Kinetic Analysis of Protein Stability Reveals Age-Dependent Degradation.

Do young and old protein molecules have the same probability to be degraded? We addressed this question using metabolic pulse-chase labeling and quantitative mass spectrometry to obtain degradation profiles for thousands of proteins. We find that >10% of proteins are degraded non-exponentially. Specifically, proteins are less stable in the first few hours of their life and stabilize with age. Degradation profiles are conserved and similar in two cell types. Many non-exponentially degraded (NED) proteins are subunits of complexes that are produced in super-stoichiometric amounts relative to their exponentially degraded (ED) counterparts. Within complexes, NED proteins have larger interaction interfaces and assemble earlier than ED subunits. Amplifying genes encoding NED proteins increases their initial degradation. Consistently, decay profiles can predict protein level attenuation in aneuploid cells. Together, our data show that non-exponential degradation is common, conserved, and has important consequences for complex formation and regulation of protein abundance.

A Field Guide to Eukaryotic Transposable Elements.

Transposable elements (TEs) are mobile DNA sequences that propagate within genomes. Through diverse invasion strategies, TEs have come to occupy a substantial fraction of nearly all eukaryotic genomes, and they represent a major source of genetic variation and novelty. Here we review the defining features of each major group of eukaryotic TEs and explore their evolutionary origins and relationships. We discuss how the unique biology of different TEs influences their propagation and distribution within and across genomes. Environmental and genetic factors acting at the level of the host species further modulate the activity, diversification, and fate of TEs, producing the dramatic variation in TE content observed across eukaryotes. We argue that cataloging TE diversity and dissecting the idiosyncratic behavior of individual elements are crucial to expanding our comprehension of their impact on the biology of genomes and the evolution of species.

Protein aggregation mediates stoichiometry of protein complexes in aneuploid cells.

Aneuploidy, a condition characterized by chromosome gains and losses, causes reduced fitness and numerous cellular stresses, including increased protein aggregation. Here, we identify protein complex stoichiometry imbalances as a major cause of protein aggregation in aneuploid cells. Subunits of protein complexes encoded on excess chromosomes aggregate in aneuploid cells, which is suppressed when expression of other subunits is coordinately altered. We further show that excess subunits are either degraded or aggregate and that protein aggregation is nearly as effective as protein degradation at lowering levels of excess proteins. Our study explains why proteotoxic stress is a universal feature of the aneuploid state and reveals protein aggregation as a form of dosage compensation to cope with disproportionate expression of protein complex subunits.

Transposable elements drive the evolution of metazoan zinc finger genes.

Cys2-His2 zinc finger genes (ZNFs) form the largest family of transcription factors in metazoans. ZNF evolution is highly dynamic and characterized by the rapid expansion and contraction of numerous subfamilies across the animal phylogeny. The forces and mechanisms underlying rapid ZNF evolution remain poorly understood, but there is growing evidence that, in tetrapods, the targeting and repression of lineage-specific transposable elements (TEs) plays a critical role in the evolution of the Krüppel-associated box ZNF (KZNF) subfamily. Currently, it is unknown whether this function and coevolutionary relationship is unique to KZNFs or is a broader feature of metazoan ZNFs. Here, we present evidence that genomic conflict with TEs has been a central driver of the diversification of ZNFs in animals. Sampling from 3221 genome assemblies, we show that the copy number of retroelements correlates with that of ZNFs across at least 750 million years of metazoan evolution. Using computational predictions, we show that ZNFs preferentially bind TEs in diverse animal species. We further investigate the largest ZNF subfamily found in cyprinid fish, which is characterized by a conserved sequence we dubbed the fish N-terminal zinc finger-associated (FiNZ) domain. Zebrafish possess approximately 700 FiNZ-ZNFs, many of which are evolving adaptively under positive selection. Like mammalian KZNFs, most zebrafish FiNZ-ZNFs are expressed at the onset of zygotic genome activation, and blocking their translation using morpholinos during early embryogenesis results in derepression of transcriptionally active TEs. Together, these data suggest that ZNF diversification has been intimately connected to TE expansion throughout animal evolution.

E-Tattoos: Toward Functional but Imperceptible Interfacing with Human Skin.

The human body continuously emits physiological and psychological information from head to toe. Wearable electronics capable of noninvasively and accurately digitizing this information without compromising user comfort or mobility have the potential to revolutionize telemedicine, mobile health, and both human-machine or human-metaverse interactions. However, state-of-the-art wearable electronics face limitations regarding wearability and functionality due to the mechanical incompatibility between conventional rigid, planar electronics and soft, curvy human skin surfaces. E-Tattoos, a unique type of wearable electronics, are defined by their ultrathin and skin-soft characteristics, which enable noninvasive and comfortable lamination on human skin surfaces without causing obstruction or even mechanical perception. This review article offers an exhaustive exploration of e-tattoos, accounting for their materials, structures, manufacturing processes, properties, functionalities, applications, and remaining challenges. We begin by summarizing the properties of human skin and their effects on signal transmission across the e-tattoo-skin interface. Following this is a discussion of the materials, structural designs, manufacturing, and skin attachment processes of e-tattoos. We classify e-tattoo functionalities into electrical, mechanical, optical, thermal, and chemical sensing, as well as wound healing and other treatments. After discussing energy harvesting and storage capabilities, we outline strategies for the system integration of wireless e-tattoos. In the end, we offer personal perspectives on the remaining challenges and future opportunities in the field.

Long-term trends in human body size track regional variation in subsistence transitions and growth acceleration linked to dairying.

Evidence for a reduction in stature between Mesolithic foragers and Neolithic farmers has been interpreted as reflective of declines in health, however, our current understanding of this trend fails to account for the complexity of cultural and dietary transitions or the possible causes of phenotypic change. The agricultural transition was extended in primary centers of domestication and abrupt in regions characterized by demic diffusion. In regions such as Northern Europe where foreign domesticates were difficult to establish, there is strong evidence for natural selection for lactase persistence in relation to dairying. We employ broad-scale analyses of diachronic variation in stature and body mass in the Levant, Europe, the Nile Valley, South Asia, and China, to test three hypotheses about the timing of subsistence shifts and human body size, that: 1) the adoption of agriculture led to a decrease in stature, 2) there were different trajectories in regions of in situ domestication or cultural diffusion of agriculture; and 3) increases in stature and body mass are observed in regions with evidence for selection for lactase persistence. Our results demonstrate that 1) decreases in stature preceded the origins of agriculture in some regions; 2) the Levant and China, regions of in situ domestication of species and an extended period of mixed foraging and agricultural subsistence, had stable stature and body mass over time; and 3) stature and body mass increases in Central and Northern Europe coincide with the timing of selective sweeps for lactase persistence, providing support for the "Lactase Growth Hypothesis."

Zebrafish transposable elements show extensive diversification in age, genomic distribution, and developmental expression.

There is considerable interest in understanding the effect of transposable elements (TEs) on embryonic development. Studies in humans and mice are limited by the difficulty of working with mammalian embryos and by the relative scarcity of active TEs in these organisms. The zebrafish is an outstanding model for the study of vertebrate development, and over half of its genome consists of diverse TEs. However, zebrafish TEs remain poorly characterized. Here we describe the demography and genomic distribution of zebrafish TEs and their expression throughout embryogenesis using bulk and single-cell RNA sequencing data. These results reveal a highly dynamic genomic ecosystem comprising nearly 2000 distinct TE families, which vary in copy number by four orders of magnitude and span a wide range of ages. Longer retroelements tend to be retained in intergenic regions, whereas short interspersed nuclear elements (SINEs) and DNA transposons are more frequently found nearby or within genes. Locus-specific mapping of TE expression reveals extensive TE transcription during development. Although two-thirds of TE transcripts are likely driven by nearby gene promoters, we still observe stage- and tissue-specific expression patterns in self-regulated TEs. Long terminal repeat (LTR) retroelements are most transcriptionally active immediately following zygotic genome activation, whereas DNA transposons are enriched among transcripts expressed in later stages of development. Single-cell analysis reveals several endogenous retroviruses expressed in specific somatic cell lineages. Overall, our study provides a valuable resource for using zebrafish as a model to study the impact of TEs on vertebrate development.

Correlates of Body Composition in Children with Stunting: A Cross-sectional Study in Uganda.

BACKGROUND: Development of body composition (BC) may be disrupted in children with stunting. Such disruption may affect the later risk of excess adiposity and metabolic health, yet few studies have investigated correlates of BC in children with stunting. OBJECTIVES: We aimed to investigate nutritional status, infection and inflammation, breastfeeding behaviors, and other factors as correlates of BC in children with stunting. METHODS: Among Ugandan children with a height-for-age z-score <-2, BC was estimated using bioelectrical impedance analysis and compared with United Kingdom references. We used multiple linear regression analysis to identify correlates of fat mass (FM), fat-free mass (FFM), FM-index (FMI), and FFM index (FFMI) and height, adjusting for gender and age. RESULTS: In 750 children aged 1-5 y, FMI was 0.46 (95% confidence interval [CI]: 0.38, 0.54] and FFMI 0.18 [95% CI: 0.11, 0.26) z-scores lower than United Kingdom references. Elevated serum α1-acid glycoprotein was associated with 1.14 [0.76, 1.52] cm lower height, 0.50 [0.35, 0.65] kg/m2 less FFMI, and 0.48 [0.31, 0.66] kg/m2 greater FMI. Similar, weaker, associations for elevated serum C-reactive protein were detected. A positive malaria rapid test was associated with 0.64 [0.25, 1.02] cm shorter height, but 0.36 [0.18, 0.54] kg/m2 greater FMI. Anemia (according to hemoglobin) was associated with 0.20 [0.07, 0.33] kg less FFM in proportion to shorter height. Longer breastfeeding duration was associated with 0.03 [0.02, 0.04] kg greater FFM per month, in proportion to greater height. CONCLUSIONS: These children exhibited deficits in FM and FFM, proportionally to their stunted height, compared with United Kingdom references. Systemic inflammation correlated inversely with linear growth and FFM but positively with fatness, making it a possible target for intervention where fat-free tissue accretion is desirable. Longer breastfeeding may offer protection to lean linear growth, but findings for micronutrients were less clear. Longitudinal studies are warranted to support these findings. The study was registered at www.isrctn.com (Ref. ISRCTN13093195).

Preservation of fat mass at the expense of lean mass in children with end-stage chronic liver disease.

BACKGROUND: Sarcopenia predicts morbidity and mortality in end-stage chronic liver disease (ESCLD). Here, we describe changes in body composition in children with ESCLD before and after liver transplantation (LT). METHODS: Retrospective analysis of whole body DXA scans performed before and after LT over 4 years. Appendicular and whole-body fat mass and lean mass were expressed as fat mass (FMI) and lean mass (LMI) index z-scores. Sarcopenia was defined as leg LMI z-score <-1.96. RESULTS: Eighty-three DXA scans of children before or after LT were studied. Sarcopenia had a positive correlation with weight (0.8, p < .01), height (0.48, p < .05), and BMI z-score (0.77, p < .01), as well as arm, trunk, and total mean mass indices. It correlated negatively with indices of hypersplenism: PLTs (-0.57, p < .01), Neu (-0.50, p < .05), WCC (-0.44, p < .05), and days to discharge (-0.46, p < .05). At baseline: 13/25 (52%) children were sarcopenic and stayed in the hospital after LT for longer. Eight were stunted with a higher WCC and Ne/Ly ratio. All had normal FM indices. One year after LT, 12/26 children remained sarcopenic. Seven were stunted. Two years after LT, 5/15 were sarcopenic, and 5 were stunted. Three years after LT, 1/10 was sarcopenic, and 2 were stunted. By 4 years after LT, 1/7 was sarcopenic, and the same one was stunted. FM indices remained normal. CONCLUSIONS: Sarcopenic patients stayed longer in the hospital after LT. Lean mass indices were mostly within the normal range by 4 years after LT. 32% of children were stunted, and markers of inflammation were correlated with stunting. Fat mass was preserved at the cost of lean mass.

Providing recurrence risk counselling for parents after diagnosis of a serious genetic condition caused by an apparently de novo mutation in their child: a qualitative investigation of the PREGCARE strategy with UK clinical genetics practitioners.

BACKGROUND: Diagnosis of a child with a genetic condition leads to parents asking whether there is a risk the condition could occur again with future pregnancies. If the cause is identified as an apparent de novo mutation (DNM), couples are currently given a generic, population average, recurrence risk of ~1%-2%, depending on the condition. Although DNMs usually arise as one-off events, they can also originate through the process of mosaicism in either parent; in this instance, the DNM is present in multiple germ cells and the actual recurrence risk could theoretically be as high as 50%. METHODS: Our qualitative interview study examined the views and reflections on current practice provided by UK practitioners working in clinical genetics (n=20) regarding the potential impact of PREcision Genetic Counselling And REproduction (PREGCARE)-a new preconception personalised recurrence risk assessment strategy. RESULTS: Those interviewed regarded PREGCARE as a very useful addition to risk management, especially for cases where it revised the risk downwards or clarified that a couple's personalised recurrence risk meets National Health Service thresholds for non-invasive prenatal testing, otherwise inaccessible based on the generic DNM recurrence risk. CONCLUSION: Participants said it could release some couples requiring reassurance from undergoing unnecessary invasive testing in future pregnancies. However, they regarded mosaicism and PREGCARE as complex concepts to communicate, requiring further training and additional appointment time for pre-test genetic counselling to prepare couples for all the possible outcomes of a personalised risk assessment, including potentially identifying the parental origin of the DNM, and to ensure informed consent.