Normal Cycle Research Articles

Intracytoplasmic sperm injection compared with in vitro fertilisation in patients with non-male factor infertility with low oocyte retrieval: a single-centre, retrospective cohort study

ObjectiveTo investigate the effects of in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI) on the clinical outcomes of non-male factor patients aged >35 with three or fewer oocytes retrieved.DesignRetrospective...

The Limping Child: A Guide for the Trainees.

Limping is a common presenting complaint in children. Despite this, it remains to be a diagnostic challenge for treating physicians due to an expanded list of etiologies. It arises from a spectrum of disorders, ranging from physiological variations of gait at different stages of development to systemic causes, such as inflammatory diseases or musculoskeletal infections. On rare occasions, non-musculoskeletal causes could result in limping. The diagnostic challenge increases in younger age children where a detailed physical examination that helps identify the exact source of pathology may not be possible. In older patients who have a well-developed gait cycle, the physical assessment might be easier. Clinical assessment in a child presenting with a limp includes gait analysis, which is essential to guide the appropriate request of diagnostic laboratory tests and imaging studies. In this paper, we provide a practical guide for a trainee in General Pediatric and Pediatric Rheumatology on an approach to a limping child, aiming to identify the common causes of limping and to describe normal and abnormal gait cycles. We also discuss other diagnostic considerations in the assessment of these children.

Characterization of the cardiac cycle in Royal Canadian Mounted Police Cadets.

Royal Canadian Mounted Police (RCMP) cadets experience high volumes of potentially psychologically traumatic events, suggesting a need of normal cardiac cycle interval data on the cadets for comparison. We characterize the cardiac cycle of incoming RCMP cadets starting the 26-week training program. The cadets collected their cardiac data using the LLA Recordis™ device. Male RCMP cadets had higher (p<0.05) myocardial and diastolic performance indices, aortic valve open to aortic twist time, and isovolumic relaxation time than female RCMP cadets. Monitoring the cardiac cycle intervals in RCMP cadets can provide insights to changes in their heart function from their occupational demands.

Stochastic Boolean model of normal and aberrant cell cycles in budding yeast

The cell cycle of budding yeast is governed by an intricate protein regulatory network whose dysregulation can lead to lethal mistakes or aberrant cell division cycles. In this work, we model this network in a Boolean framework for stochastic simulations. Our model is sufficiently detailed to account for the phenotypes of 40 mutant yeast strains (83% of the experimentally characterized strains that we simulated) and also to simulate an endoreplicating strain (multiple rounds of DNA synthesis without mitosis) and a strain that exhibits ‘Cdc14 endocycles’ (periodic transitions between metaphase and anaphase). Because our model successfully replicates the observed properties of both wild-type yeast cells and many mutant strains, it provides a reasonable, validated starting point for more comprehensive stochastic-Boolean models of cell cycle controls. Such models may provide a better understanding of cell cycle anomalies in budding yeast and ultimately in mammalian cells.

Role of viscoelasticity in the adhesion of mushroom-shaped pillars

The contact behaviour of mushroom-shaped pillars has been extensively studied for their superior adhesive properties, often inspired by natural attachment systems observed in insects. Typically, pillars are modeled with linear elastic materials in the literature; in reality, the soft materials used for their fabrication exhibit a rate-dependent constitutive behaviour. Additionally, conventional models focus solely on the detachment phase of the pillar, overlooking the analysis of the attachment phase. As a result, they are unable to estimate the energy loss during a complete loading-unloading cycle.&#xD;This study investigates the role of viscoelasticity in the adhesion between a mushroom-shaped pillar and a rigid flat countersurface. Interactions at the interface are assumed to be governed by van der Waals forces, and the material is modeled using a standard linear solid model. Normal push and release contact cycles are simulated&#xD;at different approaching and retracting speeds.&#xD;Results reveal that, in the presence of an interfacial defect, a monotonically increasing trend in the pull-off force with pulling speed is observed. The corresponding change in the contact pressure distribution suggests a transition from short-range to long-range adhesion, corroborating recent experimental and theoretical investigations.&#xD;Moreover, the pull-off force remains invariant to the loading history due to our assumption of a flat-flat contact interface. Conversely, in the absence of defects and under the parameters used in this study, detachment occurs after reaching the theoretical contact strength, and the corresponding pull-off force is found to be rate&#xD;independent. Notably, the hysteretic loss exhibits a peak at intermediate detachment speeds, where viscous dissipation occurs, which holds true in both the presence and absence of a defect. However, the presence of a defect shifts the region where the majority of viscous dissipation takes place.

Ketogenic β-hydroxybutyrate regulates β-hydroxybutyrylation of TCA cycle-associated enzymes and attenuates disease-associated pathologies in Alzheimer's mice.

Lysine β-hydroxybutyrylation (Kbhb) is a post-translational modification that has recently been found to regulate protein functions. However, whether and how protein Kbhb modification participates in Alzheimer's disease (AD) remains unknown. Herein, we carried out 4D label-free β-hydroxybutylation quantitative proteomics using brain samples of 8-month-old and 2-month-old APP/PS1 AD model mice and wild-type (WT) controls. We identified a series of tricarboxylic acid (TCA) cycle-associated enzymes including citrate synthase (CS) and succinate-CoA ligase subunit alpha (SUCLG1), whose Kbhb modifications were decreased in APP/PS1 mice at pathological stages. Sodium β-hydroxybutyrate (Na-β-OHB) treatment markedly increased Kbhb modifications of CS and SUCLG1 and their enzymatic activities, leading to elevated ATP production. We further found that Kbhb modifications at lysine 393 site in CS and at lysine 81 site in SUCLG1 were crucial for their enzymatic activities. Finally, we found that β-OHB levels were decreased in the brain of APP/PS1 mice at pathological stages. While ketogenic diet not only significantly increased β-OHB levels, Kbhb modifications and enzymatic activities of CS and SUCLG1, and ATP production, but also dramatically attenuated β-amyloid plaque pathologies and microgliosis in APP/PS1 mice. Together, our findings indicate the importance of protein Kbhb modification for maintaining normal TCA cycle and ATP production and provide a novel molecular mechanism underlying the beneficial effects of ketogenic diet on energy metabolism and AD intervention.

Suppression of epithelial proliferation and tumourigenesis by immunoglobulin A.

Immunoglobulin A (IgA) is the most abundant antibody isotype produced across mammals and plays a specialized role in mucosal homeostasis 1 . Constantly secreted into the lumen of the intestine, IgA binds commensal microbiota to regulate their colonization and function 2,3 with unclear implications for health. IgA deficiency is common in humans but is difficult to study due to its complex aetiology and comorbidities 4-8 . Using genetically and environmentally controlled mice, here we show that IgA-deficient animals have increased susceptibility to endogenous colorectal tumours. Cellular and molecular analyses revealed that, in the absence of IgA, colonic epithelial cells induce antibacterial factors and accelerate cell cycling in response to the microbiota. Oral treatment with IgA was sufficient to both reduce steady-state proliferation and protect mice from tumours, but this function was due to antibody structure rather than binding specificity. In both organoid and monolayer culture systems, IgA directly suppressed epithelial growth. Co-immunoprecipitation mass spectrometry and a targeted CRISPR screen identified DMBT1 as an IgA-binding epithelial surface protein required for IgA-mediated suppression of proliferation. Together, IgA and DMBT1 regulate Notch signalling and tune the normal cycling of absorptive colonocyte progenitors. In mice, deleting the transmembrane and cytoplasmic signalling portions of DMBT1 or blocking Notch signalling was sufficient to reverse both the increased proliferation and tumour susceptibility of IgA knockouts. These experiments establish a homeostatic function for IgA in tempering physiological epithelial responses to microbiota to maintain mucosal health.

Rescue of morphological defects in Streptomyces venezuelae by the alkaline volatile compound trimethylamine.

Bacterial volatiles have a wide range of biological roles at intra- or inter-kingdom levels. The impact of volatiles has mainly been observed between producing bacteria and recipient bacteria, mostly of different species. In this study, we report that the wild-type, soil-dwelling bacterium Streptomyces venezuelae, which forms aerial hypha and spores as part of its normal developmental cycle, also produces the alkaline volatile compound trimethylamine (TMA) under multiple growth conditions. We showed that the environmental dispersion of TMA produced by S. venezuelae promotes the growth and differentiation of growth-deficient mutants of the same species or other slowly growing Streptomyces bacteria, and thus aids in their survival and their ability to compete in complex environmental communities such as soil. Our novel findings suggest a potentially profound biological role for volatile compounds in the growth and survival of communities of volatile-producing Streptomyces species.

Effects of cyanotoxins on nitrogen transformation in aquaculture systems with microplastics coexposure: Adsorption behavior, bacterial communities and functional genes

Microcystin-LR (MC-LR) and microplastics (MPs) have attracted increasing attention as important new pollutants in freshwater fishery environments. However, there are few reports on the effects of long-term combined MC-LR and MPs pollution on nitrogen transformation and microbial communities in aquaculture ponds, and the resulting risks have yet to be determined. Therefore, in this study, traditional refractory MPs (polystyrene, PS), biodegradable MPs (polylactic acid, PLA) and MC-LR, which are common in freshwater fishery environments in China, were selected as pollutants to construct a microcosm that simulates freshwater aquaculture ponds. MC-LR coexposure to PS and PLA was tested to reveal the effects of these pollutants on nitrogen transformation and microbial communities in aquaculture ponds, as well as to elucidate the potential risks posed by traditional refractory MPs and biodegradable MPs to freshwater aquaculture ecosystems. The results revealed that the MPs had a relatively high adsorption rate for MC-LR and that PS presented a relatively high adsorption capacity, whereas PLA presented a relatively high desorption capacity. Single or combined MPs and MC-LR pollution disrupted the normal nitrogen cycle in the aquaculture system, causing an overall loss of nitrogen in the water, and denitrification and nitrogen fixation in the water were inhibited to a certain extent through the inhibition of nitrogen cycle-related functional genes, with the PS + MC-LR group having the greatest inhibitory effect. In addition, compared with single-pollutant exposure, combined exposure to MC-LR and MPs had a greater effect on the microbial community composition. Analysis of the integrated biomarker response (IBR) index revealed that the risk of combined exposure to MC-LR and PS was greater than that of single exposure, so this phenomenon merits further attention.

Effects of wet-dry-freeze-thaw cycles on the response of the frozen soil-composite geotextile interface in direct shear tests

Composite geotextiles are frequently utilized in water delivery canals and other projects in cold regions. However, the peak strength of the soil-geotextile interface can be degrade due to continuous wet-dry-freeze-thaw (WDFT) cycles, potentially compromising the stability of the infrastructure. This paper presents the use of a temperature-controlled direct shear system to conduct direct shear tests on the interface between the soil and the geotextile composite under a variety of normal pressures, temperatures, and WDFT cycles. The study shows that WDFT has minimal effect on the shear stress-shear displacement curve at positive temperatures. At negative temperatures, the curve transitions from strain hardening to strain softening. At negative temperatures, the average increase in peak strength was 39 %, 56.9 %, and 65.3 % after a single WDFT cycle at −2 °C, −6 °C, and −10 °C, respectively. A gradual decline in peak strength was observed with each subsequent cycle, although the peak strength remained slightly higher than the initial strength. The average growth rates were 6.6 %, 19.3 %, and 29.2 % after ten cycles, respectively. The interfacial cohesion and friction angle exhibited similar trends to those of peak strength. The sensitivity analysis revealed that temperature and WDFT cycles exert a considerable influence on the interface cohesion.

Pd/Cu Dual Catalysis for the Oxidative Dearomatization of PyrroleDerivatives: Mechanistic Insights and Biological Studies

AbstractHerein we report dearomatization of pyrrole ring followed by rearomatization of cyclohexyl ring to obtain isoindolinone scaffold by a Pd/Cu dual catalysis approach in an atom economic way with moderate to high yield. The expected Pd/Cu catalyzed dual C(sp2)‐H activation via normal catalytic cycle can be override by unusual oxidative dearomatization reaction which has been established by DFT calculation. The biological importance of isoindolinone scaffold insists us to successfully investigate in vitro antileishmanial activity of L.Donovani.

An efficient beam sweeping scheme with backup paging occasions in NR-Unlicensed Spectrum

With the increasing demand of user applications and the shortage of cellular spectrum, New Radio (NR) access to Unlicensed Spectrum (NR-U) is getting significant attention. Listen Before Talk (LBT) procedure is used to sense unlicensed channel availability prior to transmission. The transmissions are subjected to LBT procedure failure, which brings extra delay as they are postponed to the next available transmission opportunity. This excess delay also affects time-critical procedures, such as paging. The directional communication in NR requires beamforming, which further complicates paging procedure as additional paging message transmissions are needed to cover all the beams. In this work, we propose an NR-U paging mechanism (called FF_BP) consisting of Full and Fast Paging Cycles with Backup Paging Occasions (POs). Full Paging uses a normal NR-U paging cycle and broadcasts a paging message on all the beams. On the other hand, Fast Paging, which targets delay-sensitive mobile users, uses a shorter paging cycle and broadcasts a paging message on selected beams only. The Backup POs deal with LBT procedure failure impairments while paging broadcast on selective beams reduces paging resource usage. We analyze FF_BP using a discrete-time semi-Markov chain model and validate the model by extensive simulations. The simulation results show that FF_BP outperforms several baseline mechanisms in terms of average paging delay and paging resource usage.

Impact of Ultrasound Scanning Plane on Common Carotid Artery Longitudinal Wall Motion

ObjectiveThe arterial wall not only moves in the radial direction to expand circumferentially but also moves in the axial (longitudinal) direction in a predictable bidirectional pattern during a normal cardiac cycle. While common carotid artery (CCA) longitudinal wall motion (CALM) has been described previously, there is a lack of evidence-based method standardization to align practices for human measurement. The purpose of this study was to evaluate whether different scanning planes impact CALM outcomes in healthy males and females to provide clarity on data collection strategies. MethodsThirty-one healthy adults (16 females, 23 ± 3 y of age) underwent ultrasound scanning of the right CCA in the anterior, lateral, and posterior imaging planes. CALM was evaluated using a custom speckle-tracking algorithm and was analyzed as segmental motion outcomes (anterograde, retrograde, maximum displacement and radial-axial path length). ResultsNo differences in any CALM outcome were observed between imaging planes (p > 0.05), and equivalence testing indicated that retrograde CALM displacement was similar between anterior and posterior distal walls (p = 0.04). We observed no differences (p > 0.05) in CALM outcomes between the proximal (free-wall, adjacent to the internal jugular vein [IJV]) and distal wall in the posterior imaging plane. Qualitatively, it was more difficult to successfully track vascular tissue between the IJV and CCA due to the thin wall components and highly mobile wall in the radial direction. ConclusionIn the absence of clear differences between scanning planes, we recommend standardizing acquisition in the lateral plane and avoiding the IJV free-wall when evaluating CALM in humans.

USP37 prevents unscheduled replisome unloading through MCM complex deubiquitination.

The CMG helicase (CDC45-MCM2-7-GINS) unwinds DNA as a component of eukaryotic replisomes. Replisome (dis)assembly is tightly coordinated with cell cycle progression to ensure genome stability. However, factors that prevent premature CMG unloading and replisome disassembly are poorly described. Since disassembly is catalyzed by ubiquitination, deubiquitinases (DUBs) represent attractive candidates for safeguarding against untimely and deleterious CMG unloading. We combined a targeted loss-of-function screen with quantitative, single-cell analysis to identify human USP37 as a key DUB preventing replisome disassembly. We demonstrate that USP37 maintains active replisomes on S-phase chromatin and promotes normal cell cycle progression. Proteomics and enzyme assays revealed USP37 interacts with the CMG complex to deubiquitinate MCM7, thus antagonizing replisome disassembly. Significantly, USP37 protects normal epithelial cells from oncoprotein-induced replication stress. Our findings reveal USP37 to be critical to the maintenance of replisomes in S-phase and suggest USP37-targeting as a potential strategy for treating malignancies with defective DNA replication control.

Autotaxin Expression in the Uterus of Cycling Rats.

Autotaxin (ATX), also known as ectonucleotide pyrophosphatase/phosphodiesterase family member 2 (ENPP 2), is an enzyme with lysophospholipase D activity that converts lysophosphatidylcholine into lysophosphatidic acid (LPA). One of the LPA receptors, LPA3, is positively and negatively regulated by progesterone and estrogen, respectively. Furthermore, ATX expression in the rat uterus could be under the control of estrous cycle. In the present study, we used young normal cycling rats for further assess the uterine ATX expression and localization by reverse transcription PCR (RT-PCR) and immunohistochemistry, respectively. In the RT-PCR study, ATX mRNA level at Metestrus (1.00±0.026 AU) was significantly higher than that at Proestrus (0.42±0.046 AU, p<0.001) and the level at Diestrus (0.75±0.107 AU, p<0.05) was significantly higher than that at Proestrus. Among the luminal epithelial cells, the order of the ATX signal intensities was Metestrus>Diestrus>Proestrus>Estrus. Among the myometrial cells, the order of the signal intensities was Diestrus>Proestrus>Estrus>Metestrus. Among the glandular epithelial cells, the order of the signal intensities was Proestrus>Estrus=Metestrus= Estrus. The present study indicates that expression and localization of uterine ATX may be under the control of sex steroids during the estrous cycle. Further studies on the ATX signaling-sex steroid relationship will be providing better understanding on in normal and pathophysiological state of uterus.

Ovariectomy and Estradiol Supplementation Prevents Cyclophosphamide- and Doxorubicin-Induced Spatial Memory Impairment in Tumor-Bearing MMTV-PyVT Mice.

Chemotherapy-related cognitive impairments (CRCIs) encompass cognitive deficits in memory, attention, and executive function that arise during and following chemotherapy. CRCI symptoms are predominantly reported by female cancer patients but also occur in males. These impairments may involve reduced estradiol levels, which then increases vulnerability to the impact of tumors and chemotherapy on cognition. This study utilized the MMTV-PyVT mouse model of breast cancer to test the hypothesis that impaired ovarian function and associated estradiol levels play a critical role in CRCI susceptibility. Mice were either ovariectomized (OVX) or underwent sham surgery. The OVX group then received supplemental estradiol (E2) ad libitum in the drinking water to maintain physiological hormone levels. After tumor development, mice were trained in the Morris water maze to assess spatial memory, and subsequently, they received weekly injections of either saline or a combination of cyclophosphamide (CYP; 66.7 mg/kg, i.v.) and doxorubicin (DOX; 6.7 mg/kg, i.v.) for 4 weeks. Spatial memory was reassessed 10 d and then 35 d, after the final injections. Results demonstrated a significant disruption of normal ovarian cycling in sham-operated mice treated with CYP + DOX, as well as significant spatial memory impairments when compared with OVX mice supplemented with E2 This study suggests that chemotherapy-induced ovarian damage and the consequent drop in circulating estrogens significantly contribute to vulnerability to CRCIs, underscoring the importance of estradiol in mitigating CRCI risks.

A Fungicide, Fludioxonil, Formed the Polyploid Giant Cancer Cells and Induced Metastasis and Stemness in MDA-MB-231 Triple-Negative Breast Cancer Cells.

Fludioxonil, an antifungal agent used as a pesticide, leaves a measurable residue in fruits and vegetables. It has been identified to cause endocrine disruption, interrupt normal development, and cause various diseases such as cancers. In this study, fludioxonil was examined for its effects on the development and metastasis of breast cancer cells. On fludioxonil exposure (10-5 M) for 72 h, mutant p53 (mutp53) MDA-MB-231 triple-negative breast cancer (TNBC) cells significantly inhibited cell viability and developed into polyploid giant cancer cells (PGCCs), with an increase in the number of nuclei and expansion in the cell body size. Fludioxonil exposure disrupted the normal cell cycle phase ratio, resulting in a new peak. In addition, PGCCs showed greater motility than the control and were resistant to anticancer drugs, i.e., doxorubicin, cisplatin, and 5-fluorouracil. Cyclin E1, nuclear factor kappa B (NF-κB), and p53 expressions were remarkably increased, and the expression of cell cycle-, epithelial-mesenchymal-transition (EMT)-, and cancer stemness-related proteins were increased in the PGCCs. The daughter cells obtained from PGCCs had the single nucleus but maintained their enlarged cell size and showed greater cell migration ability and resistance to the anticancer agents. Consequently, fludioxonil accumulated Cyclin E1 and promoted the inflammatory cytokine-enriched microenvironment through the up-regulation of TNF and NF-κB which led to the transformation to PGCCs via abnormal cell cycles such as mitotic delay and mitotic slippage in mutp53 TNBC MDA-MB-231 cells. PGCCs and their daughter cells exhibited significant migration ability, chemo-resistance, and cancer stemness. These results strongly suggest that fludioxonil, as an inducer of potential genotoxicity, may induce the formation of PGCCs, leading to the formation of metastatic and stem cell-like breast cancer cells.

Evaluation of ovulation by urinary LH surge kits versus transvaginal sonography

The study was conducted to evaluate the efficacy of urinary LH surge kits and transvaginal ultrasonography (TVS) to detect ovulation in induced cycles and to compare the ovulation rates by both methods. Prospective observational cohort study on 144 women with anovulatory infertility aged 18-35 years, fulfilling the inclusion criteria were given letrozole for ovulation induction. All were randomly divided into two groups. Group 1 women were asked to check ovulation by urinary LH surge kits and group 2 women were called for follicle monitoring by TVS. Letrozole has no negative effect on the endometrium; the induced cycle has a larger diameter of follicle (median: 22 mm). In the induced cycle ovulation occurs later compared to normal cycle (D-16) and half of the women had a BMI more than the recommended WHO criteria (average was 25.28 kg/m2). Number of letrozole cycles (p=0.2642), dose requirement (p=0.0812) and pregnancy rates (10.26% versus 18.19%) were comparable in both groups. TVS is objective, accurate, and thus a standard modality for ovulation detection. LH surge kit is subjective, having more chances of error but can be used as a good alternative in certain settings like women from the remote area, and women having fear of invasive modality.

Nicotinamide riboside activates SIRT3 to prevent paclitaxel-induced peripheral neuropathy

Paclitaxel (PTX) is a microtubule stabilizer that disrupts the normal cycle of microtubule depolymerization and repolymerization, leading to cell cycle arrest and cancer cell death. It is commonly used as a first-line chemotherapeutics for various malignancies, such as breast cancer, non-small cell lung cancer, and ovarian cancer. However, PTX chemotherapy is associated with common and serious side effects, including chemotherapy-induced peripheral neuropathy (CIPN). As cancer treatment advances and survival rates increase, the impact of CIPN on patients' quality of life has become more significant. To date, there is no effective treatment strategy for CIPN. Surtuin3 (SIRT3) is a nicotinamide adenine dinucleotide (NAD+) dependent protein deacetylase located on mitochondria. It transfers the acetyl group of the lysine side chain of acetylated substrate proteins to NAD+, producing deacetylated proteins to regulate mitochondrial energy metabolic processes. SIRT3 has been found to play an important role in various diseases, including aging, neurodegenerative diseases, cancer, heart disease, metabolic diseases, etc. However, the role of SIRT3 in CIPN is still unknown. This study found for the first time that activating SIRT3 helps to improve paclitaxel-induced CIPN. Nicotinamide riboside (NR) can protect dorsal root ganglion (DRG) mitochondria against oxidative damage caused by paclitaxel through activating SIRT3-MnSOD2 and SIRT3-Nrf2 pathway. Moreover, NR can enhance the anticancer activity of paclitaxel. Together, our research provides new strategy and candidate drug for the treatment of CIPN.

Circadian disruptions and their role in the development of hypertension.

Circadian fluctuations in physiological setpoints are determined by the suprachiasmatic nucleus (SCN) which exerts control over many target structures within and beyond the hypothalamus via projections. The SCN, or central pacemaker, orchestrates synchrony between the external environment and the internal circadian mechanism. The resulting cycles in hormone levels and autonomic nervous system (ANS) activity provide precise messages to specific organs, adjusting, for example, their sensitivity to approaching hormones or metabolites. The SCN responds to both photic (light) and non-photic input. Circadian patterns are found in both heart rate and blood pressure, which are linked to daily variations in activity and autonomic nervous system activity. Variations in blood pressure are of great interest as several cardiovascular diseases such as stroke, arrhythmias, and hypertension are linked to circadian rhythm dysregulation. The disruption of normal day-night cycles, such as in shift work, social jetlag, or eating outside of normal hours leads to desynchronization of the central and peripheral clocks. This desynchronization leads to disorganization of the cellular processes that are normally driven by the interactions of the SCN and photic input. Here, we review autonomic system function and dysfunction due to regulation and interaction between different cardiorespiratory brain centers and the SCN, as well as social, lifestyle, and external factors that may impact the circadian control of blood pressure.