The Transition Period Updated: A Review of the New Insights into the Adaptation of Dairy Cows to the New Lactation

Recent research on the transition period (TP) of dairy cows has highlighted the pivotal role of immune function in affecting the severity of metabolic challenges the animals face when approaching calving. This suggests that the immune system may play a role in the etiology of metabolic diseases occurring in early lactation. Several studies have indicated that the roots of immune dysfunctions could sink way before the “classical” TP (e.g., 3 weeks before and 3 weeks after calving), extending the time frame deemed as “risky” for the development of early lactation disorders at the period around the dry-off. Several distressing events occurring during the TP (i.e., dietary changes, heat stress) can boost the severity of pre-existing immune dysfunctions and metabolic changes that physiologically affect this phase of the lactation cycle, further increasing the likelihood of developing diseases. Based on this background, several operational and nutritional strategies could be adopted to minimize the detrimental effects of immune dysfunctions on the adaptation of dairy cows to the new lactation. A suitable environment (i.e., optimal welfare) and a balanced diet (which guarantees optimal nutrient partitioning to improve immune functions in cow and calf) are key aspects to consider when aiming to minimize TP challenges at the herd level. Furthermore, several prognostic behavioral and physiological indicators could help in identifying subjects that are more likely to undergo a “bad transition”, allowing prompt intervention through specific modulatory treatments. Recent genomic advances in understanding the linkage between metabolic disorders and the genotype of dairy cows suggest that genetic breeding programs aimed at improving dairy cows’ adaptation to the new lactation challenges (i.e., through increasing immune system efficiency or resilience against metabolic disorders) could be expected in the future. Despite these encouraging steps forward in understanding the physiological mechanisms driving metabolic responses of dairy cows during their transition to calving, it is evident that these processes still require further investigation, and that the TP—likely extended from dry-off—continues to be “the final frontier” for research in dairy sciences.

A novel class of small tRNA-like noncoding transcripts arising from the human NEAT1-MALAT1 region critically influences innate immunity and angiogenesis

Background The evolutionary conserved NEAT1-MALAT1 gene cluster encounters high interest in cardiovascular medicine and oncology. The cluster generates large primary transcripts which remain nuclear, whereas novel tRNA-like transcripts (mascRNA, menRNA) enzymatically generated from these precursors translocate to the cytosol. We previously found that NEAT1 and MALAT1 deficient mice display accelerated atherosclerosis and vascular inflammation due to immune dysfunctions. Methods While the previously investigated mice were deficient in the entire NEAT1 or MALAT1 locus, here we aimed to selectively disrupt only tRNA-like transcripts “menRNA” arising from NEAT1, or “mascRNA” arising from MALAT1. To none of these a biological function has been assigned so far. Both lncRNAs give rise to transcripts of vastly different size (NEAT1: 23kb MENb, 3.7kb MENe, 59nt “menRNA”; MALAT1: 8.3 kb primary, 59nt “mascRNA”), and traditional knockout methods are unable to selectively inactivate one of the small transcripts only. Through CRISPR/Cas9 editing we therefore developed human monocyte-macrophage cell lines with short deletions in the respective tRNA-encoding sequences to disrupt normal menRNA or mascRNA formation, respectively. These editing procedures do not affect transcription of the respective lncRNA parent transcripts, and also not disturb regular formation of the triple-helix structures at their 3'-ends which support stabilization of the respective lncRNAs (Fig. 1). Results We found the tRNA-like transcripts menRNA and mascRNA critically influence innate immunity and angiogenesis. In addition to common anomalies resulting from their selective CRISPR-Cas9 mediated deletion (Fig. 1), there are specific disturbances associated with either Δmasc or Δmen cells (Fig. 2). Both ΔmascRNA and ΔmenRNA human monocytes show profoundly altered ribosomal RNA/protein and tRNA-modifying enzyme expression, display anomalous growth/ angiogenetic factor expression, fundamentally change angiogenetic patterns in co-cultures with human endothelial cells, and have gravely disturbed innate immune responses (LPS, DNA and RNA viruses) (Fig. 1). CRISPR-engineered ΔmenRNA cells share remakable similarities with human post-MI PBMCs, suggesting the NEAT1-menRNA system may significantly contribute to post-MI residual inflammatory risk despite optimal standard therapy (Fig. 2). Conclusions Beyond prior work in knockout mice documenting immune function of the NEAT1-MALAT1 cluster, the current study identifies menRNA and mascRNA as important novel components of human innate immunity with relevance for angiogenetic processes. These data provide a second mechanistic link for the apparent relevance of the NEAT1-MALAT1 gene cluster in cardiovascular and malignant diseases. As prototypes of a novel class of small noncoding RNAs (distinct from miRNAs and siRNAs) they may constitute cytosolic therapeutic targets. FUNDunding Acknowledgement Type of funding sources: Other. Main funding source(s): DZHK Shared Expertise Project/B19-006_SE/FKZ 81X2100257/Transcriptome analysis of circulating immune cells to improve the assessment of prognosis and the response to novel anti-inflammatory treatments after myocardial infarction Figure 1. Common anomalies Figure 2. Specific anomalies

Immunoprophylaxis. Its role in sports medicine

Achieving high results in sports directly depends on the biological characteristics of the athlete’s body and the state of his health, which, in turn, is determined by the adequate functioning of the integrative systems of the body: immune, endocrine and nervous. At the same time, modern sport is associated with the presence of many factors that adversely affect the state of the athlete’s immunity. These include physical activity that is on the verge of a person’s physiological capabilities, states of extreme psychological stress, changes in climatic-zone conditions when moving athletes over long distances, unfavorable environmental factors leading to hypothermia (the same stress). A decrease in the activity of the immune system leads to the emergence of immune dysfunctions, as a result of which the risk of the occurrence of infectious colds and exacerbation of chronic pathology significantly increases. The presence of these facts indicates the need for the prophylactic use of immunotherapy.

Impact of Immune Parameters and Immune Dysfunctions on the Prognosis of Patients with Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is characterized by a wide spectrum of immune alterations, affecting both the innate and adaptive immunity. These immune dysfunctions strongly impact the immune surveillance, facilitate tumor progression and eventually affect the disease course. Quantitative and functional alterations involving conventional T cells, γδ T cells, regulatory T cells, NK and NKT cells, and myeloid cells, together with hypogammaglobulinemia, aberrations in the complement pathways and altered cytokine signature have been reported in patients with CLL. Some of these immune parameters have been shown to associate with other CLL-related characteristics with a known prognostic relevance or to correlate with disease prognosis. Also, in CLL, the complex immune response dysfunctions eventually translate in clinical manifestations, including autoimmune phenomena, increased risk of infections and second malignancies. These clinical issues are overall the most common complications that affect the course and management of CLL, and they also may impact overall disease prognosis.

Evaluation of Peripheral Immune Activation in Amyotrophic Lateral Sclerosis

Accumulating evidence has revealed that immunity plays an important role in amyotrophic lateral sclerosis (ALS) progression. However, the results regarding the serum levels of immunoglobulin and complement are inconsistent in patients with ALS. Although immune dysfunctions have also been reported in patients with other neurodegenerative diseases, few studies have explored whether immune dysfunction in ALS is similar to that in other neurodegenerative diseases. Therefore, we performed this study to address these gaps. In the present study, serum levels of immunoglobulin and complement were measured in 245 patients with ALS, 65 patients with multiple system atrophy (MSA), 60 patients with Parkinson's disease (PD), and 82 healthy controls (HCs). Multiple comparisons revealed that no significant differences existed between patients with ALS and other neurodegenerative diseases in immunoglobulin and complement levels. Meta-analysis based on data from our cohort and eight published articles was performed to evaluate the serum immunoglobulin and complement between patients with ALS and HCs. The pooled results showed that patients with ALS had higher C4 levels than HCs. In addition, we found that the IgG levels were lower in early-onset ALS patients than in late-onset ALS patients and HCs, and the correlations between age at onset of ALS and IgG or IgA levels were significant positive. In conclusion, our data supplement existing literature on understanding the role of peripheral immunity in ALS.

The Landscape of Signaling Pathways and Proteasome Inhibitors Combinations in Multiple Myeloma

Multiple myeloma is a malignancy of terminally differentiated plasma cells, characterized by an extreme genetic heterogeneity that poses great challenges for its successful treatment. Due to antibody overproduction, MM cells depend on the precise regulation of the protein degradation systems. Despite the success of PIs in MM treatment, resistance and adverse toxic effects such as peripheral neuropathy and cardiotoxicity could arise. To this end, the use of rational combinatorial treatments might allow lowering the dose of inhibitors and therefore, minimize their side-effects. Even though the suppression of different cellular pathways in combination with proteasome inhibitors have shown remarkable anti-myeloma activities in preclinical models, many of these promising combinations often failed in clinical trials. Substantial progress has been made by the simultaneous targeting of proteasome and different aspects of MM-associated immune dysfunctions. Moreover, targeting deranged metabolic hubs could represent a new avenue to identify effective therapeutic combinations with PIs. Finally, epigenetic drugs targeting either DNA methylation, histone modifiers/readers, or chromatin remodelers are showing pleiotropic anti-myeloma effects alone and in combination with PIs. We envisage that the positive outcome of patients will probably depend on the availability of more effective drug combinations and treatment of early MM stages. Therefore, the identification of sensitive targets and aberrant signaling pathways is instrumental for the development of new personalized therapies for MM patients.

Soil Lead (Pb) in New Orleans: A Spatiotemporal and Racial Analysis

Spatialized racial injustices drive morbidity and mortality inequalities. While many factors contribute to environmental injustices, Pb is particularly insidious, and is associated with cardio-vascular, kidney, and immune dysfunctions and is a leading cause of premature death worldwide. Here, we present a revised analysis from the New Orleans dataset of soil lead (SPb) and children’s blood Pb (BPb), which was systematically assembled for 2000–2005 and 2011–2016. We show the spatial–temporal inequities in SPb, children’s BPb, racial composition, and household income in New Orleans. Comparing medians for the inner city with outlying areas, soil Pb is 7.5 or 9.3 times greater, children’s blood Pb is ~2 times higher, and household income is lower. Between 2000–2005 and 2011–2016, a BPb decline occurred. Long-standing environmental and socioeconomic Pb exposure injustices have positioned Black populations at extreme risk of adverse health consequences. Given the overlapping health outcomes of Pb exposure with co-morbidities for conditions such as COVID-19, we suggest that further investigation be conducted on Pb exposure and pandemic-related mortality rates, particularly among Black populations. Mapping and remediating invisible environmental Pb provides a path forward for preventing future populations from developing a myriad of Pb-related health issues.

DIAGNOSIS AND TREATMENT OF PRIMARY MINOR IMMUNODEFICIENCIES IN PATIENTS WITH RECURRENT UROGENITAL INFECTIONS AND IMMUNE-DEPENDENT INFERTILITY

It has now been established that immunosuppressive status is observed in patients with recurrent urogenital infections caused by opportunistic and low virulent microflora. A pooled analysis of the known prevalence rates of the 30 currently known mild human immune dysfunctions suggests that at least 20% of the current population (in one in five people) is currently affected by at least one primary minor immunodeficiency. This contradicts the established but erroneous view of the rarity of primary immunodeficiencies in humans.Therefore, the diagnosis of primary minor immunodeficiencies should be an integral part of modern routine medical practice of specialists in various fields. This article presents the classification of minor primary human immunodeficiencies, considers the differences between major and minor immune dysfunctions, as well as the algorithm of clinical diagnosis of primary minor immunodeficiencies and modern approaches to treatment.Detection of genetically determined disease of the immune system can not only explain the atypical course of opportunistic or low virulent infections of the urogenital tract and reduced fertility, but can also open the way to the appointment of targeted immunotherapy to compensate for the causative immunodeficiency. This can take the effectiveness of the applied interventions to a qualitatively new level, solving even severe clinical problems.

Functional Bowel Disorders and Obesity in Children: State of the Problem

Obesity and functional bowel disorders (FBDs) are often observed in children and have common risk factors. The present review aimed to summarize the published data on the association between obesity and FBDs in children and a discussion of possible pathophysiological mechanisms that may be involved. Published data indicates that obesity and FBDs could be associated conditions. There is substantial evidence that obesity in children is associated with constipation. However, it should be noted that there were few studies in this direction, and those studies were heterogeneous in both the composition of participants and studied diagnostic criteria, and in the majority of cases, they were not adjusted for potential confounders. The association between obesity and FBDs can be explored through diet, peculiarities of eating behavior, and psychological factors. The most promising direction in the study could be the study of the GM, the changes in which can contribute to the development of immune dysfunctions of the bowel, chronic low-grade inflammation, increased colonic permeability, motility disturbances, and visceral hypersensitivity. The studies in this area can provide important data for developing a strategy of treatment and prevention of both groups of diseases.