The actin-myosin regulatory MRCK kinases: regulation, biological functions and associations with human cancer

The contractile actin-myosin cytoskeleton provides much of the force required for numerous cellular activities such as motility, adhesion, cytokinesis and changes in morphology. Key elements that respond to various signal pathways are the myosin II regulatory light chains (MLC), which participate in actin-myosin contraction by modulating the ATPase activity and consequent contractile force generation mediated by myosin heavy chain heads. Considerable effort has focussed on the role of MLC kinases, and yet the contributions of the myotonic dystrophy-related Cdc42-binding kinases (MRCK) proteins in MLC phosphorylation and cytoskeleton regulation have not been well characterized. In contrast to the closely related ROCK1 and ROCK2 kinases that are regulated by the RhoA and RhoC GTPases, there is relatively little information about the CDC42-regulated MRCKα, MRCKβ and MRCKγ members of the AGC (PKA, PKG and PKC) kinase family. As well as differences in upstream activation pathways, MRCK and ROCK kinases apparently differ in the way that they spatially regulate MLC phosphorylation, which ultimately affects their influence on the organization and dynamics of the actin-myosin cytoskeleton. In this review, we will summarize the MRCK protein structures, expression patterns, small molecule inhibitors, biological functions and associations with human diseases such as cancer

Protective Intestinal Effects of Pituitary Adenylate Cyclase Activating Polypeptide

Pituitary adenylate cyclase activating polypeptide (PACAP) is an endogenous neuropeptide widely distributed throughout the body, including the gastrointestinal tract. Several effects have been described in human and animal intestines. Among others, PACAP infl uences secretion of intestinal glands, blood fl ow, and smooth muscle contraction. PACAP is a well-known cytoprotective peptide with strong anti-apoptotic, anti-infl ammatory, and antioxidant effects. The present review gives an overview of the intestinal protective actions of this neuropeptide. Exogenous PACAP treatment was protective in a rat model of small bowel autotransplantation. Radioimmunoassay (RIA) analysis of the intestinal tissue showed that endogenous PACAP levels gradually decreased with longer-lasting ischemic periods, prevented by PACAP addition. PACAP counteracted deleterious effects of ischemia on oxidative stress markers and cytokines. Another series of experiments investigated the role of endogenous PACAP in intestines in PACAP knockout (KO) mice. Warm ischemia–reperfusion injury and cold preservation models showed that the lack of PACAP caused a higher vulnerability against ischemic periods. Changes were more severe in PACAP KO mice at all examined time points. This fi nding was supported by increased levels of oxidative stress markers and decreased expression of antioxidant molecules. PACAP was proven to be protective not only in ischemic but also in infl ammatory bowel diseases. A recent study showed that PACAP treatment prolonged survival of Toxoplasma gondii infected mice suffering from acute ileitis and was able to reduce the ileal expression of proinfl ammatory cytokines. We completed the present review with recent clinical results obtained in patients suffering from infl ammatory bowel diseases. It was found that PACAP levels were altered depending on the activity, type of the disease, and antibiotic therapy, suggesting its probable role in infl ammatory events of the intestine

Simultaneous medial unicompartmental knee replacement and anterior cruciate ligament reconstruction: a narrative review and technical note

Background and Objective: Reconstruction of the anterior cruciate ligament (ACL) simultaneously with medial unicompartmental knee arthroplasty (UKA) has been suggested as an alternative treatment in patients with ACL deficiency and localized osteoarthritis (OA) in young patients. The objectives of this review were to report the current concepts on the topic and describe an original surgical technique of simultaneous medial UKA and ACL reconstruction. Methods: A literature search was performed on PubMed, including articles written in English until June 2021. The articles regarding ACL reconstruction and UKA were reviewed using the narrative approach. Inclusion criteria: (I) original articles about ACL reconstruction and unicompartmental knee replacement; (II) written in English; (III) involving three or more cases. Two non-blinded authors reviewed the titles and abstracts of each article identified in the literature search. Key Content and Findings: The articles regarding ACL reconstruction and UKA were reviewed using the narrative approach. Conclusions: There is controversial evidence about performing the UKA simultaneously with an ACL reconstruction. Biomechanical and clinical studies show that the benefits of restoring good joint stability outweigh the possible risks associated with performing both surgeries at the same time. With this strategy, it is possible to obtain good clinical results with a high survival rate of the implant and patient satisfaction

Parity-related molecular signatures and breast cancer subtypes by estrogen receptor status

INTRODUCTION: Relationships of parity with breast cancer risk are complex. Parity is associated with decreased risk of postmenopausal hormone receptor–positive breast tumors, but may increase risk for basal-like breast cancers and early-onset tumors. Characterizing parity-related gene expression patterns in normal breast and breast tumor tissues may improve understanding of the biological mechanisms underlying this complex pattern of risk. METHODS: We developed a parity signature by analyzing microRNA microarray data from 130 reduction mammoplasty (RM) patients (54 nulliparous and 76 parous). This parity signature, together with published parity signatures, was evaluated in gene expression data from 150 paired tumors and adjacent benign breast tissues from the Polish Breast Cancer Study, both overall and by tumor estrogen receptor (ER) status. RESULTS: We identified 251 genes significantly upregulated by parity status in RM patients (parous versus nulliparous; false discovery rate = 0.008), including genes in immune, inflammation and wound response pathways. This parity signature was significantly enriched in normal and tumor tissues of parous breast cancer patients, specifically in ER-positive tumors. CONCLUSIONS: Our data corroborate epidemiologic data, suggesting that the etiology and pathogenesis of breast cancers vary by ER status, which may have implications for developing prevention strategies for these tumors

How large-scale geographic factors affect the different dimensions of functional diversity: evidence from the beech forest herb layer (Apennines, Italy)

Background and aims – The research aim was to investigate the relation between large-scale geographic factors and the functional structure of the herbaceous layer of calcareous beech forests in the Apennines, managed as high forest. Material and methods – We selected 163 plots (20 × 20 m), ranging from Central to South Italy, using a random stratified sampling design. We correlated the effect sizes of traits’ community-weighted means, functional richness, evenness, divergence, dispersion, and Rao’s quadratic entropy, with the main axes of variation in species composition. Key results – The geographical range played a weak role in shaping the species composition of the herbaceous layer. However, we found evidence of functional convergence towards the northern sectors of the study area, where traits linked to resource retention strategies and vegetative spread are filtered. We did not find any evidence of convergence northwards for leaf phenology and pollination types. Conclusion – The increase of the intensity in the environmental stress was associated with a decrease of diversity for traits related to resource conservation strategies and vegetative propagation. On the contrary, the lower cold stress intensity southwards fostered a better niche partitioning, ensuring the coexistence of species with different modalities of resource acquisition and conservation

New national and regional Annex I Habitat records: from #26 to #36

New Italian data on the distribution of the Annex I Habitats 1510*, 2130*, 2250*, 3180*, 3260, 5230*, 6410, 7140, 7220*, 9320 are reported in this contribution. Specifically, 14 new occurrences in Natura 2000 sites are presented and 20 new cells are added in the EEA 10 km × 10 km reference grid. The new data refer to the Italian administrative regions of Abruzzo, Apulia, Friuli Venezia Giulia, Liguria, Marche, Molise, Sardinia, Sicily, Tuscany and Umbria

Bistability versus Bimodal Distributions in Gene Regulatory Processes from Population Balance

In recent times, stochastic treatments of gene regulatory processes have appeared in the literature in which a cell exposed to a signaling molecule in its environment triggers the synthesis of a specific protein through a network of intracellular reactions. The stochastic nature of this process leads to a distribution of protein levels in a population of cells as determined by a Fokker-Planck equation. Often instability occurs as a consequence of two (stable) steady state protein levels, one at the low end representing the “off” state, and the other at the high end representing the “on” state for a given concentration of the signaling molecule within a suitable range. A consequence of such bistability has been the appearance of bimodal distributions indicating two different populations, one in the “off” state and the other in the “on” state. The bimodal distribution can come about from stochastic analysis of a single cell. However, the concerted action of the population altering the extracellular concentration in the environment of individual cells and hence their behavior can only be accomplished by an appropriate population balance model which accounts for the reciprocal effects of interaction between the population and its environment. In this study, we show how to formulate a population balance model in which stochastic gene expression in individual cells is incorporated. Interestingly, the simulation of the model shows that bistability is neither sufficient nor necessary for bimodal distributions in a population. The original notion of linking bistability with bimodal distribution from single cell stochastic model is therefore only a special consequence of a population balance model