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Infertility represents a growing health problem in industrialized countries. Thus, a greater understanding of the molecular networks involved in this disease could be critical for the development of new therapies. A recent finding revealed that circadian rhythmicity disruption is one of the main causes of poor reproductive outcome. The circadian clock system beats circadian rhythms and modulates several physiological functions such as the sleep-wake cycle, body temperature, heart rate, and hormones secretion, all of which enable the body to function in response to a 24 h cycle. This intricated machinery is driven by specific genes, called “clock genes” that fine-tune body homeostasis. Stress of modern lifestyle can determine changes in hormone secretion, favoring the onset of infertility-related conditions that might reflect disfunctions within the hypothalamic–pituitary–gonadal axis. Consequently, the loss of rhythmicity in the suprachiasmatic nuclei might affect pulsatile sexual hormones release. Herein, we provide an overview of the recent findings, in both animal models and humans, about how fertility is influenced by circadian rhythm. In addition, we explore the complex interaction among hormones, fertility and the circadian clock. A deeper analysis of these interactions might lead to novel insights that could ameliorate the therapeutic management of infertility and related disorders.

We investigated the role of KNOX genes in legume root nodule organogenesis. Class 1 KNOX homeodomain transcription factors (TFs) are involved in plant shoot development and leaf shape diversity. Class 2 KNOX genes are less characterized, even though an antagonistic function relative to class 1 KNOXs was recently proposed. In silico expression data and further experimental validation identified in the Medicago truncatula model legume three class 2 KNOX genes, belonging to the KNAT3/4/5-like subclass (Mt KNAT3/4/5-like), as expressed during nodulation from early stages. RNA interference (RNAi)-mediated silencing and overexpression studies were used to unravel a function for KNOX TFs in nodule development. Mt KNAT3/4/5-like genes encoded four highly homologous proteins showing overlapping expression patterns during nodule organogenesis, suggesting functional redundancy. Simultaneous reduction of Mt KNAT3/4/5-like genes indeed led to an increased formation of fused nodule organs, and decreased the expression of the MtEFD (Ethylene response Factor required for nodule Differentiation) TF and its direct target MtRR4, a cytokinin response gene. Class 2 KNOX TFs therefore regulate legume nodule development, potentially through the MtEFD/MtRR4 cytokinin-related regulatory module, and may control nodule organ boundaries and shape like class 2 KNOX function in leaf development.

Phosphodiesterases (PDEs) are a huge superfamily of enzymes that fine-tune the intracellular levels of cyclic nucleotides —cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP)—thus playing a pivotal role in the control of many cellular processes. While traditionally studied in the context of cardiovascular and neurological systems, mounting evidences highlight a crucial involvement of PDEs in metabolic homeostasis. This review explores the expanding landscape of PDEs function beyond classical cyclic nucleotide degradation, focusing on their roles in glucose and lipid metabolism and their implications in metabolic disorders, including obesity, type 2 diabetes (T2DM), and metabolic syndrome (MetS). Starting from an overview of the PDE superfamily, this work deeply examines the compartmentalized actions of cAMP-dependent protein kinase A (PKA) and cGMP-dependent protein kinase G (PKG) signaling pathways in key metabolically active tissues integrating PDE activities across different organs and disease states to offer a holistic view of their metabolic relevance. Special attention is given to the therapeutic relevance of PDE inhibitors (PDEi), distinguishing between established applications and emerging strategies targeting specific PDE isoforms in metabolic disease contexts to underscore the evolving concept that PDEs act as dynamic regulators of metabolic signaling networks. Understanding their isoform-specific and tissue-specific actions could thus open new avenues for therapeutic intervention in complex metabolic disorders.

BackgroundThe ageing population has led to an increased prevalence of chronic diseases, posing challenges for the management of critically ill cardiac patients with multiple comorbidities. The Palliative Performance Scale (PPS), initially developed for terminally ill cancer patients, has shown prognostic value in various medical settings but remains understudied in cardiac intensive care units (CICUs). This study evaluates the PPS as a prognostic tool for in-hospital and 1-year all-cause mortality in CICU patients.MethodsWe conducted a single-centre, prospective, observational study at the Maggiore Hospital in Bologna, including 1131 patients admitted to the CICU between August 2022 and November 2023. Patients were stratified into two groups based on their PPS at admission (≤70 and >70). Multivariable regression models were used to assess predictors of mortality, and Kaplan-Meier survival curves were generated. Model accuracy and calibration were evaluated using receiver operating characteristic curves and the Hosmer-Lemeshow test.ResultsPatients with PPS ≤70 had significantly higher 1-year all-cause mortality (37.0% vs 9.8%, p<0.001) and in-hospital all-cause mortality (17.7% vs 3.3%, p<0.001). In the multivariable regression models, PPS emerged as an independent predictor of both 1-year and in-hospital all-cause mortality, along with age and Sequential Organ Failure Assessment score. The models demonstrated good discriminatory performance (area under the curve of 0.841 for 1-year mortality, 0.862 for in-hospital mortality) and acceptable calibration.ConclusionsThe PPS is a reliable and independent predictor of mortality in CICU patients. Incorporating PPS into clinical practice may enhance risk stratification, guide decision-making and optimise resource allocation in this high-risk population.

Sex hormones are key determinants of gender-related differences and regulate growth and development during puberty. They also exert a broad range modulation of immune cell functions, and a dichotomy exists in the immune response between the sexes. Both clinical and animal models have demonstrated that androgens, estrogens, and progestogens mediate many of the gender-specific differences in immune responses, from the susceptibility to infectious diseases to the prevalence of autoimmune disorders. Androgens and progestogens mainly promote immunosuppressive or immunomodulatory effects, whereas estrogens enhance humoral immunity both in men and in women. This study summarizes the available evidence regarding the physiological effects of sex hormones on human immune cell function and the underlying biological mechanisms, focusing on gender differences triggered by different amounts of androgens between males and females.

Background: SARS-CoV-2 related immunopathology may be the driving cause underlying severe COVID-19. Through an immunophenotyping analysis on paired bronchoalveolar lavage fluid (BALF) and blood samples collected from mechanically ventilated patients with COVID-19-associated Acute Respiratory Distress Syndrome (CARDS), this study aimed to evaluate the cellular immune responses in survivors and non-survivors of COVID-19. Methods: A total of 36 paired clinical samples of bronchoalveolar lavage fluid (BALF) mononuclear cells (BALF-MC) and peripheral blood mononuclear cells (PBMC) were collected from 18 SARS-CoV-2-infected subjects admitted to the intensive care unit (ICU) of the Policlinico Umberto I, Sapienza University Hospital in Rome (Italy) for severe interstitial pneumonia. The frequencies of monocytes (total, classical, intermediate and non-classical) and Natural Killer (NK) cell subsets (total, CD56bright and CD56dim), as well as CD4+ and CD8+ T cell subsets [naïve, central memory (TCM) and effector memory (TEM)], and those expressing CD38 and/or HLADR were evaluated by multiparametric flow cytometry. Results: Survivors with CARDS exhibited higher frequencies of classical monocytes in blood compared to non-survivors (p < 0.05), while no differences in the frequencies of the other monocytes, NK cell and T cell subsets were recorded between these two groups of patients (p > 0.05). The only exception was for peripheral naïve CD4+ T cells levels that were reduced in non-survivors (p = 0.04). An increase in the levels of CD56bright (p = 0.012) and a decrease in CD56dim (p = 0.002) NK cell frequencies was also observed in BALF-MC samples compared to PBMC in deceased COVID-19 patients. Total CD4+ and CD8+ T cell levels in the lung compartment were lower compared to blood (p = 0.002 and p < 0.01, respectively) among non-survivors. Moreover, CD38 and HLA-DR were differentially expressed by CD4+ and CD8+ T cell subsets in BALF-MC and in PBMC among SARS-CoV-2-infected patients who died from COVID-19 (p < 0.05). Conclusions: These results show that the immune cellular profile in blood and pulmonary compartments was similar in survivors and non-survivors of COVID-19. T lymphocyte levels were reduced, but resulted highly immune-activated in the lung compartment of patients who faced a fatal outcome.

Human blood has historically been considered a sterile environment. Recently, a thriving microbiome dominated by Firmicutes, Actinobacteria, Proteobacteria, and Bacteroidetes phyla was detected in healthy blood. The localization of these microbes is restricted to some blood cell populations, particularly the peripheral blood mononuclear cells and erythrocytes. It was hypothesized that the blood microbiome originates from the skin–oral–gut axis. In addition, many studies have evaluated the potential of blood microbiome dysbiosis as a prognostic marker in cardiovascular diseases, cirrhosis, severe liver fibrosis, severe acute pancreatitis, type 2 diabetes, and chronic kidney diseases. The present review aims to summarize current findings and most recent evidence in the field.

Abstract Context Despite the pivotal role of calcium signaling in immune response, little is known about immune function in patients affected by hypoparathyroidism. Objective This work aimed to evaluate immune function in hypoparathyroidism. Methods The Evaluation of iMmune function in Postsurgical and AuToimmune HYpoparathyroidism (NCT04059380) is a case-control, cross-sectional study set in an Italian referral center. Participants included 20 patients with postsurgical hypoparathyroidism (12 females) and 20 age- and sex-matched controls. Main outcome measures included calcium metabolism assessment, peripheral blood mononuclear cells (PBMC) profiling via flow cytometry, parathyroid hormone receptor 1 (PTHr1) expression analysis using immunofluorescence and PrimeFlow RNA assay, gene expression analysis via real-time polymerase chain reaction, cytokine measurement, and evaluation of infectious disease frequency and severity. Results Immune cell profiling revealed decreased monocytes, regulatory, naive, and total CD4+ T lymphocytes, which correlated with total calcium, ionized calcium, and PTH levels, in patients with hypoparathyroidism. Patients with hypoparathyroidism had a higher CD3−CD56+ natural killer (NK) cell count, which inversely correlated with calcium, PTH, and vitamin D levels. Furthermore, they exhibited decreased tumor necrosis factor (TNF) and granulocyte-macrophage colony-stimulating factor gene expression and decreased circulating TNF levels. Gene expression and immunofluorescence analysis confirmed PTHr1 expression in all PBMC lineages; however, the percentage of cells expressing PTHr1 was lower, whereas the intensity of PTHr1 expression in monocytes, total T lymphocytes, CD8+CD4+ and CD4+ T lymphocytes, and total NK cells was higher in patients with hypoparathyroidism. Conclusions This study describes for the first time the immune alterations in patients with hypoparathyroidism receiving conventional therapies, supporting the immunoregulatory role of PTH and proposing an explanation for the increased susceptibility to infections observed in epidemiological studies.

Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of tumors. Natural killer (NK) cells can play an important role in cancer immune surveillance. The aim of this prospective observational study was to analyze peripheral blood mononuclear cells (PBMCs) in patients with advanced non-small-cell lung cancer (NSCLC) receiving ICIs in order to identify predictive factors for better survival outcomes. Methods: Forty-seven stage IV NSCLC patients were enrolled. Patients underwent baseline (T0) and longitudinal (T1) evaluations after ICIs. Peripheral immune blood cell counts were analyzed using flow cytometry. Results: Basal levels of CD3−CD56+ NK cells were higher in patients with controlled disease (DC) compared to progression disease (PD) patients (127 cells/µL vs. 27.8 cells/µL, p < 0.001). Lower NK cell values were independent prognostic factors for shorter overall survival (OS) (HR 0.992; 95% CI 0.987–0.997, p < 0.001) and progression-free survival (PFS) (HR 0.988; 95% CI 0.981–0.994, p < 0.001). During the longitudinal evaluation, CD3−CD56+ NK cells (138.1 cells/µL vs. 127 cells/µL, p = 0.025) and CD56bright NK cells (27.4 cells/µL vs. 18.1 cells/µL, p = 0.034) significantly increased in the DC group. Finally, lower values of CD3−CD56+ NK cells (28.3 cells/µL vs. 114.6 cells/µL, p = 0.004) and CD56dim NK cells (13.2 cells/µL vs. 89.4 cells/µL, p < 0.001) were found in sarcopenic patients compared to patients without sarcopenia. Conclusions: Peripheral NK cells could represent a non-invasive and useful tool to predict ICI therapy response in NSCLC patients, and the association of low NK cell levels with sarcopenia deserves even more attention in clinical evaluation.