Homeostatic Balance Research Articles

Mechanisms of vagus nerve stimulation for the treatment of neurodevelopmental disorders: a focus on microglia and neuroinflammation

The vagus nerve (VN) is the primary parasympathetic nerve, providing two-way communication between the body and brain through a network of afferent and efferent fibers. Evidence suggests that altered VN signaling is linked to changes in the neuroimmune system, including microglia. Dysfunction of microglia, the resident innate immune cells of the brain, is associated with various neurodevelopmental disorders, including schizophrenia, attention deficit hyperactive disorder (ADHD), autism spectrum disorder (ASD), and epilepsy. While the mechanistic understanding linking the VN, microglia, and neurodevelopmental disorders remains incomplete, vagus nerve stimulation (VNS) may provide a better understanding of the VN’s mechanisms and act as a possible treatment modality. In this review we examine the VN’s important role in modulating the immune system through the inflammatory reflex, which involves the cholinergic anti-inflammatory pathway, which releases acetylcholine. Within the central nervous system (CNS), the direct release of acetylcholine can also be triggered by VNS. Homeostatic balance in the CNS is notably maintained by microglia. Microglia facilitate neurogenesis, oligodendrogenesis, and astrogenesis, and promote neuronal survival via trophic factor release. These cells also monitor the CNS microenvironment through a complex sensome, including groups of receptors and proteins enabling microglia to modify neuroimmune health and CNS neurochemistry. Given the limitations of pharmacological interventions for the treatment of neurodevelopmental disorders, this review seeks to explore the application of VNS as an intervention for neurodevelopmental conditions. Accordingly, we review the established mechanisms of VNS action, e.g., modulation of microglia and various neurotransmitter pathways, as well as emerging preclinical and clinical evidence supporting VNS’s impact on symptoms associated with neurodevelopmental disorders, such as those related to CNS inflammation induced by infections. We also discuss the potential of adapting non-invasive VNS for the prevention and treatment of these conditions. Overall, this review is intended to increase the understanding of VN’s potential for alleviating microglial dysfunction involved in schizophrenia, ADHD, ASD, and epilepsy. Additionally, we aim to reveal new concepts in the field of CNS inflammation and microglia, which could serve to understand the mechanisms of VNS in the development of new therapies for neurodevelopmental disorders.

A gut instinct for childhood leukemia prevention: microbiome-targeting recommendations aimed at parents and caregivers.

Childhood leukemia accounts for 30% of all pediatric cancer cases with acute lymphoblastic leukemia (ALL) being the most common subtype. Involvement of the gut microbiome in ALL development has recently garnered interest due to an increasing recognition of the key contribution the microbiome plays in maintaining the immune system's homeostatic balance. Commensal gut microbiota provide a first line of defense against different pathogens and gut microbiome immaturity has been implicated in ALL pathogenesis. Several environmental factors such as nutrition, mode of delivery, breastfeeding and, early social or livestock contacts are known to alter the composition of the gut microbiota. Variations in these factors influence the risk of childhood leukemia onset. This review aims to elucidate the risk factors influencing microbial composition in the context of childhood ALL. The link between gut microbiome diversity and childhood ALL offers the opportunity to develop risk-reducing strategies that can be communicated to a broad target population of (future) parents and caregivers for childhood leukemia prevention. Here, we summarize evidence on how promoting a diverse gut microbiome in newborns through simple measures such as increasing social contacts early in life may decrease the risk of developing ALL in these children later on.

Rhythm is essential: Unraveling the relation between the circadian clock and cancer.

Physiological processes such as the sleep-wake cycle, metabolism, hormone secretion, neurotransmitter release, sensory capabilities, and a variety of behaviors, including sleep, are controlled by a circadian rhythm adapted to 24-hour day-night periodicity. Disruption of circadian rhythm may lead to the risks of numerous diseases, including cancers. Several epidemiological and clinical data reveal a connection between the disruption of circadian rhythms and cancer. On the contrary, oncogenic processes may suppress the homeostatic balance imposed by the circadian clock. The integration of circadian biology into cancer research offers new options for making cancer treatment more effective, and the pharmacological modulation of core clock genes is a new approach in cancer therapy. This review highlights the role of the circadian clock in tumorigenesis, how clock disruption alters the tumor microenvironment, and discusses how pharmacological modulation of circadian clock genes can lead to new therapeutic options.

170 CD271 neurotrophin receptor regulates skin homeostatic balance and inflammatory pattern in novel epidermal knock-out mouse models

170 CD271 neurotrophin receptor regulates skin homeostatic balance and inflammatory pattern in novel epidermal knock-out mouse models

Lubricating and Dual-Responsive Injectable Hydrogels Formulated From ZIF-8 Facilitate Osteoarthritis Treatment by Remodeling the Microenvironment.

Osteoarthritis (OA) is a progressively developing condition primarily characterized by the deterioration of articular cartilage and the proliferation of bone, along with ongoing inflammation. Although the precise pathogenesis remains somewhat elusive, restoring the homeostatic balance of the intra-articular microenvironment is crucial for the management of OA. Intra-articular injection of medication is one of the most direct and effective treatment methods; however, most injectable drugs used for osteoarthritis treatment, due to their rapid breakdown, quick release, poor biological activity, and frequent injections, leading to increased risk of infection and suboptimal therapeutic outcomes. In this study, a lubricating and dual-responsive injectable hydrogel based on zeolitic imidazolate frameworks-8 (ZIF-8) impregnated with Quercetin (Que) is designed, which can facilitate OA treatment by remodeling the microenvironment. The prepared injectable nanocomposite hydrogel (MH/CCM@ZIF-8@Que) exhibits pH and reactive oxygen species (ROS) responsiveness, alongside a controllable release of bioactive substances to modulate the microenvironment of bone tissue, thereby mitigating synovitis and the degeneration of cartilage matrix, while simultaneously facilitating cartilage repair. This developed thermosensitive injectable hydrogel, which effectively balances lubrication with the controlled release of bioactive substances, represents a highly promising therapeutic approach for osteoarthritis.

Hunger modulates exploration through suppression of dopamine signaling in the tail of striatum.

Caloric depletion leads to behavioral changes that help an animal find food and restore its homeostatic balance. Hunger increases exploration and risk-taking behavior, allowing an animal to forage for food despite risks; however, the neural circuitry underlying this change is unknown. Here, we characterize how hunger restructures an animal's spontaneous behavior as well as its directed exploration of a novel object. We show that hunger-induced changes in exploration are accompanied by and result from modulation of dopamine signaling in the tail of the striatum (TOS). Dopamine signaling in the TOS is modulated by internal hunger state through the activity of agouti-related peptide (AgRP) neurons, putative "hunger neurons" in the arcuate nucleus of the hypothalamus. These AgRP neurons are poly-synaptically connected to TOS-projecting dopaminergic neurons through the lateral hypothalamus, the central amygdala, and the periaqueductal grey. We thus delineate a hypothalamic-midbrain circuit that coordinates changes in exploration behavior in the hungry state.

Autoimmune and Neoplastic Outcomes After the mRNA Vaccination: The Role of T Regulatory Cell Responses

A plethora of autoimmune disease incidences occured after COVID-19 mRNA injections were rolled out. Aggressive cancer cases have occurred in the bodies of recipients at sites where the mRNA was injected and at distant metastatic sites. The mRNA vaccines cause thymic involution (shrinking) and dysregulation of the T regulatory (Treg) and T effector (Teff) homeostatic cell balance. Activated immune cells deliver spike protein to the thymic epithelial cells, damaging them. The Treg/Teff balance may determine the fate of autoimmunity and/or cancer and is different for patients with cancer versus those without any cancerous tissues. Repeated mRNA injections lead to empirical evidence of impaired immune functions (elevated IgG4, PD-L1), associated with increased autoimmunity and cancer risks, and decreased resistance to infections. In the with-cancer recipients, the mRNA vaccine may be associated with either autoimmunity or further progression of the cancer(s) depending on the immunotherapy treatment the patient receives. When an antigen stimulates the immune system, specific T regulatory (Treg) and T effector (Teff) subpopulations develop from naïve T cells. An imbalance between Treg and Teff cells can lead to either cancer or autoimmunity. Treg cells are beneficial in that they protect from autoimmunity. However, they suppress the immune response to tumors. In this review, we analyze Treg responses after SARS-CoV-2 mRNA vaccination and find distinct pathological responses under differing conditions. Injection with modified mRNA can lead to a delayed but highly active immune response, resulting in overactivation of the inflammasome. The mRNA “vaccine” induces a very strong IgG antibody response, while suppressing CD8+ T cell activation. Exosomes distribute the recombinant, synthetic spike protein and the mRNA encoding it throughout the organism. In cancer patients, disease progression depends on the starting point of the cancer patient at the time of injection and the type of cancer treatment underway. Migration of circulating dendritic cells and Treg cells back to the thymus, while they are carrying spike protein, damages the medullary thymic epithelial cells and accelerates thymic involution, a direct cause of inflammaging and immunosenescence. In summary, the Treg responses to mRNA injections and subsequent mRNA-encoded SARS-CoV-2 spike protein expression may disrupt immune capacities resulting in accelerated development of autoimmune disease and cancer. The processes discussed here are consistent with both epidemiological findings and case reports.

Causes and consequences of DNA double-stranded breaks in cardiovascular disease.

The genome, whose stability is essential for survival, is incessantly exposed to internal and external stressors, which introduce an estimated 104 to 105 lesions, such as oxidation, in the nuclear genome of each mammalian cell each day. A delicate homeostatic balance between the generation and repair of DNA lesions maintains genomic stability. To initiate transcription, DNA strands unwind to form a transcription bubble and provide a template for the RNA polymerase II (RNAPII) complex to synthesize nascent RNA. The process generates DNA supercoils and introduces torsional stress. To enable RNAPII processing, the supercoils are released by topoisomerases by introducing strand breaks, including double-stranded breaks (DSBs). Thus, DSBs are intrinsic genomic features of gene expression. The breaks are quickly repaired upon processing of the transcription. DNA lesions and damaged proteins involved in transcription could impede the integrity and efficiency of RNAPII processing. The impediment, which is referred to as transcription stress, not only could lead to the generation of aberrant RNA species but also the accumulation of DSBs. The latter is particularly the case when topoisomerase processing and/or the repair mechanisms are compromised. The DSBs activate the DNA damage response (DDR) pathways to repair the damaged DNA and/or impose cell cycle arrest and cell death. In addition, the release of DSBs into the cytosol activates the cytosolic DNA-sensing proteins (CDSPs), which along with the nuclear DDR pathways induce the expression of senescence-associated secretory phenotype (SASP), cell cycle arrest, senescence, cell death, inflammation, and aging. The primary stimulus in hereditary cardiomyopathies is a mutation(s) in genes encoding the protein constituents of cardiac myocytes; however, the phenotype is the consequence of intertwined complex interactions among numerous stressors and the causal mutation(s). Increased internal DNA stressors, such as oxidation, alkylation, and cross-linking, are expected to be common in pathological conditions, including in hereditary cardiomyopathies. In addition, dysregulation of gene expression also imposes transcriptional stress and collectively with other stressors provokes the generation of DSBs. In addition, the depletion of nicotinamide adenine dinucleotide (NAD), which occurs in pathological conditions, impairs the repair mechanism and further facilitates the accumulation of DSBs. Because DSBs activate the DDR pathways, they are expected to contribute to the pathogenesis of cardiomyopathies. Thus, interventions to reduce the generation of DSBs, enhance their repair, and block the deleterious DDR pathways would be expected to impart salubrious effects not only in pathological states, as in hereditary cardiomyopathies but also aging.

A Multi-Channel Urine Sensing Detection System Based on Creatinine, Uric Acid, and pH.

Urine analysis represents a crucial diagnostic technique employed in clinical laboratories. Creatinine and uric acid in urine are essential biomarkers in the human body and are widely utilized in clinical analysis. Research has demonstrated a correlation between the normal physiological concentrations of creatinine and uric acid in urine and an increased risk of hypertension, cardiovascular diseases, and kidney disease. Furthermore, the pH of urine indicates the body's metabolic processes and homeostatic balance. In this study, an integrated multi-channel electrochemical sensing system was developed, combining electrochemical analysis techniques, microelectronic design, and nanomaterials. The architecture of an intelligent medical detection system and the production of an interactive interface for smartphones were accomplished. Initially, multi-channel selective electrodes were designed for creatinine, uric acid, and pH detection. The detection range was 10 nM to 100 μM for creatinine, 100 μM to 500 μM for uric acid, and 4 to 9 for pH. Furthermore, interference experiments were also conducted to verify the specificity of the sensors. Subsequently, multi-channel double-sided sensing electrodes and function-integrated hardware were designed, with the standard equations of target analytes stored in the system's read-only memory. Moreover, a WeChat mini-program platform was developed for smartphone interaction, enabling off-body detection and real-time display of target analytes through smartphones. Finally, the aforementioned electrochemical detection electrodes were integrated with the smart sensing system and wirelessly interfaced with smartphones, allowing for intelligent real-time detection in primary healthcare and individual household settings.

Effect of Bovine Lactoferrin Treatment on Iron Homeostasis and Gene Expression Changes in Multiple Organ Dysfunctions During Wound Healing Process in Rats.

Injury systemically disrupts the homeostatic balance and can cause organ failure. LF mediates both iron-dependent and iron-independent mechanisms, and the role of LF in regulating iron homeostasis is vital in terms of metabolism. In this study, we evaluated the organ-level effect and gene expression change of bLf in the cutaneous repair process. An excisional full-thickness skin defect (FTSD) wound model was created in male Sprague Dawley rats (180-250 g) (n = 48) fed a high-fat diet (HFD) and the PHGPx, SLC7A11 and SLC40A1 genes and iron metabolism were evaluated. The animals were randomly divided into 6 groups: 1- Control, 2- bLf (200 mg/kg/day, oral), 3- FTSD (12 mm in diameter, dorsal), 4- HFD + bLf, 5- HFD + FTSD, 6- HFD + FTSD + bLf. Histologically, iron accumulation was demonstrated by Prussian blue staining in the liver, kidney, and intestinal tissues. Gene expression analysis was performed with qPCR. Histologically, iron accumulation was demonstrated by Prussian blue staining in the liver, kidney, and intestinal tissues. Prussian blue reactions were detected in the kidney. PHPGx and SLC7A11 genes in kidney and liver tissue were statistically significant (P < 0.05) except for the SLC40A1 gene (P > 0.05). Expression changes of the three genes were not statistically significant in analyses of rat intestinal tissue (P = 0.057). In the organ-level ferroptotic damage mechanism triggered by wound formation. BLf controls the expression of three genes and manages iron deposition in these three tissues. In addition, it suppressed the increase in iron that would drive the cell to ferroptosis and anemia caused by inflammation, thereby eliminating iron deposition in the tissues.

Tilting homeostatic and dyshomeostatic microglial balance in health and disease: transforming growth factor-beta1 as a critical protagonist.

Tilting homeostatic and dyshomeostatic microglial balance in health and disease: transforming growth factor-beta1 as a critical protagonist.

The Kir channel in the nucleus tractus solitarius integrates the chemosensory system with REM sleep executive machinery for homeostatic balance

The locus coeruleus (LC), nucleus tractus solitarius (NTS), and retrotrapezoid nucleus (RTN) are critical chemosensory regions in the brainstem. In the LC, acid-sensing ion channels and proton pumps serve as H+ sensors and facilitate the transition from non-rapid eye movement (NREM) to rapid eye movement (REM) sleep. Interestingly, the potassium inward rectifier (KIR) channels in the LC, NTS, and RTN also act as H+-sensors and are a primary target for improving sleep in obstructive sleep apnea and Rett syndrome patients. However, the role of Kir channels in NREM to REM sleep transition for H+ homeostasis is not known. Male Wistar rats were surgically prepared for chronic sleep–wake recording and drug delivery into the LC, NTS, and RTN. In different animal cohorts, microinjections of the Kir channel inhibitor, barium chloride (BaCl2), at concentrations of 1 mM (low dose) and 2 mM (high dose) in the LC and RTN significantly increased wakefulness and decreased NREM sleep. However, BaCl2 microinjection into the LC notably reduced REM sleep, whereas it didn’t change in the RTN-injected group. Interestingly, BaCl2 microinjections into the NTS significantly decreased wakefulness and increased the percent amount of NREM and REM sleep. Additionally, with the infusion of BaCl2 into the NTS, the mean REM sleep episode numbers significantly increased, but the length of the REM sleep episode didn’t change. These findings suggest that the Kir channels in the NTS, but not in the LC and RTN, modulate state transition from NREM to REM sleep.

JAK inhibitor selectivity: new opportunities, better drugs?

Cytokines function as communication tools of the immune system, serving critical functions in many biological responses and shaping the immune response. When cytokine production or their biological activity goes awry, the homeostatic balance of the immune response is altered, leading to the development of several pathologies such as autoimmune and inflammatory disorders. Cytokines bind to specific receptors on cells, triggering the activation of intracellular enzymes known as Janus kinases (JAKs). The JAK family comprises four members, JAK1, JAK2, JAK3 and tyrosine kinase 2, which are critical for intracellular cytokine signalling. Since the mid-2010s multiple JAK inhibitors have been approved for inflammatory and haematological indications. Currently, approved JAK inhibitors have demonstrated clinical efficacy; however, improved selectivity for specific JAKs is likely to enhance safety profiles, and different strategies have been used to accomplish enhanced JAK selectivity. In this update, we discuss the background of JAK inhibitors, current approved indications and adverse effects, along with new developments in this field. We address the issue of JAK selectivity and its relevance in terms of efficacy, and describe new modalities of JAK targeting, as well as new aspects of JAK inhibitor action.

Analysis of heart rate variability in assessing the autonomic status of tuberculosis patients and in combination with HIV infection

In this study, a comprehensive instrumental assessment of the autonomic status of tuberculosis patients and those with concomitant HIV infection at the beginning and during treatment was conducted, revealing the structure of dysfunction through heart rate variability analysis. Correcting the identified disorders will enhance the effectiveness of treatment through a comprehensive individualized approach.The aim of the study: to assess the autonomic status of patients with tuberculosis and concomitant HIV infection during the course of treatment using spectral analysis of heart rate variability and to determine its clinical significance.Materials and methods. The study involved 195 participants. They were divided into two groups: a control group of 70 healthy individuals and an observation group of 125 newly diagnosed patients with infiltrative and disseminated pulmonary tuberculosis, further divided into two subgroups. The first subgroup included 64 patients with pulmonary tuberculosis, and the second subgroup included 61 patients with tuberculosis combined with HIV infection. The structure of the autonomic nervous system was studied using the computer complex «Varicard 2.51» for processing variocardiograms and analyzing heart rate variability (Registration certificate for medical device dated 10.12.2007 No. FSR 2007/01390). All patients were examined under identical conditions. Calculations were performed using SPSS Statistics v. 23.Results and discussion. The data on the assessment of the state and dynamics of the total power spectrum of RR intervals (TP) in the control group and in patients with tuberculosis and concomitant HIV infection in subgroups 1 and 2 of the observation group during treatment are presented. When comparing the frequency of TP above the «normal zone» in the control group and subgroup 1 of the observation group (t1= 3.30; p1&lt;0.01; t2=1.70; p2&gt;0.05), in the control group and subgroup 2 of the observation group (t1=3.51; p1&lt;0.01; t2=2.64; p2&lt;0.01), statistically significant differences were found in subgroup 1 before treatment and in subgroup 2 before and after treatment. The significant decrease in TP levels above the «normal zone» in patients of subgroups 1 and 2 before treatment indicated significant mobilization of the body’s regulatory system reserves needed to maintain vital functions. By the end of the hospital treatment stage, TP levels had not recovered in patients of subgroup 2, marking more pronounced regulatory disturbances in patients with pulmonary tuberculosis combined with HIV infection.Conclusion. The assessment of the state of regulatory systems and the body’s reserves based on heart rate variability indicators showed that in healthy individuals, these systems were at levels ensuring the body’s normal homeostatic balance with the regulatory systems functioning normally without excessive stress and high resource mobilization. In patients with pulmonary tuberculosis, the state of regulatory systems was at a lower level, especially in patients with concomitant HIV infection.

Extracellular purines in lung endothelial permeability and pulmonary diseases.

The purinergic signaling system is an evolutionarily conserved and critical regulatory circuit that maintains homeostatic balance across various organ systems and cell types by providing compensatory responses to diverse pathologies. Despite cardiovascular diseases taking a leading position in human morbidity and mortality worldwide, pulmonary diseases represent significant health concerns as well. The endothelium of both pulmonary and systemic circulation (bronchial vessels) plays a pivotal role in maintaining lung tissue homeostasis by providing an active barrier and modulating adhesion and infiltration of inflammatory cells. However, investigations into purinergic regulation of lung endothelium have remained limited, despite widespread recognition of the role of extracellular nucleotides and adenosine in hypoxic, inflammatory, and immune responses within the pulmonary microenvironment. In this review, we provide an overview of the basic aspects of purinergic signaling in vascular endothelium and highlight recent studies focusing on pulmonary microvascular endothelial cells and endothelial cells from the pulmonary artery vasa vasorum. Through this compilation of research findings, we aim to shed light on the emerging insights into the purinergic modulation of pulmonary endothelial function and its implications for lung health and disease.

Sensitivity analysis of fibrous thick-walled tubes with mechano-sensitive remodeling fibers in homeostasis

In this article, we apply the sensitivity analysis method to capture the influence of various parameters on the inflation pressure, axial force, and the deformation for an inflated and axially stretched cylinder. The material consists of an isotropic ground substance material reinforced with fibers that undergo a continuous and mechano-sensitive remodeling process. The input parameters of the mechanical system are assumed to be distributed according to the uniform probability distribution function. In the sensitivity analysis, we apply the Sobol method to determine how the variations of input parameters affect the inflation as well as the axial force in the cylinder. Special attention is given to the fiber remodeling process associated with a homeostatic balance between the constant fiber creation process and the strain-stabilized fiber dissolution. The results may help to understand the importance of the effect of material parameter changes, for example, due to remodeling processes in the context of diseases or recovering processes, on the overall tissue behavior.

Membrane Receptor-Mediated Disruption of Cellular Homeostasis: Changes in Intracellular Signaling Pathways Increase the Toxicity of Ochratoxin A.

Organisms maintain their cellular homeostatic balance by interacting with their environment through the use of their cell surface receptors. Membrane based receptors such as the transforming growth factor β receptor (TGFR), the prolactin receptor (PRLR), and hepatocyte growth factor receptor (HGFR), along with their associated signaling cascade, play significant roles in retaining cellular homeostasis. While these receptors and related signaling pathways are essential for health of cell and organism, their dysregulation can lead to imbalance in cell function with severe pathological conditions such as cell death or cancer. Ochratoxin A (OTA) can disrupt cellular homeostasis by altering expression levels of these receptors and/or receptor-associated intracellular downstream signaling modulators and/or pattern and levels of their phosphorylation/dephosphorylation. Recent studies have shown that the activity of the TGFR, the PRLR, and HGFR and their associated signaling cascades change upon OTA exposure. A critical evaluation of these findings suggests that while increased activity of the HGFR and TGFR signaling pathways leads to an increase in cell survival and fibrosis, decreased activity of the PRLR signaling pathway leads to tissue damage. This review explores the roles of these receptors in OTA-related pathologies and effects on cellular homeostasis.

Spliceosomal snRNAs, the Essential Players in pre-mRNA Processing in Eukaryotic Nucleus: From Biogenesis to Functions and Spatiotemporal Characteristics.

Spliceosomal small nuclear RNAs (snRNAs) are a fundamental class of non-coding small RNAs abundant in the nucleoplasm of eukaryotic cells, playing a crucial role in splicing precursor messenger RNAs (pre-mRNAs). They are transcribed by DNA-dependent RNA polymerase II (Pol II) or III (Pol III), and undergo subsequent processing and 3' end cleavage to become mature snRNAs. Numerous protein factors are involved in the transcription initiation, elongation, termination, splicing, cellular localization, and terminal modification processes of snRNAs. The transcription and processing of snRNAs are regulated spatiotemporally by various mechanisms, and the homeostatic balance of snRNAs within cells is of great significance for the growth and development of organisms. snRNAs assemble with specific accessory proteins to form small nuclear ribonucleoprotein particles (snRNPs) that are the basal components of spliceosomes responsible for pre-mRNA maturation. This article provides an overview of the biological functions, biosynthesis, terminal structure, and tissue-specific regulation of snRNAs.

Hypercalcemia in Cancer: Causes, Effects, and Treatment Strategies.

Calcium plays central roles in numerous biological processes, thereby, its levels in the blood are under strict control to maintain homeostatic balance and enable the proper functioning of living organisms. The regulatory mechanisms ensuring this balance can be affected by pathologies such as cancer, and as a result, hyper- or hypocalcemia can occur. These states, characterized by elevated or decreased calcium blood levels, respectively, have a significant effect on general homeostasis. This article focuses on a particular form of calcium metabolism disorder, which is hypercalcemia in neoplasms. It also constitutes a summary of the current knowledge regarding the diagnosis of hypercalcemia and its management. Hypercalcemia of malignancy is estimated to affect over 40% of cancer patients and can be associated with both solid and blood cancers. Elevated calcium levels can be an indicator of developing cancer. The main mechanism of hypercalcemia development in tumors appears to be excessive production of parathyroid hormone-related peptides. Among the known treatment methods, bisphosphonates, calcitonin, steroids, and denosumab should be mentioned, but ongoing research promotes progress in pharmacotherapy. Given the rising global cancer prevalence, the problem of hypercalcemia is of high importance and requires attention.

Interactions between immune cell types facilitate the evolution of immune traits.

An essential prerequisite for evolution by natural selection is variation among individuals in traits that affect fitness1. The ability of a system to produce selectable variation, known as evolvability2, thus markedly affects the rate of evolution. Although the immune system is among the fastest-evolving components in mammals3, the sources of variation in immune traits remain largely unknown4,5. Here we show that an important determinant of the immune system's evolvability is its organization into interacting modules represented by different immune cell types. By profiling immune cell variation in bone marrow of 54 genetically diverse mouse strains from the Collaborative Cross6, we found that variation in immune cell frequencies is polygenic and that many associated genes are involved in homeostatic balance through cell-intrinsic functions of proliferation, migration and cell death. However, we also found genes associated with the frequency of a particular cell type that are expressed in a different cell type, exerting their effect in what we term cyto-trans. The vertebrate evolutionary record shows that genes associated in cyto-trans have faced weaker negative selection, thus increasing the robustness and hence evolvability2,7,8 of the immune system. This phenomenon is similarly observable in human blood. Our findings suggest that interactions between different components of the immune system provide a phenotypic space in which mutations can produce variation with little detriment, underscoring the role of modularity in the evolution of complex systems9.