Does heterochromatin variation potentiate speciation? A study in Nesokia

An increasing incidence of sex-chromosome variation in constitutive heterochromatin, including individuals with mosaic genotypes, has been observed in a single natural population of Nesokia indica, the Indian mole rat. Variations in the heterochromatic areas of the X chromosome are largely due to deletions at R-band-positive regions corresponding to folate-sensitive fragile sites. All individuals with either a pre- or post-zygotic loss or gain of sex-chromosome heterochromatin have so far proved to be infertile. Whether such F1 sterility is due to abnormal gonadal development, gametic incompetence, or other factors is not clear. More important is the indication that the constitutive heterochromatin of this species may contain coding DNA sequences with putative regulatory functions.     

Heterochromatin variation and sex chromosome polymorphism in Nesokia indica: a population study

Nesokia indica, the Indian mole rat, exhibits extensive variability (polymorphism) for the constitutive heterochromatin of the X and Y chromosomes. These polymorphic X and Y types range from a large metacentric chromosome to a small acrocentric one and occur in different frequencies in the population. On the assumption that there is random mating among individuals carrying these various X and Y chromosomes, the population shows Hardy-Weinberg proportions for the genotypes. However, notwithstanding the partial or total loss of constitutive heterochromatin of the X and Y chromosomes in a few individuals, its retention in most of the animals seems obligatory to the population at large. Hence, we suggest that the C-heterochromatin plays a "regulatory" role in the population dynamics of this species.     

Haploinsufficiency of cytosolic serine hydroxymethyltransferase in the Smith-Magenis syndrome.

Folate-dependent one-carbon metabolism is critical for the synthesis of numerous cellular constituents required for cell growth, and serine hydroxymethyltransferase (SHMT) is central to this process. Our studies reveal that the gene for cytosolic SHMT (cSHMT) maps to the critical interval for Smith-Magenis syndrome (SMS) on chromosome 17p11.2. The basic organization of the cSHMT locus on chromosome 17 was determined and was found to be deleted in all 26 SMS patients examined by PCR, FISH, and/or Southern analysis. Furthermore, with respect to haploinsufficiency, cSHMT enzyme activity in patient lymphoblasts was determined to be approximately 50% that of unaffected parent lymphoblasts. Serine, glycine, and folate levels were also assessed in three SMS patients and were found to be within normal ranges. The possible effects of cSHMT hemizygosity on the SMS phenotype are discussed.     

Atypical Human Infections by Animal Trypanosomes

The two classical forms of human trypanosomoses are sleeping sickness due to Trypanosoma brucei gambiense or T. brucei rhodesiense, and Chagas disease due to T. cruzi. However, a number of atypical human infections caused by other T. species (or sub-species) have been reported, namely due to T. brucei brucei, T. vivax, T. congolense, T. evansi, T. lewisi, and T. lewisi-like. These cases are reviewed here. Some infections were transient in nature, while others required treatments that were successful in most cases, although two cases were fatal. A recent case of infection due to T. evansi was related to a lack of apolipoprotein L-I, but T. lewisi infections were not related to immunosuppression or specific human genetic profiles. Out of 19 patients, eight were confirmed between 1974 and 2010, thanks to improved molecular techniques. However, the number of cases of atypical human trypanosomoses might be underestimated. Thus, improvement, evaluation of new diagnostic tests, and field investigations are required for detection and confirmation of these atypical cases.

Key Learning Points

• The classical human trypanosomoses are human African trypanosomosis (HAT) or sleeping sickness, and Chagas disease, the Latin American human trypanosomosis.
• Atypical human infections caused by Trypanosoma species that normally are restricted to animals have been reported. These cases of atypical human trypanosomoses (a-HT) are mostly transient, but some require treatment and can be fatal.
• Only a few cases of a-HT have been fully confirmed, especially in Asia, leading to the hypothesis that the actual prevalence is probably underestimated.
• The detection of a case of a-HT should be based on observation of the parasite by direct microscopy. Evaluating/improving the diagnoses through serological and PCR assays would help in detecting and identifying atypical trypanosomosis infections in humans. These laboratory research and field activities are needed to evaluate the actual occurrence of atypical cases.

Top Five Papers

1. Verma A, Manchanda S, Kumar N, Sharma A, Goel M, et al. (2011) Trypanosoma lewisi or Trypanosoma lewisi-like infection in a 37-day-old infant. Am J Trop Med Hyg 85: 221–224.
2. Deborggraeve S, Koffi M, Jamonneau V, Bonsu FA, Queyson R, et al. (2008) Molecular analysis of archived blood slides reveals an atypical human Trypanosoma infection. Diagn Microbiol Infect Dis 61: 428–433.
3. Vanhollebeke B, Truc P, Poelvoorde P, Pays A, Joshi PP, et al. (2006) Human Trypanosoma evansi infection linked to a lack of apolipoprotein L-I. N Engl J Med 355: 2752–2756.
4. Joshi PP, Shegokar V, Powar S, Herder S, Katti R, et al. (2005) Human trypanosomiasis caused by Trypanosoma evansi in India: the first case report. Am J Trop Med Hyg 73: 491–495.
5. Howie S, Guy M, Fleming L, Bailey W, Noyes H, et al. (2006) A Gambian infant with fever and an unexpected blood film. PLoS Med 3: e355. doi:10.1371/journal.pmed.0030355.

     

On the Reversibility and Fragility of Sodium Metal Electrodes

Metallic sodium is receiving renewed interest as a battery anode material because the metal is earth‐abundant, inexpensive, and offers a high specific storage capacity (1166 mAh g^?1 at ?2.71 V vs the standard hydrogen potential). Unlike metallic lithium, the case for Na as the anode in rechargeable batteries has already been demonstrated on a commercial scale in high‐temperature Na||S and Na||NiCl₂ secondary batteries, which increases interest. The reversibility of room temperature sodium anodes is investigated in galvanostatic plating/stripping reactions using in situ optical visualization and galvanostatic polarization measurements. It is discovered that electronic disconnection of mossy metallic Na deposits (“orphaning”) is a dominant source of anode irreversibility in liquid electrolytes. The disconnection is shown by means of direct visualization studies to be triggered by a root‐breakage process during the stripping cycle. As a further step toward electrode designs that are able to accommodate the fragile Na deposits, electrodeposition of Na is demonstrated in nonplanar electrode architectures, which provide continuous and morphology agnostic access to the metal at all stages of electrochemical cycling. On this basis, nonplanar Na electrodes are reported, which exhibit exceptionally high levels of reversibility (Coulombic efficiency >99.6% for 1 mAh cm^?2 Na throughput) in room‐temperature, liquid electrolytes.     

Targeting AMPK signaling pathway by natural products for treatment of diabetes mellitus and its complications

Diabetes affects a large population of the world. Lifestyle, obesity, dietary habits, and genetic factors contribute to this metabolic disease. A target pathway to control diabetes is the 5′-adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. AMPK is a heterotrimeric protein with α, β, and γ subunits. In several studies, AMPK activation enhanced glucose uptake into cells and inhibited intracellular glucose production. Impairment of AMPK activity is present in diabetes, according to some studies. Drugs used in the treatment of diabetes, such as metformin, are also known to act through regulation of AMPK. Thus, drugs that activate and regulate AMPK are potential candidates for the treatment of diabetes. In addition, many patients encounter important adverse effects, like hypoglycemia, while using allopathic drugs. As a result, the investigation of plant-derived natural drugs that lack adverse side effects and treat diabetes is necessary. Natural products like berberine, quercetin, resveratrol, and so forth have shown significant potential in regulating and activating the AMPK pathway which can lead to manage diabetes mellitus and its complications.     

APOE polymorphism in a rural older population-based sample in India

Allele frequencies are most often reported from small convenience samples of unknown demographics and limited generalizability. We determined the distribution of apolipoprotein E genotype (APOE) and allele frequencies for a large, well-defined, representative, rural, population-based sample (n = 4450) aged 55-95 years in Ballabgarh, in the northern Indian state of Haryana. The overall APOE E*2, E*3, and E*4 allele frequencies were 0.039, 0.887, and 0.073, respectively; frequencies are also reported by age, sex, and religious/caste groups. The APOE*4 frequency is among the lowest reported anywhere in the world. APOE allele frequencies did not vary significantly by age or sex in this study. To our knowledge, this is the largest Indian sample ever genotyped for the APOE polymorphism. The representativeness of the sample and its known demographics provide a much-needed normative background for studies of gene-disease associations.     

Breast Cancer Anti-estrogen Resistance 3 (BCAR3) Protein Augments Binding of the c-Src SH3 Domain to Crk-associated Substrate (p130cas)

The focal adhesion adapter protein p130(cas) regulates adhesion and growth factor-related signaling, in part through Src-mediated tyrosine phosphorylation of p130(cas). AND-34/BCAR3, one of three NSP family members, binds the p130(cas) carboxyl terminus, adjacent to a bipartite p130(cas) Src-binding domain (SBD) and induces anti-estrogen resistance in breast cancer cell lines as well as phosphorylation of p130(cas). Only a subset of the signaling properties of BCAR3, specifically augmented motility, are dependent upon formation of the BCAR3-p130(cas) complex. Using GST pull-down and immunoprecipitation studies, we show that among NSP family members, only BCAR3 augments the ability of p130(cas) to bind the Src SH3 domain through an RPLPSPP motif in the p130(cas) SBD. Although our prior work identified phosphorylation of the serine within the p130(cas) RPLPSPP motif, mutation of this residue to alanine or glutamic acid did not alter BCAR3-induced Src SH3 domain binding to p130(cas). The ability of BCAR3 to augment Src SH3 binding requires formation of a BCAR3-p130(cas) complex because mutations that reduce association between these two proteins block augmentation of Src SH3 domain binding. Similarly, in MCF-7 cells, BCAR3-induced tyrosine phosphorylation of the p130(cas) substrate domain, previously shown to be Src-dependent, was reduced by an R743A mutation that blocks BCAR3 association with p130(cas). Immunofluorescence studies demonstrate that BCAR3 expression alters the intracellular location of both p130(cas) and Src and that all three proteins co-localize. Our work suggests that BCAR3 expression may regulate Src signaling in a BCAR3-p130(cas) complex-dependent fashion by altering the ability of the Src SH3 domain to bind the p130(cas) SBD.     

Nested ANOVA for Repeated Surveys with Autocorrelated Errors

Diet surveys in the science of human nutrition involve longitudinal observations on the same individuals repeated at distinct time points. Consequently a common feature of such surveys is inherent correlation between successive observations. In this paper, an autoregressive model of order 1 is assumed for the successive observations on the same individual in a survey. Further, observations on the same individual in two different surveys are assumed to be correlated. The technique of analysis of variance is modified suitably for this set up and applied to two nutritional surveys carried on army recruits.