Factors influencing diurnal variation in height among adults

This study evaluates height loss during the day in light of variables assessable through participant self-report. Participants were 19 female and 15 male staff and students who met with us twice with a mean interval between measurement sessions of 6.96 h (SD = 0.86). Hypotheses were evaluated using two-stage least squares regression analysis (SYSTAT 10). Males and females lost similar amounts of height between sessions $(\text{male},\overline{x}=6.9\text{mm};\text{female},\overline{x}=7.4\text{mm})$. Among factors considered to impact overall height loss, sleep duration (Adj. R² = 0.181, p = 0.022) and height (Adj. R² = 0.121, p = 0.048) were useful in univariate analyses, though they were not significant in any models that included variables other than sex. Judging from log-transformed BMI variation, heavier males and females lost more height (F_{(2, 31)} = 4.59, Adj. R² = 0.179, p = 0.018). Among factors anticipated to reduce height loss by acting prior to morning measurements, only time spent walking was significantly associated (β = 2.6 ± 0.8 mm, t = 3.16, p = 0.004) when included as a predictor along with sex (p = 0.17) and log-BMI (p = 0.003). This model explained about 38% of height loss variance. None of the factors considered as potentially acting between measurement sessions showed statistically significant influences when included in the model just described, though predictor coefficients were in the anticipated direction. Results suggest that self-reported activities may be an important supplement to anthropometric studies, both for planning and later evaluation, particularly in large studies.     

30 years of repeat expansion disorders: What have we learned and what are the remaining challenges?

Tandem repeats represent one of the most abundant class of variations in human genomes, which are polymorphic by nature and become highly unstable in a length-dependent manner. The expansion of repeat length across generations is a well-established process that results in human disorders mainly affecting the central nervous system. At least 50 disorders associated with expansion loci have been described to date, with half recognized only in the last ten years, as prior methodological difficulties limited their identification. These limitations still apply to the current widely used molecular diagnostic methods (exome or gene panels) and thus result in missed diagnosis detrimental to affected individuals and their families, especially for disorders that are very rare and/or clinically not recognizable. Most of these disorders have been identified through family-driven approaches and many others likely remain to be identified. The recent development of long-read technologies provides a unique opportunity to systematically investigate the contribution of tandem repeats and repeat expansions to the genetic architecture of human disorders. In this review, we summarize the current and most recent knowledge about the genetics of repeat expansion disorders and the diversity of their pathophysiological mechanisms and outline the perspectives of developing personalized treatments in the future.

Tandem repeats represent one of the most abundant class of variations in human genomes, which are polymorphic by nature and become highly unstable in a length-dependent manner. The expansion of repeat length across generations is a well-established process that results in human disorders mainly affecting the central nervous system. At least 50 disorders associated with expansion loci have been described to date, with half recognized only in the last ten years, as prior methodological difficulties limited their identification. These limitations still apply to the current widely used molecular diagnostic methods (exome or gene panels) and thus result in missed diagnosis detrimental to affected individuals and their families, especially for disorders that are very rare and/or clinically not recognizable. Most of these disorders have been identified through family-driven approaches and many others likely remain to be identified. The recent development of long-read technologies provides a unique opportunity to systematically investigate the contribution of tandem repeats and repeat expansions to the genetic architecture of human disorders. In this review, we summarize the current and most recent knowledge about the genetics of repeat expansion disorders and the diversity of their pathophysiological mechanisms and outline the perspectives of developing personalized treatments in the future.     

Multiple abnormalities in the feet and associated changes elsewhere in the skeleton: The case of 3A-7 from a Capsian Site in Algeria

A skeleton with a number of abnormalities is described with full discussion of alternative diagnoses. In this complex case, the primary diagnosis is of avulsion of the stem of the bifurcate ligament causing a fracture of the anterior process of the calcaneus. The bilateral fracture identified in Skeleton 3A-7 from Site 12, a Capsian site in Algeria, is a result of the feet being inverted and plantar flexed: the fracture is prone to non-union, which is asymmetrical here. There is also a separate anomaly of the feet, 3rd cuneiform and 3rd metatarsal coalition, which was not the cause of trauma. The bifurcate ligament is a major stabilizer of the lateral Chopart (transverse talar) joint, and the trauma could lead to further issues: however, multiple other traumatic changes in 3A-7 most likely occurred at the same time, rather than as the result of pre-existing foot trauma. The asymmetry of the calcaneal condition and asymmetry of the sequelae of the original trauma led to long bone asymmetry, the result of locomotor difficulties.     

Hormonal correlates of pathogen disgust: testing the compensatory prophylaxis hypothesis

Raised progesterone during the menstrual cycle is associated with suppressed physiological immune responses, reducing the probability that the immune system will compromise the blastocyst's development. The Compensatory Prophylaxis Hypothesis proposes that this progesterone-linked immunosuppression triggers increased disgust responses to pathogen cues, compensating for the reduction in physiological immune responses by minimizing contact with pathogens. Although a popular and influential hypothesis, there is no direct, within-woman evidence for correlated changes in progesterone and pathogen disgust. To address this issue, we used a longitudinal design to test for correlated changes in salivary progesterone and pathogen disgust (measured using the pathogen disgust subscale of the Three Domain Disgust Scale) in a large sample of women (N = 375). Our analyses showed no evidence that pathogen disgust tracked changes in progesterone, estradiol, testosterone, or cortisol. Thus, our results provide no support for the Compensatory Prophylaxis Hypothesis of variation in pathogen disgust.     

Tetrahydrobenzothiophene carboxamides: Beyond the kinase domain and into the fatty acid realm

A series of tetrahydrobenzothiophene carboxamides, inspired by structural features present in kinase and SCD1 inhibitors, are presented here. Prototype compound 8 (MMDD13) modulates fatty acid elongase and desaturase indexes, lipid accumulation, while preserving kinase inhibitory activity. This chemotype represents a stepping stone towards chemical probes to study the consequences of lipid metabolism modulation through non-redundant pathways.     

Neural reapportionment: an hypothesis to account for the function of sleep

Sleep is a ubiquitous component of animal life, and prolonged sleep deprivation is fatal in both vertebrates and invertebrates. The physiologic function of sleep, however, is not known. We propose here that sleep provides a period of time necessary to reapportion resources within neurons and neural systems that become sub-optimally distributed during active waking. Three specific examples of such reapportionment during sleep are suggested: (1) the return of the neurotransmitter, glutamate, to synaptic vesicles at presynaptic sites most active during waking, (2) the intracellular movement of mitochondria from neuronal processes to the cells soma where mitochondrial replication can occur, and (3) the readjustment of the level and distribution of neurotransmitters within the brainstem modulatory systems and elsewhere that must function in an integrated fashion during waking. Experimental approaches that might be utilized to test these hypotheses are suggested.     

Reprint of Hormonal correlates of pathogen disgust: testing the compensatory prophylaxis hypothesis

Raised progesterone during the menstrual cycle is associated with suppressed physiological immune responses, reducing the probability that the immune system will compromise the blastocyst's development. The Compensatory Prophylaxis Hypothesis proposes that this progesterone-linked immunosuppression triggers increased disgust responses to pathogen cues, compensating for the reduction in physiological immune responses by minimizing contact with pathogens. Although a popular and influential hypothesis, there is no direct, within-woman evidence for correlated changes in progesterone and pathogen disgust. To address this issue, we used a longitudinal design to test for correlated changes in salivary progesterone and pathogen disgust (measured using the pathogen disgust subscale of the Three Domain Disgust Scale) in a large sample of women (N?=?375). Our analyses showed no evidence that pathogen disgust tracked changes in progesterone, estradiol, testosterone, or cortisol. Thus, our results provide no support for the Compensatory Prophylaxis Hypothesis of variation in pathogen disgust.     

Selectivity of different biological products to the egg parasitoid Telenomus remus (Hymenoptera: Platygastridae)

The selectivity of five entomopathogens and a chemical insecticide (positive control) to pupae and adults of the egg parasitoid Telenomus remus (Nixon) was evaluated in the laboratory under controlled environmental conditions according to protocols established by the International Organization for Biological Control. Baculovirus anticarsia (Baculovirus AEE^®), Bacillus thuringiensis var. kurstaki (Thuricide^®), Bacillus thuringiensis var. aizawai (Agree^®), Beauveria bassiana (Boveril^®), Metarhizium anisopliae (Metarril^®) and Trichoderma harzianum (Trichodermil^®) are harmless to T. remus pupae, and adults. Thus, our results suggest that the insect control strategies applied here are compatible since entomopathogens were classified as harmless to T. remus in most examined cases and therefore facilitate a joint application to control different pests. Bacillus thuringiensis var. kurstaki (Dipel^®), despite being classified as slightly harmful in some of the evaluations, can still be considered compatible for use together with T. remus, especially when compared with chemical insecticides such as chlorpyrifos that might be considered harmful to the parasitoid survival.     

Changes in the sexual dimorphism of the human mandible during the last 1200 years in Central Europe

According to many investigations, changes in mandibular morphology can occur synchronously with changes in the environment, and sexual dimorphism of the mandible can be influenced by the environment. Sexual dimorphism during the last 1200 years was evaluated using geometric morphometric analysis of virtual cranial models. The method of geometric morphometrics allows differences in size and shape to be assessed separately. We analyzed groups of adult individuals dating to Early Middle Ages, High Middle Ages, Early Modern Ages and from a modern Czech population (21st century). Significant sexual dimorphism in mandibular size was found in all populations. A trend in the sexual dimorphism of size was seen, with differences between the sexes increasing gradually over time. Size changes in female mandibles were a better reflection of environmental conditions and climate than size changes in male mandibles. Regarding changes in the sexual dimorphism of shape, significant dimorphism was found in all four samples. However, the pattern of mandibular shape dimorphism was different and varied considerably between samples. There was only one stable shape trait showing sexual dimorphism across all four samples in our study: the gonion lies more laterally in male than in female mandibles and male mandibles are relatively wider than female mandibles. Sexual dimorphism of shape is not influenced by the climate; instead sexual selection might play a role. This research supports earlier studies that have found that the degree and pattern of sexual dimorphism is population-specific and the factors regulating sexual dimorphism today may not be the same as those in the past.     

BET bromodomain ligands: Probing the WPF shelf to improve BRD4 bromodomain affinity and metabolic stability

Ligands for the bromodomain and extra-terminal domain (BET) family of bromodomains have shown promise as useful therapeutic agents for treating a range of cancers and inflammation. Here we report that our previously developed 3,5-dimethylisoxazole-based BET bromodomain ligand (OXFBD02) inhibits interactions of BRD4(1) with the RelA subunit of NF-κB, in addition to histone H4. This ligand shows a promising profile in a screen of the NCI-60 panel but was rapidly metabolised (t_½?=?39.8?min). Structure-guided optimisation of compound properties led to the development of the 3-pyridyl-derived OXFBD04. Molecular dynamics simulations assisted our understanding of the role played by an internal hydrogen bond in altering the affinity of this series of molecules for BRD4(1). OXFBD04 shows improved BRD4(1) affinity (IC₅₀?=?166?nM), optimised physicochemical properties (LE?=?0.43; LLE?=?5.74; SFI?=?5.96), and greater metabolic stability (t_½?=?388?min).     

Scientific Note: First record of the remarkable clearwing moth,Akaisphecia melanopuncta O. Gorbunov & Arita, 1995 (Sesiidae: Sesiinae: Osminiini), from Thailand,with comments on likely Batesian mimicry

The sesiid moth, Akaisphecia melanopuncta O. Gorbunov & Arita, 1995, is recorded from Thailand for the first time, having originally been described from Vietnam and subsequently recorded from Laos. Photographs of a living individual are presented that illustrate that in life it is a very good mimic of red-and-black aposematic Hemiptera (Heteroptera) such as various predatory pyrrhocorids.     

Sensory domain of the cell cycle kinase CckA regulates the differential DNA binding of the master regulator CtrA in Caulobacter crescentus

Sophisticated signaling mechanisms allow bacterial cells to cope with environmental and intracellular challenges. Activation of specific pathways ameliorates these challenges and thereby warrants integrity. Here, we demonstrate the pliability of the CckA-CtrA two-component signaling system in the freshwater bacterium Caulobacter crescentus. Our forward genetic screen to analyze suppressor mutations that can negate the chromosome segregation block induced by the topoisomerase IV inhibitor, NstA, yielded various point mutations in the cell cycle histidine kinase, CckA. Notably, we identified a point mutation in the PAS-B domain of CckA, which resulted in increased levels of phosphorylated CtrA (CtrA~P), the master cell cycle regulator. Surprisingly, this increase in CtrA~P levels did not translate into a genome-wide increase in the DNA occupancy of CtrA, but specifically enriched its affinity for the chromosomal origin of replication, C_ori, and for a very small sub-set of CtrA regulated promoters. We show that through this enhanced binding of CtrA to the C_ori, cells are able to overcome the toxic defects rendered by stable NstA through a possible slow down in the chromosome replication cycle. Taken together, our work opens up an unexplored and intriguing aspect of the CckA-CtrA signal transduction pathway. The distinctive DNA binding nature of CtrA and its regulation by CckA might also be crucial for pathogenesis because of the highly conserved nature of the CckA-CtrA pathway in alphaproteobacteria.