The evolutionary history of infectious disease in the ancient Americas and the pathogenic consequences of European contact

The increasing availability of next generation sequencing techniques in recent decades has led to new discoveries, and sometimes the redefinition of conventional hypotheses, regarding many complex human-pathogen evolutionary relationships. These new discoveries are particularly poignant in studies of the Americas, where research into Indigenous ancestry and migration has historically been ignored. As a result, conventional hypotheses regarding the origin of global pathogens like tuberculosis, syphilis, and malaria in the Americas and their spread within the continents have been mischaracterized. Fortunately, recent studies using molecular techniques have now superseded these missteps, which were often based in anecdotal accounts from colonial missionary reports rather than rigorous scientific study. It is now clear that there was not a unidirectional pipeline of pathogen introduction that began with European contact; instead, a rich and varied microbiological landscape already existed in the Americas. This synthesis of research regarding the origin and spread of pathogens in the Americas examines the scope of this changing perception within the fields of paleogenomics and paleomicrobiology.     

Dynamic control of neuroexocytosis by phosphoinositides in health and disease

Phosphoinositides are a group of phospholipids whose inositol headgroups can be phosphorylated at three distinct positions thereby generating seven different isotypes. The conversion between these lipid species depends on the activity of specific sets of phosphoinositide kinases and phosphatases whose targeting and activity is critical to establish the landscape of phosphoinositides on the cytosol-facing hemi-membrane of all organelles and plasmalemma. Phosphoinositides play pleiotropic roles ranging from signalling and membrane trafficking to modulation of ion channels and survival. In neurons and neurosecretory cells, whose main function is to communicate through the release of neurotransmitter, most of the work has focused on the role played by phosphatidylinositol (4,5) bisphosphate in controlling the mechanism underpinning neurotransmitter release through the fusion of secretory vesicles with the plasmalemma. Emerging evidence supports a multi-faceted regulation of neuroexocytosis by 3-phosphorylated phosphoinositides. In this review, we summarise the molecular mechanism by which these lipids control exocytosis and how minute changes in their metabolism can have devastating effects in the nervous system and lead to neurodegeneration.     

A Skin-depth Analysis of Integrins: Role of the Integrin Network in Health and Disease

Abstract

In the skin epidermis, adhesion to the underlying basement membrane is mediated through trans-membrane integrin receptors. In addition to a structural role, integrins can signal in a bi-directional manner though the membrane and thus play a crucial role in cell adhesion, migration, proliferation, and differentiation. In this review we will discuss the role of integrins and their network of partner proteins in normal skin development, and how dysregulation influences disease states such as skin blistering disorders and cancers. We also discuss major integrin-specific therapeutic advances that have been made over the past few years in treating these skin disorders as well as targeting angiogenesis, neo-vasculature, and tumorigenesis.     

Molecular connexin partner remodeling orchestrates connexin traffic: From physiology to pathophysiology

Connexins, through gap junctional intercellular communication, are known to regulate many physiological functions involved in developmental processes such as cell proliferation, differentiation, migration and apoptosis. Strikingly, alterations of connexin expression and trafficking are often, if not always, associated with human developmental diseases and carcinogenesis. In this respect, disrupted trafficking dynamics and aberrant intracytoplasmic localization of connexins are considered as typical features of functionality failure leading to the pathological state. Recent findings demonstrate that interactions of connexins with numerous protein partners, which take place throughout connexin trafficking, are essential for gap junction formation, membranous stabilization and degradation. In the present study, we give an overview of the physiological molecular machinery and of the specific interactions between connexins and their partners, which are involved in connexin trafficking, and we highlight their changes in pathological situations.     

Effect of genetic and environmental factors on protein biomarkers for common non-communicable disease and use of personally normalized plasma protein profiles (PNPPP)

Abstract

Objective: To study the impact of genetic and lifestyle factors on protein biomarkers and develop personally normalized plasma protein profiles (PNPPP) controlling for non-disease-related variance.

Materials and methods: Proximity extension assays were used to measure 145 proteins in 632 controls and 344 cases with non-communicable diseases.

Results: Genetic and lifestyle factors explained 20–88% of the variation in healthy controls. Adjusting for these factors reduced the number of candidate biomarkers by 63%.

Conclusion: PNPPP efficiently controls for non-disease-related variance, allowing both for efficient discovery of novel biomarkers and for covariate-independent linear cut-offs suitable for clinical use.     

Adaptive Admixture of HLA Class I Allotypes Enhanced Genetically Determined Strength of Natural Killer Cells in East Asians

Human natural killer (NK) cells are essential for controlling infection, cancer, and fetal development. NK cell functions are modulated by interactions between polymorphic inhibitory killer cell immunoglobulin-like receptors (KIR) and polymorphic HLA-A, -B, and -C ligands expressed on tissue cells. All HLA-C alleles encode a KIR ligand and contribute to reproduction and immunity. In contrast, only some HLA-A and -B alleles encode KIR ligands and they focus on immunity. By high-resolution analysis of KIR and HLA-A, -B, and -C genes, we show that the Chinese Southern Han (CHS) are significantly enriched for interactions between inhibitory KIR and HLA-A and -B. This enrichment has had substantial input through population admixture with neighboring populations, who contributed HLA class I haplotypes expressing the KIR ligands B*46:01 and B*58:01, which subsequently rose to high frequency by natural selection. Consequently, over 80% of Southern Han HLA haplotypes encode more than one KIR ligand. Complementing the high number of KIR ligands, the CHS KIR locus combines a high frequency of genes expressing potent inhibitory KIR, with a low frequency of those expressing activating KIR. The Southern Han centromeric KIR region encodes strong, conserved, inhibitory HLA-C-specific receptors, and the telomeric region provides a high number and diversity of inhibitory HLA-A and -B-specific receptors. In all these characteristics, the CHS represent other East Asians, whose NK cell repertoires are thus enhanced in quantity, diversity, and effector strength, likely augmenting resistance to endemic viral infections.     

Biochemical and molecular identification of Xanthomonas translucens pv. undulosa causing bacterial leaf streak of wheat in Punjab,Pakistan

Xanthomonas translucens pv. undulosa, (Xtu.), causal agent of Bacterial leaf streak (BLS) of wheat, was characterised through pathogencity, hypersensitivity, biochemical and molecular assays. Fifty symptomatic leaves of wheat were collected from eight agro-ecological zones of Punjab out of which 25 were isolated and purified. Maximum incidence and severity in Faisalabad were followed by Multan and Rahim Yar Khan. The pathogen isolated from diseased leaves was identified on the basis of colonies pattern, colour, biochemical and pathogencity test as X. translucens pv. undulosa and confirmed its pathogencity through pathogencity test. For molecular characterization, the bacterial 16S–23S rDNA spacer fragments were amplified by PCR with conserved primers (C1 and C2) and then in combination with specific primers (T1 & T2). 300?bp product amplified by C1 and C2 primer pair confirmed the presence of Xanthomonas, while specific primers T1 and T2 amplified a product of 200?bp, confirmed the presence of X. translucens pv. undulosa. This work will be quite helpful for wheat pathologist and breeders for future management strategy for this disease.