Role of Repetitive Transcranial Magnetic Stimulation in Treatment of Fibromyalgia: A Randomized Controlled Trial.

Background and Objective: Fibromyalgia syndrome (FMS) is a chronic disease characterized by widespread, persistent musculoskeletal pain in association with impaired health-related quality of life. Repetitive transcranial magnetic stimulation (rTMS) is an emerging tool for the management of fibromyalgia. There is no standardized protocol of rTMS for the treatment of FMS, and both low- and high-frequency stimulation of the dorsolateral prefrontal cortex (DLPFC) are described in the literature with variable efficacy. The objective of this study was to determine the effectiveness of rTMS in people with fibromyalgia and compare the response of low- and high-frequency stimulation with sham stimulation. Materials and Methods: This study was a single-blinded, randomized, placebo-controlled trial. Ninety patients with the diagnosis of FMS were randomly allocated into one of the following three groups: low-frequency (1 Hz) group, high-frequency (10 Hz) group, and sham group. Pain, depression, anxiety, and quality of life were measured using the Numerical Pain Rating Scale (NPRS), Hamilton Anxiety Rating Scale (HAM-A), Hamilton Depression Rating Scale (HDRS), and Revised Fibromyalgia Impact Questionnaire (FIQR) immediately following treatment as well as at 1 and 3 months after treatment. The data was statistically analyzed using Statistical Package for the Social Sciences version 23 software. P value < 0.05 was considered statistically significant. Results: Intergroup analysis revealed a significant improvement in NPRS, HAM-A, HDRS, and FIQR scores in both low- and high- frequency groups immediately following treatment and for 3 months after treatment. No significant difference in the efficacy of low- and high-frequency stimulation was noticed. Conclusions: rTMS is an effective mode of treatment in people with FMS. Both low and high frequencies of stimulation at DLPFC are equally effective in reducing pain and associated symptoms.

Age of Antibiotic Resistance in MDR/XDR Clinical Pathogen of Pseudomonas aeruginosa.

Antibiotic resistance in Pseudomonas aeruginosa remains one of the most challenging phenomena of everyday medical science. The universal spread of high-risk clones of multidrug-resistant/extensively drug-resistant (MDR/XDR) clinical P. aeruginosa has become a public health threat. The P. aeruginosa bacteria exhibits remarkable genome plasticity that utilizes highly acquired and intrinsic resistance mechanisms to counter most antibiotic challenges. In addition, the adaptive antibiotic resistance of P. aeruginosa, including biofilm-mediated resistance and the formation of multidrug-tolerant persisted cells, are accountable for recalcitrance and relapse of infections. We highlighted the AMR mechanism considering the most common pathogen P. aeruginosa, its clinical impact, epidemiology, and save our souls (SOS)-mediated resistance. We further discussed the current therapeutic options against MDR/XDR P. aeruginosa infections, and described those treatment options in clinical practice. Finally, other therapeutic strategies, such as bacteriophage-based therapy and antimicrobial peptides, were described with clinical relevance.

Association of antibiotics and heavy metal arsenic to horizontal gene transfer from multidrug-resistant clinical strains to antibiotic-sensitive environmental strains.

The emergence of multidrug-resistant bacteria is currently posing a significant threat to global public health. By testing for resistance to different antibiotic classes, we discovered that the majority of clinical bacteria are multidrug-resistant. These clinical multidrug-resistant species have antibiotic resistance genes on their plasmids that can be horizontally transferred to various antibiotic susceptible environmental bacterial species, resulting in antibiotic-resistant transconjugates. Furthermore, we discovered that the presence of an optimal concentration of antibiotics or heavy metal (arsenic) facilitates horizontal gene transfer through the formation of transconjugants. Notably, the addition of a conjugation inhibitor (2-hexadecynoic acid, a synthetic fatty acid) completely blocked the formation of antibiotic or arsenic-induced transconjugants. We discovered a high level of arsenic in water from the Shukratal region, Uttarakhand, India, which corresponded to a high serum level of arsenic in clinically infected individuals from the Shukratal region compared to other locations in Uttarakhand. Importantly, bacterial strains isolated from infected people who drink water from the Shukratal region with high arsenic levels were found to be more antibiotic-resistant than strains isolated from other sites. We discovered that bacterial strains isolated from individuals with high serum arsenic levels are significantly more resistant to antibiotics than individuals with low serum arsenic levels within the Shurkratal. This research sheds light on imminent threats to global health in which improper clinical, industrial, and other waste disposal, increased antibiotic concentrations in the environment, and increased human interference can easily transform commensal and pathogenic bacteria found in environmental niches into life-threatening multidrug-resistant superbugs.

Association of multidrug resistance behavior of clinical Pseudomonas aeruginosa to pigment coloration.

Pseudomonas aeruginosa is an adaptable bacterial pathogen that infects a variety of organs, including the respiratory tract, vascular system, urinary tract, and central nervous system, causing significant morbidity and mortality. As the primary goal of this study, we wanted to determine how pigment color production differed between clinical strains of P. aeruginosa, and whether or not that variation was associated with multidrug resistance or the ability to form biofilms. We screened in total 30.1% of yellow, 39.8% green and 30.1% of no pigment-producing P. aeruginosa strains from a total of 143 various clinical isolates. Yellow pigment-producing strains presented significant resistance to antibiotics groups, including ß-lactam (91.5%), aminoglycosides (70.5%), and carbapenems (51.9%) compared to green and non-pigmented strains. Notably, 16.3% of yellow pigment-producing strains were resistant to colistin which is used as a last-resort treatment for multidrug-resistant bacteria, whereas only 2.3% of non-pigmented and 1.8% of green pigmented strains were resistant to colistin. Aside from that, yellow pigment-producing strains were frequent producers of enzymes belonging to the lactamase family, including ESBL (55.6%), MBL (55.6%), and AmpC (50%). Compared to the green groups (7.14%) and non-pigmented groups (28.5%), they had a higher frequency of efflux positive groups (64.2%). Notably, when compared to non-pigmented groups, green pigment-producing strains also displayed antibiotic susceptibility behavior similar to yellow pigment-producing strains. The majority of yellow pigment-producing strains outperformed the green and non-pigmented strains in terms of MIC levels when compared to the other two groups of strains. Despite the fact that previous studies have demonstrated a direct correlation between multidrug resistance behaviors and biofilm production, no such statistically significant association between pigment and biofilm formation was found in our investigation. Our research has demonstrated that the correlation of bacterial pigments on their susceptibility to antimicrobial agents. Yellow pigment-producing P. aeruginosa strains posed a significant problem due to the lack of alternative agents against such transformed strains, which may be associated with the development of multidrug resistance.

Neuroimmune communication regulating pruritus in atopic dermatitis.

Atopic dermatitis (AD) is a common, chronic-relapsing inflammatory skin disease with significant disease burden. Genetic and environmental trigger factors contribute to AD, activating 2 of our largest organs, the nervous system and the immune system. Dysregulation of neuroimmune circuits plays a key role in the pathophysiology of AD, causing inflammation, pruritus, pain, and barrier dysfunction. Sensory nerves can be activated by environmental or endogenous trigger factors, transmitting itch stimuli to the brain. On stimulation, sensory nerve endings also release neuromediators into the skin, contributing again to inflammation, barrier dysfunction, and itch. In addition, dysfunctional peripheral and central neuronal structures contribute to neuroinflammation, sensitization, nerve elongation, and neuropathic itch, thus chronification and therapy resistance. Consequently, neuroimmune circuits in skin and central nervous system may be targets to treat pruritus in AD. Cytokines, chemokines, proteases, lipids, opioids, and ions excite/sensitize sensory nerve endings, which not only induces itch but further aggravates/perpetuates inflammation, skin barrier disruption, and pruritus as well. Thus, targeted therapies for neuroimmune circuits as well as pathway inhibitors (eg, kinase inhibitors) may be beneficial to control pruritus in AD either in systemic and/or in topical form. Understanding neuroimmune circuits and neuronal signaling will optimize our approach to control all pathological mechanisms in AD, inflammation, barrier dysfunction, and pruritus.

Potential Synergistic Antibiotic Combinations against Fluoroquinolone-Resistant Pseudomonas aeruginosa.

The rise in multiple-drug-resistant (MDR) phenotypes in Gram-negative pathogens is a major public health crisis. Pseudomonas aeruginosa is one of the leading causes of nosocomial infections in clinics. Treatment options for P. aeruginosa have become increasingly difficult due tdo its remarkable capacity to resist multiple antibiotics. The presence of intrinsic resistance factors and the ability to quickly adapt to antibiotic monotherapy warrant us to look for alternative strategies like combinatorial antibiotic therapy. Here, we report the frequency of P. aeruginosa multidrug-resistant and extensively drug-resistance (XDR) phenotypes in a super-specialty tertiary care hospital in north India. Approximately 60 percent of all isolated P. aeruginosa strains displayed the MDR phenotype. We found highest antibiotic resistance frequency in the emergency department (EMR), as 20 percent of isolates were resistant to 15 antipseudomonal antibiotics. Presence of plasmids with quinolone-resistance determinants were major drivers for resistance against fluoroquinolone. Additionally, we explored the possible combinatorial therapeutic options with four antipseudomonal antibiotics-colistin, ciprofloxacin, tobramycin, and meropenem. We uncovered an association between different antibiotic interactions. Our data show that the combination of colistin and ciprofloxacin could be an effective combinatorial regimen to treat infections caused by MDR and XDR P. aeruginosa.

Correlation of serotype-specific strain in patients with dengue virus infection with neurological manifestations and its outcome.

INTRODUCTION: Neurological manifestation of dengue virus infection is a rare entity. Serotypes commonly associated with neurological manifestation are DENV-2 and DENV-3. We plan to detect the serotypes related to the neurological presentation in dengue infection and its correlation with different neurological complications and outcome. METHODS: In this case-control study, consecutive dengue cases with different neurological manifestations were enrolled along with age and sex-matched controls (dengue patients without neurological complication). Serotyping using RT-PCR of samples of cases and controls were done. Level of correlation was analyzed with various parameters and outcomes. RESULTS: In cases out of 33 samples, 6 sample serotypes were detected, which were composed of DENV-1 (n = 2) and DENV-2 (n = 4). In controls, DENV-1 (n = 5), DENV-2 (n = 6), and DENV-3 (n = 3) were detected. When statistically correlated, no significant association was found in cases and controls with dengue virus serotype. The frequency of serotype 2 was higher in hypokalemic paralysis cases than non-hypokalemic paralysis cases and the difference was significant (p < 0.05). The outcome was good (mRS < 3) in all the cases where serotypes were detected, but on statistical correlation, it was not found significant (p > 0.05). CONCLUSION: DENV-1 and DENV-2 are associated with neurological manifestation of dengue infection, which is different from the existing literature, where DENV-2 and DENV-3 are reported. The detection of DENV serotype will help in predicting and best management of neurological complication. The serotype 2 of dengue virus is more commonly associated with dengue-associated hypokalemic paralysis than other neurological complication (p < 0.05). There is no significant association of serotypes with outcome or mortality.

The Interplay of the Unfolded Protein Response in Neurodegenerative Diseases: A Therapeutic Role of Curcumin.

Abnormal accumulation of misfolded proteins in the endoplasmic reticulum and their aggregation causes inflammation and endoplasmic reticulum stress. This promotes accumulation of toxic proteins in the body tissues especially brain leading to manifestation of neurodegenerative diseases. The studies suggest that deregulation of proteostasis, particularly aberrant unfolded protein response (UPR) signaling, may be a common morbific process in the development of neurodegeneration. Curcumin, the mixture of low molecular weight polyphenolic compounds from turmeric, Curcuma longa has shown promising response to prevents many diseases including current global severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and neurodegenerative disorders. The UPR which correlates positively with neurodegenerative disorders were found affected by curcumin. In this review, we examine the evidence from many model systems illustrating how curcumin interacts with UPR and slows down the development of various neurodegenerative disorders (ND), e.g., Alzheimer's and Parkinson's diseases. The recent global increase in ND patients indicates that researchers and practitioners will need to develop a new pharmacological drug or treatment to manage and cure these neurodegenerative diseases.

Krüppel-homologue 1 Mediates Hormonally Regulated Dominance Rank in a Social Bee.

Dominance hierarchies are ubiquitous in invertebrates and vertebrates, but little is known on how genes influence dominance rank. Our gaps in knowledge are specifically significant concerning female hierarchies, particularly in insects. To start filling these gaps, we studied the social bumble bee Bombus terrestris, in which social hierarchies among females are common and functionally significant. Dominance rank in this bee is influenced by multiple factors, including juvenile hormone (JH) that is a major gonadotropin in this species. We tested the hypothesis that the JH responsive transcription factor Krüppel homologue 1 (Kr-h1) mediates hormonal influences on dominance behavior. We first developed and validated a perfluorocarbon nanoparticles-based RNA interference protocol for knocking down Kr-h1 expression. We then used this procedure to show that Kr-h1 mediates the influence of JH, not only on oogenesis and wax production, but also on aggression and dominance rank. To the best of our knowledge, this is the first study causally linking a gene to dominance rank in social insects, and one of only a few such studies on insects or on female hierarchies. These findings are important for determining whether there are general molecular principles governing dominance rank across gender and taxa.

Juvenile hormone affects the development and strength of circadian rhythms in young bumble bee (Bombus terrestris) workers.

The circadian and endocrine systems influence many physiological processes in animals, but little is known on the ways they interact in insects. We tested the hypothesis that juvenile hormone (JH) influences circadian rhythms in the social bumble bee Bombus terrestris. JH is the major gonadotropin in this species coordinating processes such as vitellogenesis, oogenesis, wax production, and behaviors associated with reproduction. It is unknown however, whether it also influences circadian processes. We topically treated newly-emerged bees with the allatoxin Precocene-I (P-I) to reduce circulating JH titers and applied the natural JH (JH-III) for replacement therapy. We repeated this experiment in three trials, each with bees from different source colonies. Measurements of ovarian activity suggest that our JH manipulations were effective; bees treated with P-I had inactive ovaries, and this effect was fully recovered by subsequent JH treatment. We found that JH augments the strength of circadian rhythms and the pace of rhythm development in individually isolated newly emerged worker bees. JH manipulation did not affect the free-running circadian period, overall level of locomotor activity, sleep amount, or sleep structure. Given that acute manipulation at an early age produced relatively long-lasting effects, we propose that JH effects on circadian rhythms are mostly organizational, accelerating the development or integration of the circadian system.

Differential Gene Expression in Brain and Liver Tissue of Wistar Rats after Rapid Eye Movement Sleep Deprivation.

Sleep is essential for the survival of most living beings. Numerous researchers have identified a series of genes that are thought to regulate "sleep-state" or the "deprived state". As sleep has a significant effect on physiology, we believe that lack of total sleep, or particularly rapid eye movement (REM) sleep, for a prolonged period would have a profound impact on various body tissues. Therefore, using the microarray method, we sought to determine which genes and processes are affected in the brain and liver of rats following nine days of REM sleep deprivation. Our findings showed that REM sleep deprivation affected a total of 652 genes in the brain and 426 genes in the liver. Only 23 genes were affected commonly, 10 oppositely, and 13 similarly across brain and liver tissue. Our results suggest that nine-day REM sleep deprivation differentially affects genes and processes in the brain and liver of rats.

Immune Dysfunction and Multiple Treatment Modalities for the SARS-CoV-2 Pandemic: Races of Uncontrolled Running Sweat?

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a global pandemic threat with more than 11.8 million confirmed cases and more than 0.5 million deaths as of 3 July 2020. Given the lack of definitive pharmaceutical interventions against SARS-CoV-2, multiple therapeutic strategies and personal protective applications are being used to reduce the risk of high mortality and community spread of this infection. Currently, more than a hundred vaccines and/or alternative therapeutic regimens are in clinical trials, and some of them have shown promising results in improving the immune cell environment and controlling the infection. In this review, we discussed high-performance multi-directory strategies describing the uncontrolled deregulation of the host immune landscape associated with coronavirus disease (COVID-19) and treatment strategies using an anti-neoplastic regimen. We also followed selected current treatment plans and the most important on-going clinical trials and their respective outcomes for blocking SARS-CoV-2 pathogenesis through regenerative medicine, such as stem cell therapy, chimeric antigen receptors, natural killer (NK) cells, extracellular vesicular-based therapy, and others including immunomodulatory regimens, anti-neoplastic therapy, and current clinical vaccine therapy.

Juvenile hormone interacts with multiple factors to modulate aggression and dominance in groups of orphan bumble bee (Bombus terrestris) workers.

Juvenile hormone (JH) is a key regulator of insect development and reproduction. Given that JH commonly affects adult insect fertility, it has been hypothesized to also regulate behaviors such as dominance and aggression that are associated with reproduction. We tested this hypothesis in the bumble bee Bombus terrestris for which JH has been shown to be the major gonadotropin. We used the allatoxin Precocene-I (P-I) to reduce hemolymph JH titers and replacement therapy with the natural JH to revert this effect. In small orphan groups of workers with similar body size but mixed treatment, P-I treated bees showed lower aggressiveness, oogenesis, and dominance rank compared with control and replacement therapy treated bees. In similar groups in which all bees were treated similarly, there was a clear dominance hierarchy, even in P-I and replacement therapy treatment groups in which the bees showed similar levels of ovarian activation. In a similar experiment in which bees differed in body size, larger bees were more likely to be dominant despite their similar JH treatment and ovarian state. In the last experiment, we show that JH manipulation does not affect dominance rank in groups that had already established a stable dominance hierarchy. These findings solve previous ambiguities concerning whether or not JH affects dominance in bumble bees. JH positively affects dominance, but bees with similar levels of JH can nevertheless establish dominance hierarchies. Thus, multiple factors including JH, body size, and previous experience affect dominance and aggression in social bumble bees.

Rapid Eye Movement sleep deprivation of rat generates ROS in the hepatocytes and makes them more susceptible to oxidative stress.

BACKGROUND: Rapid Eye Movement sleep deprivation (REMSD) of rats causes inflammation of the liver and apoptotic cell death of neurons and hepatocytes. Studies also suggest that REM sleep deprivation can cause muscle as well as cardiac injury and neurodegenerative diseases. OBJECTIVE AND METHODS: The aim of this research was to determine whether REM sleep deprivation of rats would increase the levels of reactive oxygen species (ROS) in the hepatocytes and create oxidative stress in them. We selectively deprived the rats for REM sleep using the standard flower pot method. RESULTS: We observed that when rats were subjected to REM sleep deprivation, the levels of ROS in their hepatocytes increased ~184.33% compared to large platform control (LPC) group by day 9 of deprivation, but it returned towards normal level (~49.27%) after recovery sleep for 5 days. Nitric oxide synthase (iNOS) gene expression and protein levels as determined by real-time PCR and western blot analysis respectively were found to be elevated in hepatocytes of REM sleep deprived rats as compared to the LPC group. The level of nitric oxide (NO) in the hepatocytes of REMSD rats also increased by ~404.40% as compared to the LPC group but sleep recovery for 5 days normalized the effect (~135.35% compared to LPC group). We used a large platform control group as a reference group to compare with the REM sleep deprived group as the effect on the hepatocytes of both LPC group and cage control groups were not significantly different. DISCUSSION: We have analyzed the oxidative stress generated in the hepatocytes of rats due to REM sleep deprivation and further consequences of it. REMS deprivation not only increased the levels of ROS in the hepatocytes but also induced iNOS and NO in them. REM sleep deprived hepatocytes became more susceptible to oxidative stresses on further exposures. Furthermore, our study has great pathological and physiological.

Linear magnetoresistance and surface to bulk coupling in topological insulator thin films.

We explore the temperature dependent magnetoresistance of bulk insulating topological insulator thin films. Thin films of Bi2Se2Te and BiSbTeSe1.6 were grown using the pulsed laser deposition technique and subjected to transport measurements. Magnetotransport measurements indicate a non-saturating linear magnetoresistance (LMR) behavior at high magnetic field values. We present a careful analysis to explain the origin of LMR taking into consideration all the existing models of LMR. Here we consider that the bulk insulating states and the metallic surface states constitute two parallel conduction channels. Invoking this, we were able to explain linear magnetoresistance behavior as a competition between these parallel channels. We observe that the cross-over field, where LMR sets in, decreases with increasing temperature. We propose that this cross-over field can be used phenomenologically to estimate the strength of surface to bulk coupling.

MEKK4 Signaling Regulates Sensory Cell Development and Function in the Mouse Inner Ear.

Mechanosensory hair cells (HCs) residing in the inner ear are critical for hearing and balance. Precise coordination of proliferation, sensory specification, and differentiation during development is essential to ensure the correct patterning of HCs in the cochlear and vestibular epithelium. Recent studies have revealed that FGF20 signaling is vital for proper HC differentiation. However, the mechanisms by which FGF20 signaling promotes HC differentiation remain unknown. Here, we show that mitogen-activated protein 3 kinase 4 (MEKK4) expression is highly regulated during inner ear development and is critical to normal cytoarchitecture and function. Mice homozygous for a kinase-inactive MEKK4 mutation exhibit significant hearing loss. Lack of MEKK4 activity in vivo also leads to a significant reduction in the number of cochlear and vestibular HCs, suggesting that MEKK4 activity is essential for overall development of HCs within the inner ear. Furthermore, we show that loss of FGF20 signaling in vivo inhibits MEKK4 activity, whereas gain of Fgf20 function stimulates MEKK4 expression, suggesting that Fgf20 modulates MEKK4 activity to regulate cellular differentiation. Finally, we demonstrate, for the first time, that MEKK4 acts as a critical node to integrate FGF20-FGFR1 signaling responses to specifically influence HC development and that FGFR1 signaling through activation of MEKK4 is necessary for outer hair cell differentiation. Collectively, this study provides compelling evidence of an essential role for MEKK4 in inner ear morphogenesis and identifies the requirement of MEKK4 expression in regulating the specific response of FGFR1 during HC development and FGF20/FGFR1 signaling activated MEKK4 for normal sensory cell differentiation. SIGNIFICANCE STATEMENT: Sensory hair cells (HCs) are the mechanoreceptors within the inner ear responsible for our sense of hearing. HCs are formed before birth, and mammals lack the ability to restore the sensory deficits associated with their loss. In this study, we show, for the first time, that MEKK4 signaling is essential for the development of normal cytoarchitecture and hearing function as MEKK4 signaling-deficient mice exhibit a significant reduction of HCs and a hearing loss. We also identify MEKK4 as a critical hub kinase for FGF20-FGFR1 signaling to induce HC differentiation in the mammalian cochlea. These results reveal a new paradigm in the regulation of HC differentiation and provide significant new insights into the mechanism of Fgf signaling governing HC formation.

Culture of embryonic mouse cochlear explants and gene transfer by electroporation.

Auditory hair cells located within the mouse organ of Corti detect and transmit sound information to the central nervous system. The mechanosensory hair cells are aligned in one row of inner hair cells and three rows of outer hair cells that extend along the basal to apical axis of the cochlea. The explant culture technique described here provides an efficient method to isolate and maintain cochlear explants from the embryonic mouse inner ear. Also, the morphology and molecular characteristics of sensory hair cells and nonsensory supporting cells within the cochlear explant cultures resemble those observed in vivo and can be studied within its intrinsic cellular environment. The cochlear explants can serve as important experimental tools for the identification and characterization of molecular and genetic pathways that are involved in cellular specification and patterning. Although transgenic mouse models provide an effective approach for gene expression studies, a considerable number of mouse mutants die during embryonic development thereby hindering the analysis and interpretation of developmental phenotypes. The organ of Corti from mutant mice that die before birth can be cultured so that their in vitro development and responses to different factors can be analyzed. Additionally, we describe a technique for electroporating embryonic cochlear explants ex vivo which can be used to downregulate or overexpress specific gene(s) and analyze their potential endogenous function and test whether specific gene product is necessary or sufficient in a given context to influence mammalian cochlear development(1-8).

REM sleep deprivation of rats induces acute phase response in liver.

REM sleep is essential for maintenance of body physiology and its deprivation is fatal. We observed that the levels of ALT and AST enzymes and pro-inflammatory cytokines like IL-1 ß, IL-6 and IL-12 circulating in the blood of REM sleep deprived rats increased in proportion to the extent of sleep loss. But in contrast the levels of IFN-γ and a ∼200 kDa protein, identified by N-terminal sequencing to be alpha-1-inhibitor-3(A1I3), decreased significantly. Quantitative PCR analysis confirmed that REM sleep deprivation down regulates AII3 gene and up regulates IL1 ß, IL6 and their respective receptors gene expression in the liver initiating its inflammation.

Effect of sociocultural cleavage on genetic differentiation: a study from North India.

Indian populations possess an exclusive genetic profile primarily due to the many migratory events, which caused an extensive range of genetic diversity, and also due to stringent and austere sociocultural barriers that structure these populations into different endogamous groups. In the present study we attempt to explore the genetic relationships between various endogamous North Indian populations and to determine the effect of stringent social regulations on their gene pool. Twenty STR markers were genotyped in 1,800 random North Indians from 9 endogamous populations belonging to upper-caste and middle-caste Hindus and Muslims. All nine populations had high allelic diversity (176 alleles) and average observed heterozygosity (0.742 +/- 0.06), suggesting strong intrapopulation diversity. The average F(ST) value over all loci was as low as 0.0084. However, within-group F(ST) and genetic distance analysis showed that populations of the same group were genetically closer to each other. The genetic distance of Muslims from middle castes (F(ST) = 0.0090; DA = 0.0266) was significantly higher than that of Muslims from upper castes (F(ST) = 0.0050; DA = 0.0148). Phylogenetic trees (neighbor-joining and maximum-likelihood) show the basal cluster pattern of three clusters corresponding to Muslims, upper-caste, and middle-caste populations, with Muslims clustered with upper-caste populations. Based on the results, we conclude that the extensive gene flow through a series of migrations and invasions has created an enormous amount of genetic diversity. The interpopulation differences are minimal but have a definite pattern, in which populations of different socioreligious groups have more genetic similarity within the same group and are genetically more distant from populations of other groups. Finally, North Indian Muslims show a differential genetic relationship with upper- and middle-caste populations.

Genetic affinities between endogamous and inbreeding populations of Uttar Pradesh.

BACKGROUND: India has experienced several waves of migration since the Middle Paleolithic. It is believed that the initial demic movement into India was from Africa along the southern coastal route, approximately 60,000-85,000 years before present (ybp). It has also been reported that there were two other major colonization which included eastward diffusion of Neolithic farmers (Elamo Dravidians) from Middle East sometime between 10,000 and 7,000 ybp and a southern dispersal of Indo Europeans from Central Asia 3,000 ybp. Mongol entry during the thirteenth century A.D. as well as some possible minor incursions from South China 50,000 to 60,000 ybp may have also contributed to cultural, linguistic and genetic diversity in India. Therefore, the genetic affinity and relationship of Indians with other world populations and also within India are often contested. In the present study, we have attempted to offer a fresh and immaculate interpretation on the genetic relationships of different North Indian populations with other Indian and world populations. RESULTS: We have first genotyped 20 tetra-nucleotide STR markers among 1800 north Indian samples of nine endogamous populations belonging to three different socio-cultural strata. Genetic distances (Nei's DA and Reynold's Fst) were calculated among the nine studied populations, Caucasians and East Asians. This analysis was based upon the allelic profile of 20 STR markers to assess the genetic similarity and differences of the north Indian populations. North Indians showed a stronger genetic relationship with the Europeans (DA 0.0341 and Fst 0.0119) as compared to the Asians (DA 0.1694 and Fst - 0.0718). The upper caste Brahmins and Muslims were closest to Caucasians while middle caste populations were closer to Asians. Finally, three phylogenetic assessments based on two different NJ and ML phylogenetic methods and PC plot analysis were carried out using the same panel of 20 STR markers and 20 geo-ethnic populations. The three phylogenetic assessments revealed that north Indians are clustering with Caucasians. CONCLUSION: The genetic affinities of Indians and that of different caste groups towards Caucasians or East Asians is distributed in a cline where geographically north Indians and both upper caste and Muslim populations are genetically closer to the Caucasians.