Trade-Offs in Relative Limb Length among Peruvian Children: Extending the Thrifty Phenotype Hypothesis to Limb Proportions

Background and Methods

Both the concept of ‘brain-sparing’ growth and associations between relative lower limb length, childhood environment and adult disease risk are well established. Furthermore, tibia length is suggested to be particularly plastic under conditions of environmental stress. The mechanisms responsible are uncertain, but three hypotheses may be relevant. The ‘thrifty phenotype’ assumes that some components of growth are selectively sacrificed to preserve more critical outcomes, like the brain. The ‘distal blood flow’ hypothesis assumes that blood nutrients decline with distance from the heart, and hence may affect limbs in relation to basic body geometry. Temperature adaptation predicts a gradient of decreased size along the limbs reflecting decreasing tissue temperature/blood flow. We examined these questions by comparing the size of body segments among Peruvian children born and raised in differentially stressful environments. In a cross-sectional sample of children aged 6 months to 14 years (n = 447) we measured head circumference, head-trunk height, total upper and lower limb lengths, and zeugopod (ulna and tibia) and autopod (hand and foot) lengths.

Results

Highland children (exposed to greater stress) had significantly shorter limbs and zeugopod and autopod elements than lowland children, while differences in head-trunk height were smaller. Zeugopod elements appeared most sensitive to environmental conditions, as they were relatively shorter among highland children than their respective autopod elements.

Discussion

The results suggest that functional traits (hand, foot, and head) may be partially protected at the expense of the tibia and ulna. The results do not fit the predictions of the distal blood flow and temperature adaptation models as explanations for relative limb segment growth under stress conditions. Rather, our data support the extension of the thrifty phenotype hypothesis to limb growth, and suggest that certain elements of limb growth may be sacrificed under tough conditions to buffer more functional traits.     

Recombinant factor VIIa in massive haemoptysis associated with chronic necrotising aspergillosis

The successful use of recombinant activated factor VII (rFVIIa), in treating massive, life-threatening haemoptysis in a 55-year-old male patient with chronic necrotising aspergillosis, is reported. Patient diagnosed with chronic necrotising aspergillosis three months ago was admitted to our department with massive haemoptysis. Patient was treated as outpatient with itraconazole. One day post-admission, two doses of rFVIIa (30 microg x kg(-1)) were administered and the haemoptysis was successfully resolved. Two further doses of rFVIIa (30 microg x kg(-1) were given the following day, and after that there were no more recurrences of pulmonary haemorrhage. No thromboembolic or other adverse events were observed following rFVIIa therapy. Our findings suggest that use of rFVIIa may represent a safe and effective treatment choice for patients with haemoptysis due to aspergillosis.     

Association of MTHFR, MTR, MTRR, RFC1, and DHFR gene polymorphisms with susceptibility to sporadic colon cancer

Altered folate levels may play an important role in colon carcinogenesis. The aim of this study was to investigate the association of polymorphisms in key folate-metabolizing genes with susceptibility to sporadic colon cancer. Six common polymorphisms (two in MTHFR and one each in MTR, MTRR, RFC1, and DHFR genes) were genotyped in 300 healthy subjects and 300 colon cancer patients from Croatia. Obtained results indicate possible protective role of MTRR 66 AA in sporadic colon cancer (OR=0.655; 95% CI=0.441-0.973; p=0.04). Maximum-likelihood analysis of haplotypes revealed a linkage disequilibrium (LD) between the two investigated polymorphisms of the MTHFR gene (C677T and A1298C), both in the control and patient groups (p<0.01 for both). LD was also detected between MTRR A66G and MTHFR A1298C polymorphisms but only in a group of patients (p<0.01). A haplotype of A66G and A1298C polymorphisms, A/A, proved to be protective (OR=0.775; 95% CI=0.603-0.996; p=0.04), whereas haplotype A/G was a risk factor for colon cancer (OR=1.270; 95% CI=1.007-1.602; p=0.04). Contrary to some previous studies, single-locus analyses identified no polymorphisms associated with risk for colon cancer, but demonstrated a possible protective effect of MTRR 66 AA genotype. The detected significant LD between two loci (MTHFR A1298C and MTRR A66G) located on different chromosomes indicates a strong selective force as a mechanism for the maintenance of their linkage. Specific combinations of alleles of these two polymorphisms showed a protective but also a risk effect on colon cancer susceptibility.     

Characterization of the SARS-CoV-2 ExoN (nsp14ExoN–nsp10) complex: implications for its role in viral genome stability and inhibitor identification

The SARS-CoV-2 coronavirus is the causal agent of the current global pandemic. SARS-CoV-2 belongs to an order, Nidovirales, with very large RNA genomes. It is proposed that the fidelity of coronavirus (CoV) genome replication is aided by an RNA nuclease complex, comprising the non-structural proteins 14 and 10 (nsp14–nsp10), an attractive target for antiviral inhibition. Our results validate reports that the SARS-CoV-2 nsp14–nsp10 complex has RNase activity. Detailed functional characterization reveals nsp14–nsp10 is a versatile nuclease capable of digesting a wide variety of RNA structures, including those with a blocked 3′-terminus. Consistent with a role in maintaining viral genome integrity during replication, we find that nsp14–nsp10 activity is enhanced by the viral RNA-dependent RNA polymerase complex (RdRp) consisting of nsp12–nsp7–nsp8 (nsp12–7–8) and demonstrate that this stimulation is mediated by nsp8. We propose that the role of nsp14–nsp10 in maintaining replication fidelity goes beyond classical proofreading by purging the nascent replicating RNA strand of a range of potentially replication-terminating aberrations. Using our developed assays, we identify drug and drug-like molecules that inhibit nsp14–nsp10, including the known SARS-CoV-2 major protease (M^pro) inhibitor ebselen and the HIV integrase inhibitor raltegravir, revealing the potential for multifunctional inhibitors in COVID-19 treatment.     

Characterization of early endosome antigen 1 in neural tissues

The finding that patients and mice bearing autoantibodies directed against early endosome antigen 1 (EEA1) develop neurological signs and deficits prompted an investigation of EEA1 distribution, localization, and interaction with synaptic proteins found in neural tissues. We detected EEA1 in a variety of neural tissues and in cells of neural origin where it co-localized with SNAP-25. The interaction between EEA1 and SNAP-25 was dependent on the leucine zipper and a newly identified methyl-accepting domain of EEA1. The C-terminal zinc-binding FYVE finger motif (EEA1(1271-1411)) of EEA1 also interacted with native SNAP-25 but only in the presence of 100microM Ca(2+). In contrast, EEA1 did not bind to cysteine string protein or synapsin in these binding assays. These results suggest that EEA1 is involved in neuronal synaptic vesicle function and axonal transport and growth. EEA1 may undergo calcium-dependent conformational changes that are required for binding to SNAP-25.     

Uridine supplementation exerts anti-inflammatory and anti-fibrotic effects in an animal model of pulmonary fibrosis

Rationale

Pulmonary fibrosis is a progressive disease with only few treatment options available at the moment. Recently, the nucleoside uridine has been shown to exert anti-inflammatory effects in different animal models, e.g. in acute lung injury or bronchial asthma.

Method

Therefore, we investigated the influence of uridine supplementation on inflammation and fibrosis in the classical bleomycin model. Male C57BL/6 mice received an intratracheal injection of bleomycin on day 0 and were treated intraperitoneally with uridine or vehicle. The degree of inflammation and fibrosis was assessed at different time points.

Results

Uridine administration resulted in attenuated inflammation, as demonstrated by reduced leukocytes and pro-inflammatory cytokines in the broncho-alveolar lavage (BAL) fluid. Furthermore, collagen deposition in the lung interstitium was also reduced by uridine supplementation. Similar results were obtained in a model in which animals received repeated intraperitoneal bleomycin injections. In addition uridine inhibited collagen and TGF-ß synthesis by primary lung fibroblasts, the release of pro-inflammatory cytokines by human lung epithelial cells, as well as the production of reactive oxygen species by human neutrophils.

Conclusion

In summary, we were able to show that uridine has potent anti-inflammatory and anti-fibrotic properties. As uridine supplementation has been shown to be well tolerated and safe in humans, this might be a new therapeutic approach for the treatment of fibrotic lung diseases.     

Parallel barcoding of antibodies for DNA‐assisted proteomics

DNA‐assisted proteomics technologies enable ultra‐sensitive measurements in multiplex format using DNA‐barcoded affinity reagents. Although numerous antibodies are available, nowadays targeting nearly the complete human proteome, the majority is not accessible at the quantity, concentration, or purity recommended for most bio‐conjugation protocols. Here, we introduce a magnetic bead‐assisted DNA‐barcoding approach, applicable for several antibodies in parallel, as well as reducing required reagents quantities up to a thousand‐fold. The success of DNA‐barcoding and retained functionality of antibodies were demonstrated in sandwich immunoassays and standard quantitative Immuno‐PCR assays. Specific DNA‐barcoding of antibodies for multiplex applications was presented on suspension bead arrays with read‐out on a massively parallel sequencing platform in a procedure denoted Immuno‐Sequencing. Conclusively, human plasma samples were analyzed to indicate the functionality of barcoded antibodies in intended proteomics applications.     

Limited dispersal and an unexpected aggression pattern in a native supercolonial ant

Understanding how social groups function requires studies on how individuals move across the landscape and interact with each other. Ant supercolonies are extreme cooperative units that may consist of thousands of interconnected nests, and their individuals cooperate over large spatial scales. However, the inner structure of suggested supercolonial (or unicolonial) societies has rarely been extensively studied using both genetic and behavioral analyses. We describe a dense supercolony‐like aggregation of more than 1,300 nests of the ant Formica (Coptoformica) pressilabris. We performed aggression assays and found that, while aggression levels were generally low, there was some aggression within the assumed supercolony. The occurrence of aggression increased with distance from the focal nest, in accordance with the genetically viscous population structure we observe by using 10 DNA microsatellite markers. However, the aggressive interactions do not follow any clear pattern that would allow specifying colony borders within the area. The genetic data indicate limited gene flow within and away from the supercolony. Our results show that a Formica supercolony is not necessarily a single unit but can be a more fluid mosaic of aggressive and amicable interactions instead, highlighting the need to study internest interactions in detail when describing supercolonies.     

Birth month associations with height,head circumference,and limb lengths among peruvian children

Associations between season of birth and body size, morbidity, and mortality have been widely documented, but it is unclear whether different parts of the body are differentially sensitive, and if such effects persist through childhood. This may be relevant to understanding the relationship between early life environment and body size and proportions. We investigated associations between birth month and anthropometry among rural highland (n = 162) and urban lowland (n = 184) Peruvian children aged 6 months to 8 years. Stature; head‐trunk height; total limb, ulna, tibia, hand, and foot lengths; head circumference; and limb measurements relative to head‐trunk height were converted to internal age‐sex‐specific z scores. Lowland and highland datasets were then analyzed separately for birth month trends using cosinor analysis, as urban conditions likely provide a more consistent environment compared with anticipated seasonal variation in the rural highlands. Among highland children birth month associations were significant most strongly for tibia length, followed by total lower limb length and stature, with a peak among November births. Results were not significant for other measurements or among lowland children. The results suggest a prenatal or early postnatal environmental effect on growth that is more marked in limb lengths than trunk length or head size, and persists across the age range studied. We suggest that the results may reflect seasonal variation in maternal nutrition in the rural highlands, but other hypotheses such as variation in maternal vitamin D levels cannot be excluded. Am J Phys Anthropol 154:115–124, 2014. © 2014 The Authors. American Journal of Physical Anthropology Published by Wiley Periodicals, Inc.