHV genes in sequential FL samples from the same patients, and address the question of whether the mutation mechanisms (SHM targeting, DNA repair or both), or selection forces acting on the tumor clones, were different in FL samples compared to healthy control samples, or in late relapsed/transformed FL samples compared to earlier ones. Our analysis revealed differences in the distribution of mutations from each of the nucleotides when tumor and non-tumor clones were compared, while FL and transformed FL (t-FL) tumor clones displayed similar mutation distributions. Lineage tree measurements suggested that either initial clone affinity or selection thresholds were lower in FL samples compared to controls, but similar between FL and t-FL samples. Finally, we observed that both FL and t-FL tumor clones tend to accumulate larger numbers of potential N-glycosylation sites due to the introduction of new SHM. Taken together, these results suggest that transformation into t-FL, in contrast to initial FL development, is not associated with any major changes in DNA targeting or repair, or the selection threshold of the tumor clone., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Michaeli, Carlotti, Hazanov, Gribben and Mehr.)

The present study aims to investigate whether a sense of relatedness to a city helps to broaden understanding of the restorative potential of urban public spaces. Findings based on a sample of German adults ( n = 249) confirm that people experience relatedness to a city. The study's 3 × 3 (built, mixed, natural environment) × (average, livability environment, bird's-eye view) design revealed disordinal interactions for being away, fascination, preference, mental fatigue, and stimulating and activating effects associated with cities. This implies that humans' place perceptions are more complex than previously assumed. Both city and nature relatedness were relevant covariates of these findings. Surprisingly, the construct 'activating effects', was found to be mostly perceived as more positive for mixed and built environments compared to natural environments. Thus, complementing restorative environments research by introducing a measure for city relatedness significantly enhances understanding of the potential of urban public spaces for promoting human health and well-being.

Aim: To find a cut-off ratio of estradiol/metaphase II oocyte (E2/M2) ratio and to evaluate the correlation with patients' characteristics, embryo morphokinetics using EmbryoScope™ and IVF cycle outcomes., Material and Methods: For this retrospective cohort study, records of all fresh cycles that were cultured and scored by EmbryoScope™ were evaluated. The peak E2/M2 ratio was calculated on the day of human chorionic gonadotropin (hCG) administration and correlated to embryo morphokinetic quality and cycle outcomes. A receiver operating characteristics analysis was calculated for the E2/M2 ratio and clinical pregnancy rates., Results: A total of 2461 oocytes were collected from 319 patients. Receiver operating characteristics analysis revealed a cutoff of 204 as a discriminative point to predict clinical pregnancy with a sensitivity of 69.5% and specificity of 62.1% (P < 0.001). E2/M2 > 204 group were older, had higher E2 concentration, fewer M2 oocytes despite elevated gonadotrophin doses. E2/M2 ratio ≤ 204 was correlated with higher fertilization rate, better embryo quality, higher pregnancy and live birth rates, and more frozen embryos., Conclusion: E2/M2 ratio < 204 yielded the best probability to achieve good quality embryos with good morphokinetic scores and better pregnancy outcomes and may be used to predict IVF cycle outcomes. Advanced maternal age and low ovarian response received higher concentrations of gonadotrophins, which resulted in higher E2/M2 ratio. Milder stimulation to those patients may improve their cycle outcomes.

The presence of Degenerated Oocyte (DEG) was mostly described after intracytoplasmic sperm injection (ICSI), with fewer reports on DEG at the time of ovum pick-up (OPU). This study aims to assess morphokinetics of embryos cultured in a time-lapse incubator and compare cohorts with and without DEG at OPU. In a retrospective cohort study from January 1, 2016 until September 31, 2017 a total of 399 IVF/ICSI cycles and 2980 embryos were evaluated. In 81 of 399 cycles at least one DEG oocyte was observed at the time of OPU. The remaining 318 cycles with no DEG oocyte were compared as a control group. In the DEG group, significantly more oocytes were collected per patient (12.9 ± 7.2 vs. 10.1 ± 6.1. P < 0.001). Fertilization rate, pregnancy and clinical pregnancy rates were comparable between the two groups, however, the morphokinetics and developmental scores of the embryos were significantly worse in the DEG group, (KID 3.4 ± 1.6 vs. 3.2 ± 1.6 P = 0.002 and ESHRE 1.5 ± 1.1 vs. 1.4 ± 1.0 P = 0.046). Significantly more patients achieved top-quality embryos in the NON DEG group (58.8% vs. 53.0%, P = 0.03), however, comparable delivery rate was achieved in both groups. In the DEG group, the frequency of DEG oocyte per cycle was negatively correlated with pregnancy rate. GnRH agonist protocol and the 17-20G needle used for OPU were significant predictors for the presence of DEG oocyte at OPU. In conclusions DEG oocyte may negatively affect IVF outcome, however, younger patients, and significantly more oocytes collected in the DEG group compensate for the IVF results.

Background: Lipids are an important source for energy production during oocyte maturation. The accumulation of intracellular lipids binds to proteins to form lipid droplets. This may lead to cellular lipotoxicity. The impact of lipotoxicity on cumulus and granulosa cells has been reported. This pilot study evaluated their correlation to oocyte and embryo quality., Design: Prospective case-control study., Setting: Referral IVF unit., Patients: Women younger than age 40, undergoing IVF with intracytoplasmic sperm injection., Interventions: 15 women with BMI > 30 (high BMI) and 26 women with BMI < 25 (low BMI) were enrolled. IVF outcomes were compared between groups based on BMI. Lipid content in cumulus and granulosa cells was evaluated using quantitative and descriptive methods. Lipid profile, hormonal profile and C-reactive protein were evaluated in blood and follicular fluid samples. Demographic and treatment data, as well as pregnancy rates were collected from electronic medical records., Results: Higher levels of LDL and CRP, slower cell division rate and lower embryo quality were found in the group with high BMI. There was no difference in pregnancy rates between groups. In light of these findings, treatment outcomes were reanalyzed according to patients who became pregnant and those who did not. We found that patients who conceived had significantly lower fat content in the granulosa cells, reflected by mean fluorescence intensity recorded by flow cytometry analysis (23,404 vs. 9370, P = 0.03)., Conclusions: BMI has no effect on lipid content in cumulus and granulosa cells, and does not affect likelihood of pregnancy. However, women who achieved pregnancy, regardless of their BMI, had lower lipid levels in their granulosa cells. This finding is important and further study is needed to evaluate lipid content in granulosa cells as a potential predictor of IVF treatment success.

To examine the effect of serum follicle-stimulating hormone (sFSH) level, body-mass index (BMI) and smoking on Testicular Sperm Extraction-Intracytoplasmic Sperm Injection (TESE-ICSI), and pregnancy outcomes.In this retrospective study, data were extracted from files of 52 azoospermic men who underwent TESE and in-vitro fertilization (IVF)-ICSI in our IVF unit. Demographic information, treatment cycle follow-up and pregnancy outcomes were collected.Fifty-two patients underwent 79 TESE due to azoospermia in 143 IVF cycles. Smoking was found to significantly affect sperm motility in TESE specimens before freezing (45.5% vs 14.8%; P <.001); however, this finding did not influence the pregnancy rate. Male FSH was inversely correlated with testicle volume (r = -0.595, P <.0001). Body weight did not affect semen parameters after TESE or ICSI outcomes.Among azoospermic patients with extremely poor sperm quality, male BMI, male FSH or smoking did not have an adverse effect sperm parameters or pregnancy and delivery rates.

Background: Obesity is associated with several fertility disorders. This prospective cohort study was designed to evaluate the effect of body mass index (BMI) (kg/m 2 ) on oocyte diameter and treatment., Methods: Women undergoing in vitro fertilization (IVF) with intracytoplasmic sperm injection (ICSI) were enrolled in the study. They were divided into two groups according to BMI: obese (BMI > 30) and normal weight (BMI < 25). Mature oocytes were evaluated according to total diameter, zona pellucida, and oolema diameters., Results: A total of 387 oocytes were obtained from the 46 women who participated. Significantly more mature oocytes (M2) were retrieved from normal weight patients compare to obese women (15.1 ± 6.8 vs. 9.7 ± 3.9, respectively, P < 0.001). Oocytes from women in the obese group were significantly smaller than those in the normal weight group, including oocyte diameter (157.9 ± 7.9 vs. 164.3 ± 5.1 μm, P < 0.0001), oolema diameter (110.3 ± 4.5 vs. 113.5 ± 3.5 μm, P < 0.0001), and zona pellucida thickness (17.9 ± 2.6 vs. 19.0 ± 2.4 μm, P < 0.000), respectively. Multivariate logistic regression analysis, including oolema diameter, female age, BMI, number of M2 oocytes, and zona pellucida, was conducted to predict pregnancy. Small oolema diameter in obese patient adversely correlated with pregnancy. Larger oolema diameter was positively associated with the probability of pregnancy in the obese group as well as thinner zona pellucida., Conclusion: Obesity is associated with smaller oocytes, which adversely affect fertility outcomes., Trial Registration: NIH number NCT01672931.

Long-lived plasma cells are critical to humoral immunity as a lifelong source of protective antibodies. Antigen-activated B cells-with T-cell help-undergo affinity maturation within germinal centres and persist as long-lived IgG plasma cells in the bone marrow. Here we show that antigen-specific, induced IgM plasma cells also persist for a lifetime. Unlike long-lived IgG plasma cells, which develop in germinal centres and then home to the bone marrow, IgM plasma cells are primarily retained within the spleen and can develop even in the absence of germinal centres. Interestingly, their expressed IgV loci exhibit somatic mutations introduced by the activation-induced cytidine deaminase (AID). However, these IgM plasma cells are probably not antigen-selected, as replacement mutations are spread through the variable segment and not enriched within the CDRs. Finally, antibodies from long-lived IgM plasma cells provide protective host immunity against a lethal virus challenge.

Objective: Increased progesterone level during follicular phase seemed to be associated with decreased pregnancy rate., Study Design and Methods: A prospective cohort study, 1.1.2012 - 31.8.13. The Progesterone (P) and Progesterone/Estrogen (P/E2) level on ovulation induction day were compared between the protocols and the different gonadotropins used. Roc analysis was calculated to determine the cutoff of P/E2 to predict delivery rates. P/E2 ratio was calculated as PX1000/e2 level., Main Results: One hundred thirty-nine patients were enrolled to the study. No difference in the P level at hCG stimulation day between different protocols, however, E2 and P/E2 ratio were significantly lower in the long protocol compare with antagonist protocol 1757.7 ± 923.2 vs. 1342.9 ± 1223; P = 0.003 and 0.48 ± 0.31 vs. 0.83 ± 0.87; P = 0.038). The endometrium was significantly thicker in the long group compare with short and antagonist. Significantly more top-quality embryos (TOP) were achieved in the antagonist group. Comparable results between the types of gonadotropins used in regards with cycle characteristics and pregnancy and delivery rates. The P/E2 ratio which can predict live birth rate was found to be 0.45, AUC = 0.632, p = 0.02 and 95 % CI 0.525-0.738 and a significantly higher pregnancy and delivery rates at a P/E2 bellow 0.45., Conclusion: Endometrial receptivity is determined by the complex interactions of E2 and P.

Understanding the dynamics of evolution of Follicular Lymphoma (FL) clones during disease progression is important for monitoring and targeting this tumor effectively. Genetic profiling of serial FL biopsies and examples of FL transmission following bone marrow transplant suggest that this disease may evolve by divergent evolution from a common ancestor cell. However where this ancestor cell resides and how it evolves is still unclear. The analysis of the pattern of somatic hypermutation of the immunoglobulin gene (Ig) is traditionally used for tracking the physiological clonal evolution of B cells within the germinal center and allows to discriminate those cells that have just entered the germinal center and display features of ancestor cells from those B cells that keep re-circulating across different lymphoid organs. Here we investigated the pattern of somatic hypermutation of the heavy chain of the immunoglobulin gene (IgH-VH) in 4 flow-sorted B cells subpopulations belonging to different stages of differentiation, from sequential lymph node biopsies of cases displaying diverse patterns of evolution, using the GS-FLX Titanium sequencing platform. We observed an unexpectedly high level of clonality, with hundreds of distinct tumor subclones in the different subpopulations from the same sample, the majority detected at a frequency <10-2. By using a lineage trees analysis we observed in all our FL and t-FL cases that the oligoclonal FL population was trapped in a narrow intermediate stage of maturation that maintains the capacity to undergo SHM, but was unable to further differentiate. The presence of such a complex architecture highlights challenges currently encountered in finding a cure for this disease.

We investigated prevalence of hepatitis E virus in a sample of the population of Israel. The overall seroprevalence of antibodies to the virus was 10.6% (95% CI 8.4%-13.0%); age-adjusted prevalence was 7.6%. Seropositivity was associated with age, Arab ethnicity, low socioeconomic status, and birth in Africa, Asia, or the former Soviet Union.

The Bio-Rad Geenius HIV 1/2 assay was evaluated as an alternative to the INNO-LIA HIV 1/2 assay for the confirmation of HIV infection in 198 serum samples reactive to 4th-generation HIV enzyme immunoassays (EIAs). The Geenius assay correctly identified 85% of the samples, compared to 75% identified by the INNO-LIA assay, reduced the number of indeterminate results, and shortened the overall turnaround time., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)

Chronic gastritis is characterized by gastric mucosal inflammation due to autoimmune responses or infection, frequently with Helicobacter pylori. Gastritis with H. pylori background can cause gastric mucosa-associated lymphoid tissue lymphoma (MALT-L), which sometimes further transforms into diffuse large B-cell lymphoma (DLBCL). However, gastric DLBCL can also be initiated de novo. The mechanisms underlying transformation into DLBCL are not completely understood. We analyzed immunoglobulin repertoires and clonal trees to investigate whether and how immunoglobulin gene repertoires, clonal diversification, and selection in gastritis, gastric MALT-L, and DLBCL differ from each other and from normal responses. The two gastritis types (positive or negative for H. pylori) had similarly diverse repertoires. MALT-L dominant clones (defined as the largest clones in each sample) presented higher diversification and longer mutational histories compared with all other conditions. DLBCL dominant clones displayed lower clonal diversification, suggesting the transforming events are triggered by similar responses in different patients. These results are surprising, as we expected to find similarities between the dominant clones of gastritis and MALT-L and between those of MALT-L and DLBCL.

Background: Immunoglobulin (that is, antibody) and T cell receptor genes are created through somatic gene rearrangement from gene segment libraries. Immunoglobulin genes are further diversified by somatic hypermutation and selection during the immune response. Studying the repertoires of these genes yields valuable insights into immune system function in infections, aging, autoimmune diseases and cancers. The introduction of high throughput sequencing has generated unprecedented amounts of repertoire and mutation data from immunoglobulin genes. However, common analysis programs are not appropriate for pre-processing and analyzing these data due to the lack of a template or reference for the whole gene., Results: We present here the automated analysis pipeline we created for this purpose, which integrates various software packages of our own development and others', and demonstrate its performance., Conclusions: Our analysis pipeline presented here is highly modular, and makes it possible to analyze the data resulting from high-throughput sequencing of immunoglobulin genes, in spite of the lack of a template gene. An executable version of the Automation program (and its source code) is freely available for downloading from our website: http://immsilico2.lnx.biu.ac.il/Software.html.

High-throughput sequencing (HTS) yields tens of thousands to millions of sequences that require a large amount of pre-processing work to clean various artifacts. Such cleaning cannot be performed manually. Existing programs are not suitable for immunoglobulin (Ig) genes, which are variable and often highly mutated. This paper describes Ig High-Throughput Sequencing Cleaner (Ig-HTS-Cleaner), a program containing a simple cleaning procedure that successfully deals with pre-processing of Ig sequences derived from HTS, and Ig Insertion-Deletion Identifier (Ig-Indel-Identifier), a program for identifying legitimate and artifact insertions and/or deletions (indels). Our programs were designed for analyzing Ig gene sequences obtained by 454 sequencing, but they are applicable to all types of sequences and sequencing platforms. Ig-HTS-Cleaner and Ig-Indel-Identifier have been implemented in Java and saved as executable JAR files, supported on Linux and MS Windows. No special requirements are needed in order to run the programs, except for correctly constructing the input files as explained in the text. The programs' performance has been tested and validated on real and simulated data sets.

Objective: To determine whether dendritic cells (DCs), innate immune cells that specialize in initiation and modulation of immune responses, are present in ovarian follicular fluid (FF) and whether their abundance and maturation state correlate with ovarian response to gonadotropins., Design: Observational study., Setting: IVF unit and laboratory for reproductive immunology., Patient(s): Patients undergoing IVF., Intervention(s): None., Main Outcome Measure(s): FF was collected from the first follicle aspirated in each patient, and cellular content was analyzed by flow cytometry. DCs were defined as CD45(+)CD11c(+)HLADR(+)-cells, and the intensity of HLADR expression indicated DC maturity., Result(s): The CD45(+)-hematopoietic cell compartment in FFs (n = 30) contained a significant fraction of CD11c(+)HLADR(+) DCs (15.4% ± 2.9%). The mean fluorescence intensity (MFI) of HLADR expression, which reflects DC maturity, correlated positively with ovarian response to gondotropins, as determined by serum levels of E(2) on the day of hCG administration (r = 0.38)., Conclusion(s): DCs make up a significant fraction of hematopoietic cells in the FF. Furthermore, DC maturation correlates positively with the ovarian response to gonadotropins. It is therefore conceivable that DCs contribute to the sterile inflammatory process in the follicle that leads to ovulation., (Copyright © 2012 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate whether "proangiogenic" CD56+CD16- natural killer (NK) cells, which accumulate in follicular fluid (FF) of patients with a good response to ovarian stimulation, are also present in earlier stages of follicular development., Design: Observational study., Setting: Academic in vitro fertilization (IVF) unit., Patient(s): Patients of similar age and ovarian reserve, undergoing in vitro maturation (IVM; n=10) or IVF (n=22) cycles., Intervention(s): None., Main Outcome Measure(s): FF was collected from the first follicle aspirated in each ovary, and flow cytometry was used to define CD56+CD16- "proangiogenic" or CD56+CD16+ "cytotoxic" NK cells., Result(s): FF derived from antral follicles of patients undergoing IVM (maximum diameter 10 mm) showed a slightly higher abundance of "proangiogenic" NK cells compared with FF from preovulatory mature follicles (>18 mm) of patients undergoing IVF (5.4±1.3% vs. 3.0±1.1% of CD45+CD3- cells). Importantly, antral FF contained a significantly higher concentration of "cytotoxic" NK cells (11.4±2.3% vs. 3.7±0.9% of CD45+CD3- cells) compared with FF from mature follicles., Conclusion(s): "Proangiogenic" NK cells accumulate in ovarian follicles from as early as the antral follicular stage. Maturation of follicles is accompanied by a decrease in the population of "cytotoxic" NK cells that may have deleterious effects on follicular maturation., (Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)