Recommendations for diagnosing STIC: a systematic review and meta-analysis

Our understanding of the oncogenesis of high-grade serous cancer of the ovary and its precursor lesions, such as serous tubal intraepithelial carcinoma (STIC), has significantly increased over the last decades. Adequate and reproducible diagnosis of these precursor lesions is important. Diagnosing STIC can have prognostic consequences and is an absolute requirement for safely offering alternative risk reducing strategies, such as risk reducing salpingectomy with delayed oophorectomy. However, diagnosing STIC is a challenging task, possessing only moderate reproducibility. In this review and meta-analysis, we look at how pathologists come to a diagnosis of STIC. We performed a literature search identifying 39 studies on risk reducing salpingo-oophorectomy in women with a known BRCA1/2 PV, collectively reporting on 6833 patients. We found a pooled estimated proportion of STIC of 2.8% (95% CI, 2.0–3.7). We focused on reported grossing protocols, morphological criteria, level of pathologist training, and the use of immunohistochemistry. The most commonly mentioned morphological characteristics of STIC are (1) loss of cell polarity, (2) nuclear pleomorphism, (3) high nuclear to cytoplasmic ratio, (4) mitotic activity, (5) pseudostratification, and (6) prominent nucleoli. The difference in reported incidence of STIC between studies who totally embedded all specimens and those who did not was 3.2% (95% CI, 2.3–4.2) versus 1.7% (95% CI, 0.0–6.2) (p 0.24). We provide an overview of diagnostic features and present a framework for arriving at an adequate diagnosis, consisting of the use of the SEE-FIM grossing protocol, evaluation by a subspecialized gynecopathologist, rational use of immunohistochemical staining, and obtaining a second opinion from a colleague.

Dietary Observations of Ultra-Endurance Runners in Preparation for and During a Continuous 24-h Event

Carbohydrate (CHO) intake recommendations for events lasting longer than 3h indicate that athletes should ingest up to 90g.h.−1 of multiple transportable carbohydrates (MTC). We examined the dietary intake of amateur (males: n=11, females: n=7) ultra-endurance runners (mean age and mass 41.5±5.1years and 75.8±11.7kg) prior to, and during a 24-h ultra-endurance event. Heart rate and interstitial glucose concentration (indwelling sensor) were also tracked throughout the event. Pre-race diet (each 24 over 48h) was recorded via weighed intake and included the pre-race meal (1–4h pre-race). In-race diet (24h event) was recorded continuously, in-field, by the research team. Analysis revealed that runners did not meet the majority of CHO intake recommendations. CHO intake over 24–48h pre-race was lower than recommended (4.0±1.4g·kg−1; 42±9% of total energy), although pre-race meal CHO intake was within recommended levels (1.5±0.7g·kg−1). In-race CHO intake was only in the 30–60g·h−1 range (mean intake 33±12g·h−1) with suboptimal amounts of multiple transportable CHO consumed. Exercise intensity was low to moderate (mean 68%HRmax 45%VO2max) meaning that there would still be an absolute requirement for CHO to perform optimally in this ultra-event. Indeed, strong to moderate positive correlations were observed between distance covered and both CHO and energy intake in each of the three diet periods studied. Independent t-tests showed significantly different distances achieved by runners consuming ≥5 vs. <5g·kg−1 CHO in pre-race diet [98.5±18.7miles (158.5±30.1km) vs. 78.0±13.5miles (125.5±21.7km), p=0.04] and ≥40 vs. <40g·h−1 CHO in-race [92.2±13.9miles (148.4±22.4km) vs. 74.7±13.5miles (120.2±21.7km), p=0.02]. Pre-race CHO intake was positively associated with ultra-running experience, but no association was found between ultra-running experience and race distance. No association was observed between mean interstitial glucose and dietary intake, or with race distance. Further research should explore approaches to meeting pre-race dietary CHO intake as well as investigating strategies to boost in-race intake of multiple transportable CHO sources. In 24-h ultra-runners, studies examining the performance enhancing benefits of getting closer to meeting pre-race and in-race carbohydrate recommendations are required.

Sarcoplasmic Reticulum Calcium Release Is Required for Arrhythmogenesis in the Mouse

Dysfunctional sarcoplasmic reticulum Ca2+ handling is commonly observed in heart failure, and thought to contribute to arrhythmogenesis through several mechanisms. Some time ago we developed a cardiomyocyte-specific inducible SERCA2 knockout mouse, which is remarkable in the degree to which major adaptations to sarcolemmal Ca2+ entry and efflux overcome the deficit in SR reuptake to permit relatively normal contractile function. Conventionally, those adaptations would also be expected to dramatically increase arrhythmia susceptibility. However, that susceptibility has never been tested, and it is possible that the very rapid repolarization of the murine action potential (AP) allows for large changes in sarcolemmal Ca2+ transport without substantially disrupting electrophysiologic stability. We investigated this hypothesis through telemetric ECG recording in the SERCA2-KO mouse, and patch-clamp electrophysiology, Ca2+ imaging, and mathematical modeling of isolated SERCA2-KO myocytes. While the SERCA2-KO animals exhibit major (and unique) electrophysiologic adaptations at both the organ and cell levels, they remain resistant to arrhythmia. A marked increase in peak L-type calcium (ICaL) current and slowed ICaL decay elicited pronounced prolongation of initial repolarization, but faster late repolarization normalizes overall AP duration. Early afterdepolarizations were seldom observed in KO animals, and those that were observed exhibited a mechanism intermediate between murine and large mammal dynamical properties. As expected, spontaneous SR Ca2+ sparks and waves were virtually absent. Together these findings suggest that intact SR Ca2+ handling is an absolute requirement for triggered arrhythmia in the mouse, and that in its absence, dramatic changes to the major inward currents can be resisted by the substantial K+ current reserve, even at end-stage disease.

Sosialisasi Konsep Lahan Pertanian Pangan Berkelanjutan Di Kecamatan Batang Tuaka, Kabupaten Indragiri Hilir

Availability of land for agriculture is an absolute requirement to achieve self-reliance, security and food sovereignty. However, Indonesian farmland tends to decline due to land conversion. Therefore, determining sustainable food farmland and regulating the conversion of food farmland is one of the most strategic policies to achieve food security. The Spatial Plan of the Province of Riau in the Spatial Pattern Plan section states that one of the areas focused on wetland agriculture (rice) is Indragiri Hilir Regency. However, the high conversion of agricultural land threatens the survival of Sustainable Food Agricultural Land. Since the LP2B policy is very dependent on the willingness of the farmers who own the fields, it is considered necessary to socialize the concept of this LP2B policy among farmers so that they can support government policy in achieving food sovereignty. The results of the analysis show that Batang Tuaka sub-district has the potential to be used as Sustainable Food Agricultural Land (LP2B), but unfortunately this is not supported by farmers' knowledge and understanding of the LP2B concept, so the conversion of farmland is becoming more common and can threaten the realization of food security in Indragiri Hilir Regency.

Abstract 107: Selective Igf-1 Production By Resident Cardiac Macrophages Orchestrates Adaptive Cardiomyocyte Growth During Hypertensive Stress

Objective: Adaptive cardiomyocyte growth is an essential compensatory response to hypertension. While hypertension activates cardiac immune cells, their role in adaptation is unclear. Here, we define the transcriptional heterogeneity and functional role of cardiac resident macrophages (RMs) in vivo in hypertensive heart disease. Methods: We performed flow cytometry, immunofluorescence, and single-cell transcriptomics on fate-mapped cardiac RMs isolated from mice with angiotensin II infusion in acute (day 4) and chronic hypertensive stress (day 28). Following inducible depletion of RMs or specific genetic deletion of Igf1 in RMs during hypertension in mice, functional outcomes were tested with echocardiography and immunohistochemistry. Lastly, we also performed single-cell RNA sequencing on human cardiac macrophages from healthy and diseased samples. Results: Cardiac RMs possess numerous transcriptionally diverse cell states with a core repertoire of reparative gene programs that includes high expression of Igf1 in normotensive animals. Individual cell states were differentially responsive during hypertension while all maintained their original transcriptional identity. Hypertension drove selective in situ proliferation and numerical expansion of some cardiac RMs, directly correlating with increased cardiomyocyte size. Inducible ablation of RMs, or selective deletion of RM-derived IGF-1 caused complete absence of adaptive cardiomyocyte growth and development of cardiac dysfunction. Single-cell transcriptomics further identified a conserved IGF1 -expressing macrophage subpopulation in human cardiomyopathy. Conclusions: Here, we defined the absolute requirement of cardiac RM-produced IGF-1 in adaptive cardiomyocyte growth during hypertension, identifying a novel and essential pathway of RM-directed cardiac adaptation to disease.

Prinsip-Prinsip Hidup yang Berkenan di Hadapan Tuhan dalam Pujian Penyembahan Menurut 2 Tawarikh 5-7 dan Aplikasinya bagi Orang Percaya Masa Kini

Praise and worship are the foundation of every believer’s live. In almost all aspects of the believer’s life, worship is contorted with praise. Praise of worship became the focus of ehaven and especially in Old Testament times, praise worship became the center of worship tog God. However, it is still not too focused on the life of worship and praise. Whereas in worship praise, Jesus was present and touched His people. Sometimes what happens praise worship also becomes a routine in achurch. Even the lives of believers are not in accordance with God’s Word, so God is not present in worship praise. Because it cannot be separated between the life of believer and the praise of worship. A life that is in holiness is and absolute requirement for praise and worship to be pleasing before God. The context of this discussion is focused on the praised and worship that Salomon did when consctrating the Temple, where the Lord was present. This study uses a descriptive method, which is to leanr about the Principles of Living A Good Life Before God in Praise and Worship According to 2 Chronicles 5-7 and its Application for Believers Today. The goal is that through writing, namely : First, believers understand how important praise and worship are; Second : believers understand and have an attitude of life that is pleasing before God in praising and worshiping Him; Third, God is present in the worship of every believers.

CTP promotes efficient ParB-dependent DNA condensation by facilitating one-dimensional diffusion from parS

Faithful segregation of bacterial chromosomes relies on the ParABS partitioning system and the SMC complex. In this work, we used single molecule techniques to investigate the role of cytidine triphosphate (CTP) binding and hydrolysis in the critical interaction between centromere-like parS DNA sequences and the ParB CTPase. Using a combined optical tweezers confocal microscope, we observe the specific interaction of ParB with parS directly. Binding around parS is enhanced by the presence of CTP or the non-hydrolysable analogue CTPgS. However, ParB proteins are also detected at a lower density in distal non-specific DNA. This requires the presence of a parS loading site and is prevented by protein roadblocks, consistent with one dimensional diffusion by a sliding clamp. ParB diffusion on non-specific DNA is corroborated by direct visualization and quantification of movement of individual quantum-dot labelled ParB. Magnetic tweezers experiments show that the spreading activity, which has an absolute requirement for CTP binding but not hydrolysis, results in the condensation of parS-containing DNA molecules at low nanomolar protein concentrations.

Eukaryotic stress induced mutagenesis is limited by a local control of Translesion Synthesis

The DNA Damage Response (DDR) preserves the genetic integrity of the cell by sensing and repairing damages after a genotoxic stress. Translesion Synthesis (TLS), an error-prone DNA damage tolerance pathway, is controlled by PCNA ubiquitination. In this report, we raise the question whether TLS is controlled locally, or globally. Using a recently developed method that allows to follow the bypass of a single lesion inserted into the yeast genome, we show that: i) TLS is controlled locally at each individual lesion by PCNA ubiquitination, ii) a single lesion is enough to induce PCNA ubiquitination, and iii) PCNA ubiquitination is an absolute requirement for TLS to occur. More importantly, we show that global PCNA ubiquitination that follows a genotoxic stress does not increase TLS at individual lesions. We conclude that unlike the SOS response in bacteria, the eukaryotic DDR does not promote TLS and mutagenesis.

Fire-mediated germination syndromes in Leucadendron (Proteaceae) and their functional correlates

A mechanistic understanding of fire-driven seedling recruitment is essential for effective conservation management of fire-prone vegetation, such as South African fynbos, especially with rare and threatened taxa. The genus Leucadendron (Proteaceae) is an ideal candidate for comparative germination studies, comprising 85 species with a mixture of contrasting life-history traits (killed by fire vs able to resprout; serotinous vs geosporous) and seed morphologies (nutlets vs winged achenes). Individual and combined effects of heat and smoke on seed germination of 40 species were quantified in the laboratory, and Bayesian inference applied to distinguish biologically meaningful treatment effects from non-zero, but biologically trivial, effects. Three germination syndromes were identified based on whether germination was dependent on, enhanced by, or independent of direct fire cues (heat and smoke). Seed storage location was the most reliable predictor of germination syndromes, with soil-stored seeds c. 80% more likely to respond to direct fire cues (primarily smoke) than canopy-stored seeds. Notable exceptions were L. linifolium, with an absolute requirement for smoke to germinate (the third serotinous species so reported), and two other serotinous species with smoke-enhanced germination. Nutlet-bearing species, whether serotinous or geosporous, were c. 70% more likely to respond to fire cues than winged seeds, but there was no evidence for an effect of phylogeny or persistence strategy on germination. This comprehensive account of seed germination characteristics and identification of germination syndromes and their predictors, supports propagation, conservation and restoration initiatives in this iconic fynbos genus and other fire-prone shrubs with canopy or soil-stored seeds.