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Background: In a secondary analysis of data taken from a publicly available database, we examined cognitive performance, postural sway, and relations between them for 4 groups: younger and older individuals with versus without a recent history of falls. Our objective was to compare linear versus nonlinear measures of postural activity as post hoc predictors of cognitive performance and falling., Methods: We evaluated standing body sway in 147 participants (18-85-years old) over 60 seconds, separately with eyes-open and with eyes-closed. We evaluated cognitive performance using portions of the Trail Making Test. We evaluated postural activity in terms of standard deviation, velocity, and amplitude of the Center of Pressure (CoP). Separately, we used detrended fluctuation analysis (DFA) to examine the complexity of CoP displacements. Using analysis of variance, we conducted separate analyses of cognitive performance and postural activity comparing Younger and Older Adults and Non-fallers and Fallers, taking into account Vision (eyes-closed vs open) and the direction of postural movements (Anteroposterior vs Mediolateral) while also controlling for participants' characteristics. We used moderation analyses to evaluate whether relationships between Trail Making Test scores and the linear and nonlinear outcomes were moderated by Age group or Fall status., Results: For postural activity, only DFA differed between Non-fallers and Fallers. Older adults exhibited increased complexity associated with better processing speed function, while fallers show an opposite association, relying on processing speed to increase postural rigidity instead of facilitating adaptive control of balance., Conclusions: We conclude that DFA can provide information regarding postural activity and cognitive performance that cannot be obtained from more traditional, linear measures of postural activity and that DFA may be a valuable tool for assessing fall risk., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The human vestibular system is adversely affected by the aging process. Recent evidence indicates that vestibular information and cognitive functions are related, suggesting that age-related vestibular loss may contribute to cognitive impairment. In this study, we aimed to investigate the effects of repetitive, home-based galvanic vestibular stimulation (GVS) on cognitive functions in healthy older adults. Twenty-one participants (age = 64.66 ± 2.97 years, 12 females) were randomly allocated to either a home-based GVS or an active control group. The GVS intervention lasted 20 min per session, five times a week, for two weeks (10 sessions). Cognitive functions were assessed before and after the intervention using the Stroop Test, Trail Making Test A&B, and Dual-Task (digit recall and paper-pencil tracking test). Our findings revealed a significant group-by-time interaction effect for the tracking accuracy (F(1,18) = 7.713, p = 0.012, η p 2  = 0.30), with only the home-based GVS group showing significant improvement (t = -2.544, p = 0.029). The proposed home-based GVS protocol offers a promising non-pharmacological avenue for enhancing visuospatial ability in healthy older adults. Further research is needed to investigate the effects of different GVS protocols on various cognitive functions, particularly in older individuals with different health conditions., Competing Interests: Declaration of competing interest The authors report there are no competing interests to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Aging is characterized by substantial changes in sleep architecture that negatively impact fitness, quality of life, mood, and cognitive functioning. Older adults often fail to reach the recommended level of physical activity to prevent the age-related decline in sleep function, partly because of geographical barriers. Implementing home-based interventions could surmount these obstacles, thereby encouraging older adults to stay active, with videoconference administration emerging as a promising solution. Increasing the availability of biological rhythms synchronizers, such as physical activity, light exposure, or vestibular stimulation, represents a viable non-pharmacological strategy for entraining circadian rhythms and potentially fortifying the sleep-wake cycle, thereby enhancing sleep in aging. This study aims to (1) assess the impact of remote physical exercise training and its combination with bright light exposure, and (2) investigate the specific contribution of galvanic vestibular stimulation, to sleep quality among healthy older adults with sleep complaints. One hundred healthy older adults aged 60-70 years with sleep complaints will be randomly allocated to one of four groups: a physical exercise training group ( n  = 25), a physical exercise training combined with bright light exposure group ( n  = 25), a galvanic vestibular stimulation group ( n  = 25) or a control group (i.e., health education) ( n  = 25). While physical exercise training and health education will be supervised via videoconference at home, bright light exposure (for the physical exercise training combined with bright light exposure group) and vestibular stimulation will be self-administered at home. Pre-and post-tests will be conducted to evaluate various parameters, including sleep (polysomnography, subjective questionnaires), circadian rhythms (actigraphy, temperature), fitness (physical: VO 2 peak, muscular function; and motor: balance, and functional mobility), cognition (executive function, long-term memory), quality of life and mood (anxiety and depression). The findings will be anticipated to inform the development of recommendations and non-pharmaceutical preventive strategies for enhancing sleep quality in older adults, potentially leading to improvements in fitness, cognition, quality of life, and mood throughout aging., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Milot, Rehel, Langeard, Bigot, Pasquier, Matveeff, Gauthier, Bessot and Quarck.)

Inflammation control is critical during the innate immune response. Such response is triggered by the detection of molecules originating from pathogens or damaged host cells by pattern-recognition receptors (PRRs). PRRs subsequently initiate intra-cellular signalling through different pathways, resulting in i) the production of inflammatory cytokines, including type I interferon (IFN), and ii) the initiation of a cascade of events that promote both immediate host responses as well as adaptive immune responses. All human PYRIN and HIN-200 domains (PYHIN) protein family members were initially proposed to be PRRs, although this view has been challenged by reports that revealed their impact on other cellular mechanisms. Of relevance here, the human PYHIN factor myeloid nuclear differentiation antigen (MNDA) has recently been shown to directly control the transcription of genes encoding factors that regulate programmed cell death and inflammation. While MNDA is mainly found in the nucleus of leukocytes of both myeloid (neutrophils and monocytes) and lymphoid (B-cell) origin, its subcellular localization has been shown to be modulated in response to genotoxic agents that induce apoptosis and by bacterial constituents, mediators of inflammation. Prior studies have noted the importance of MNDA as a marker for certain forms of lymphoma, and as a clinical prognostic factor for hematopoietic diseases characterized by defective regulation of apoptosis. Abnormal expression of MNDA has also been associated with altered levels of cytokines and other inflammatory mediators. Refining our comprehension of the regulatory mechanisms governing the expression of MNDA and other PYHIN proteins, as well as enhancing our definition of their molecular functions, could significantly influence the management and treatment strategies of numerous human diseases. Here, we review the current state of knowledge regarding PYHIN proteins and their role in innate and adaptive immune responses. Emphasis will be placed on the regulation, function, and relevance of MNDA expression in the control of gene transcription and RNA stability during cell death and inflammation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Bottardi, Layne, Ramòn, Quansah, Wurtele, Affar and Milot.)

Background: A decade ago, we proposed an index of physiological dysregulation based on Mahalanobis distance (DM) that measures how far from the norm an individual biomarker profile is. While extensive validation has been performed, focus was mostly on Western populations with little comparison to developing countries, particularly at a physiological system level. The degree to which the approach would work in other sociocultural contexts and the similarity of dysregulation signatures across diverse populations are still open questions., Methods: Using 2 data sets from China and 3 from Western countries (United States, United Kingdom, and Italy), we calculated DM globally and per physiological system. We assessed pairwise correlations among systems, difference with age, prediction of mortality and age-related diseases, and sensitivity to interchanging data sets with one another as the reference in DM calculation., Results: Overall, results were comparable across all data sets. Different physiological systems showed distinct dysregulation processes. Association with age was moderate and often nonlinear, similarly for all populations. Mahalanobis distance predicted most health outcomes, although differently by physiological system. Using a Chinese population as the reference when calculating DM for Western populations, or vice versa, led to similar associations with health outcomes, with a few exceptions., Conclusions: While small differences were noticeable, they did not systematically emerge between Chinese and Western populations, but rather diffusively across all data sets. These findings suggest that DM presents similar properties, notwithstanding sociocultural backgrounds, and that it is equally effective in capturing the loss of homeostasis that occurs during aging in diverse industrial human populations., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

IKAROS is a master regulator of cell fate determination in lymphoid and other hematopoietic cells. This transcription factor orchestrates the association of epigenetic regulators with chromatin, ensuring the expression pattern of target genes in a developmental and lineage-specific manner. Disruption of IKAROS function has been associated with the development of acute lymphocytic leukemia, lymphoma, chronic myeloid leukemia and immune disorders. Paradoxically, while IKAROS has been shown to be a tumor suppressor, it has also been identified as a key therapeutic target in the treatment of various forms of hematological malignancies, including multiple myeloma. Indeed, targeted proteolysis of IKAROS is associated with decreased proliferation and increased death of malignant cells. Although the molecular mechanisms have not been elucidated, the expression levels of IKAROS are variable during hematopoiesis and could therefore be a key determinant in explaining how its absence can have seemingly opposite effects. Mechanistically, IKAROS collaborates with a variety of proteins and complexes controlling chromatin organization at gene regulatory regions, including the Nucleosome Remodeling and Deacetylase complex, and may facilitate transcriptional repression or activation of specific genes. Several transcriptional regulatory functions of IKAROS have been proposed. An emerging mechanism of action involves the ability of IKAROS to promote gene repression or activation through its interaction with the RNA polymerase II machinery, which influences pausing and productive transcription at specific genes. This control appears to be influenced by IKAROS expression levels and isoform production. In here, we summarize the current state of knowledge about the biological roles and mechanisms by which IKAROS regulates gene expression. We highlight the dynamic regulation of this factor by post-translational modifications. Finally, potential avenues to explain how IKAROS destruction may be favorable in the treatment of certain hematological malignancies are also explored., (© 2023. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.)

The slow-fast continuum is a commonly used framework to describe variation in life-history strategies across species. Individual life histories have also been assumed to follow a similar pattern, especially in the pace-of-life syndrome literature. However, whether a slow-fast continuum commonly explains life-history variation among individuals within a population remains unclear. Here, we formally tested for the presence of a slow-fast continuum of life histories both within populations and across species using detailed long-term individual-based demographic data for 17 bird and mammal species with markedly different life histories. We estimated adult lifespan, age at first reproduction, annual breeding frequency, and annual fecundity, and identified the main axes of life-history variation using principal component analyses. Across species, we retrieved the slow-fast continuum as the main axis of life-history variation. However, within populations, the patterns of individual life-history variation did not align with a slow-fast continuum in any species. Thus, a continuum ranking individuals from slow to fast living is unlikely to shape individual differences in life histories within populations. Rather, individual life-history variation is likely idiosyncratic across species, potentially because of processes such as stochasticity, density dependence, and individual differences in resource acquisition that affect species differently and generate non-generalizable patterns across species.

Ubiquitination is an important post-translational modification (PTM) that regulates a large spectrum of cellular processes in eukaryotes. Abnormalities in ubiquitin signaling underlie numerous human pathologies including cancer and neurodegeneration. Much progress has been made during the last three decades in understanding how ubiquitin ligases recognize their substrates and how ubiquitination is orchestrated. Several mechanisms of regulation have evolved to prevent promiscuity including the assembly of ubiquitin ligases in multi-protein complexes with dedicated subunits and specific post-translational modifications of these enzymes and their co-factors. Here, we outline another layer of complexity involving the coordinated access of E3 ligases to substrates. We provide an extensive inventory of ubiquitination crosstalk with multiple PTMs including SUMOylation, phosphorylation, methylation, acetylation, hydroxylation, prolyl isomerization, PARylation, and O-GlcNAcylation. We discuss molecular mechanisms by which PTMs orchestrate ubiquitination, thus increasing its specificity as well as its crosstalk with other signaling pathways to ensure cell homeostasis., Competing Interests: The authors declare no competing interests with the content of this article., (© 2023 The Authors.)

Deubiquitinases (DUBs) are required for the reverse reaction of ubiquitination and act as major regulators of ubiquitin signaling processes. Emerging evidence suggests that these enzymes are regulated at multiple levels in order to ensure proper and timely substrate targeting and to prevent the adverse consequences of promiscuous deubiquitination. The importance of DUB regulation is highlighted by disease-associated mutations that inhibit or activate DUBs, deregulating their ability to coordinate cellular processes. Here, we describe the diverse mechanisms governing protein stability, enzymatic activity, and function of DUBs. In particular, we outline how DUBs are regulated by their protein domains and interacting partners. Intramolecular interactions can promote protein stability of DUBs, influence their subcellular localization, and/or modulate their enzymatic activity. Remarkably, these intramolecular interactions can induce self-deubiquitination to counteract DUB ubiquitination by cognate E3 ubiquitin ligases. In addition to intramolecular interactions, DUBs can also oligomerize and interact with a wide variety of cellular proteins, thereby forming obligate or facultative complexes that regulate their enzymatic activity and function. The importance of signaling and post-translational modifications in the integrated control of DUB function will also be discussed. While several DUBs are described with respect to the multiple layers of their regulation, the tumor suppressor BAP1 will be outlined as a model enzyme whose localization, stability, enzymatic activity, and substrate recognition are highly orchestrated by interacting partners and post-translational modifications., Competing Interests: Conflicts of interest The authors declare that they have no conflicts of interest with the content of this article., (Crown Copyright © 2022. Published by Elsevier Inc. All rights reserved.)

Evidence from natural populations shows that changes in environmental conditions can cause rapid modifications in the evolutionary potential of phenotypes, partly through genotype-by-environment interactions (G×E). Therefore, the overall rate of microevolution should depend on fluctuations in environmental conditions, even when directional selection is sustained over several generations. We tested this hypothesis in a preindustrial human population that experienced a microevolutionary change in age at first reproduction (AFR) of mothers, using the annual infant mortality rate (IMR) as an indicator of environmental conditions during their early life. Using quantitative genetics analyses, we found that G×Es explained a nonnegligible fraction of the additive genetic variance in AFR and in relative fitness, as well as of the genetic covariance between AFR and fitness (i.e., the Robertson-Price covariance). The covariance was stronger for individuals exposed to unfavorable early-life environmental conditions. Our results unravel the presence of G×Es in an important life history trait and its impact on the rate of microevolution, which appears to have been sensitive to short-term fluctuations in local environmental conditions., (© 2022 The Authors. Evolution © 2022 The Society for the Study of Evolution.)

Population history reconstruction, using extant genetic diversity data, routinely relies on simple demographic models to project the past through ascending genealogical-tree branches. Because genealogy and genetics are intimately related, we traced descending genealogies of the Québec founders to pursue their fate and to assess their contribution to the present-day population. Focusing on the female and male founder lines, we observed important sex-biased immigration in the early colony years and documented a remarkable impact of these early immigrants on the genetic make-up of 20th-century Québec. We estimated the immigrants' survival ratio as a proportion of lineages found in the 1931-60 Québec to their number introduced within the immigration period. We assessed the effective family size, EFS, of all immigrant parents and their Québec-born descendants. The survival ratio of the earliest immigrants was the highest and declined over centuries in association with the immigrants' EFS. Parents with high EFS left plentiful married descendants, putting EFS as the most important variable determining the parental demographic success throughout time for generations ahead. EFS of immigrant founders appears to predict their long-term demographic and, consequently, their genetic outcome. Genealogically inferred immigrants' "autosomal" genetic contribution to 1931-60 Québec from consecutive immigration periods follow the same yearly pattern as the corresponding maternal and paternal lines. Québec genealogical data offer much broader information on the ancestral diversity distribution than genetic scrutiny of a limited population sample. Genealogically inferred population history could assist studies of evolutionary factors shaping population structure and provide tools to target specific health interventions., Competing Interests: The authors have declared that no competing interests exist

Criminal offenders missing from police files limit the capacity to reconstruct criminal networks for criminological research and operational purposes. Recent studies show that forensic DNA databanks offer potential to address this problem, through large-scale analysis of DNA matches, many of which involve unidentified offenders. Applying social network analysis (SNA) to 18 years of DNA match data from Québec, Canada, we found that 1400 unknowns do not occupy more marginal positions in the network than 13,000 known offenders, and explain up to 18% of SNA values (e.g., betweenness centrality) for the latter while supporting 46% of their clustering values. Our results contrast with previous studies, showing moreover that unknown individuals who are positioned centrally in a network may have a larger impact than previously expected on investigation policing with implications for forensic intelligence., Competing Interests: Declarations of interest None., (Copyright © 2021 The Institution of Chemical Engineers. Published by Elsevier B.V. All rights reserved.)

Eukaryotic cells have evolved highly orchestrated protein catabolic machineries responsible for the timely and selective disposal of proteins and organelles, thereby ensuring amino acid recycling. However, how protein degradation is coordinated with amino acid supply and protein synthesis has remained largely elusive. Here we show that the mammalian proteasome undergoes liquid-liquid phase separation in the nucleus upon amino acid deprivation. We termed these proteasome condensates SIPAN (Starvation-Induced Proteasome Assemblies in the Nucleus) and show that these are a common response of mammalian cells to amino acid deprivation. SIPAN undergo fusion events, rapidly exchange proteasome particles with the surrounding milieu and quickly dissolve following amino acid replenishment. We further show that: (i) SIPAN contain K48-conjugated ubiquitin, (ii) proteasome inhibition accelerates SIPAN formation, (iii) deubiquitinase inhibition prevents SIPAN resolution and (iv) RAD23B proteasome shuttling factor is required for SIPAN formation. Finally, SIPAN formation is associated with decreased cell survival and p53-mediated apoptosis, which might contribute to tissue fitness in diverse pathophysiological conditions., (© 2021. The Author(s).)

The tumor suppressor IKAROS binds and represses multiple NOTCH target genes. For their induction upon NOTCH signaling, IKAROS is removed and replaced by NOTCH Intracellular Domain (NICD)-associated proteins. However, IKAROS remains associated to other NOTCH activated genes upon signaling and induction. Whether IKAROS could participate to the induction of this second group of NOTCH activated genes is unknown. We analyzed the combined effect of IKAROS abrogation and NOTCH signaling on the expression of NOTCH activated genes in erythroid cells. In IKAROS-deleted cells, we observed that many of these genes were either overexpressed or no longer responsive to NOTCH signaling. IKAROS is then required for the organization of bivalent chromatin and poised transcription of NOTCH activated genes belonging to either of the aforementioned groups. Furthermore, we show that IKAROS-dependent poised organization of the NOTCH target Cdkn1a is also required for its adequate induction upon genotoxic insults. These results highlight the critical role played by IKAROS in establishing bivalent chromatin and transcriptional poised state at target genes for their activation by NOTCH or other stress signals., Competing Interests: The authors have declared that no competing interests exist

The myeloid nuclear differentiation antigen (MNDA) is a stress-induced protein that promotes degradation of the anti-apoptotic factor MCL-1 and apoptosis in myeloid cells. MNDA is also expressed in normal lymphoid cells and in B-cell clones isolated from individuals with chronic lymphocytic leukemia (CLL), a disease characterized by abnormal apoptosis control. We found that MNDA expression levels inversely correlate with the amount of the anti-apoptotic proteins MCL-1 and BCL-2 in human CLL samples. We report that in response to chemotherapeutic agents that induce genotoxic stress, MNDA exits its typical nucleolar localization and accumulates in the nucleoplasm of CLL and lymphoid cells. Then, MNDA binds chromatin at Mcl1 and Bcl2 genes and affects the transcriptional competence of RNA polymerase II. Our data also reveal that MNDA specifically associates with Mcl1 and Bcl2 (pre-) mRNAs and favors their rapid turnover as a prompt response to genotoxic stress. We propose that this rapid dynamic tuning of RNA levels, which leads to the destabilization of Mcl1 and Bcl2 transcripts, represents a post-transcriptional mechanism of apoptosis control in CLL cells. These results provide an explanation of previous clinical data and corroborate the finding that higher MNDA expression levels in CLL are associated with a better clinical course., Competing Interests: Conflict of interest disclosure The authors declare no competing financial interests., (Copyright © 2020. Published by Elsevier Inc.)

It is now well admitted by ecologists that the conservation of biodiversity should imply preserving the evolutionary processes that will permit its adaptation to ongoing and future environmental changes. This is attested by the ever-growing reference to the conservation of evolutionary potential in the scientific literature. The impression that one may have when reading papers is that conserving evolutionary potential can only be a good thing, whatever biological system is under scrutiny. However, different objectives, such as maintaining species richness versus ecosystem services, may express different, when not conflicting, underlying values attributed to biodiversity. For instance, biodiversity can be intrinsically valued, as worth it to be conserved per se , or it can be conserved as a means for human flourishing. Consequently, both the concept of evolutionary potential and the prescriptions derived from the commitment to conserve it remain problematic, due to a lack of explicit mention of the norms underlying different conservation visions. Here, we contend that those who advocate for the conservation of evolutionary potential should position their conception along four dimensions: what vehicles instantiate the evolutionary potential relevant to their normative commitment; what temporality is involved; how measurable evolutionary potential is, and what degree of human influence is tolerated. We need to address these dimensions if we are to determine why and when the maintenance of evolutionary potential is an appropriate target for the conservation of biodiversity., Competing Interests: None declared., (© 2020 The Authors. Evolutionary Applications published by John Wiley & Sons Ltd.)

Objectives: We describe a method to identify human remains excavated from unmarked graves in historical Québec cemeteries by combining parental-lineage genetic markers with the whole-population genealogy of Québec contained in the BALSAC database., Materials and Methods: The remains of six men were exhumed from four historical cemeteries in the province of Québec, Canada. DNA was extracted from the remains and genotyped to reveal their mitochondrial and Y-chromosome haplotypes, which were compared to a collection of haplotypes of genealogically-anchored modern volunteers. Maternal and paternal genealogies were searched in the BALSAC genealogical record for parental couples matching the mitochondrial and the Y-chromosome haplotypic signatures, to identify candidate sons from whom the remains could have originated., Results: Analysis of the matching genealogies identified the parents of one man inhumed in the cemetery of the investigated parish during its operating time. The candidate individual died in 1833 at the age of 58, a plausible age at death in light of osteological analysis of the remains., Discussion: This study demonstrates the promising potential of coupling genetic information from living individuals to genealogical data in BALSAC to identify historical human remains. If genetic coverage is increased, the genealogical information in BALSAC could enable the identification of 87% of the men (n = 178,435) married in Québec before 1850, with high discriminatory power in most cases since >75% of the parental couples have unique biparental signatures in most regions. Genotyping and identifying Québec's historical human remains are a key to reconstructing the genomes of the founders of Québec and reinhuming archeological remains with a marked grave., (© 2020 Wiley Periodicals, Inc.)

USP16 (also known as UBP-M) has emerged as a histone H2AK119 deubiquitylase (DUB) implicated in the regulation of chromatin-associated processes and cell cycle progression. Despite this, available evidence suggests that this DUB is also present in the cytoplasm. How the nucleo-cytoplasmic transport of USP16, and hence its function, is regulated has remained elusive. Here, we show that USP16 is predominantly cytoplasmic in all cell cycle phases. We identified the nuclear export signal (NES) responsible for maintaining USP16 in the cytoplasm. We found that USP16 is only transiently retained in the nucleus following mitosis and then rapidly exported from this compartment. We also defined a non-canonical nuclear localization signal (NLS) sequence that plays a minimal role in directing USP16 into the nucleus. We further established that this DUB does not accumulate in the nucleus following DNA damage. Instead, only enforced nuclear localization of USP16 abolishes DNA double-strand break (DSB) repair, possibly due to unrestrained DUB activity. Thus, in contrast to the prevailing view, our data indicate that USP16 is actively excluded from the nucleus and that this DUB might indirectly regulate DSB repair.This article has an associated First Person interview with the first author of the paper., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2020. Published by The Company of Biologists Ltd.)

A nearly universal practice among forensic DNA scientists includes mentioning an unrelated person as the possible alternative source of a DNA stain, when one in fact refers to an unknown person. Hence, experts typically express their conclusions with statements like: "The probability of the DNA evidence is X times higher if the suspect is the source of the trace than if another person unrelated to the suspect is the source of the trace." Published forensic guidelines encourage such allusions to the unrelated person. However, as the authors show here, rational reasoning and population genetic principles do not require the conditioning of the evidential value on the unrelatedness between the unknown individual and the person of interest (e.g., a suspect). Surprisingly, this important semantic issue has been overlooked for decades, despite its potential to mislead the interpretation of DNA evidence by criminal justice system stakeholders., Competing Interests: We declare that this research involves no competing interests., (© 2019 The Authors.)

Nucleophosmin (NPM1) is frequently mutated or subjected to chromosomal translocation in acute myeloid leukemia (AML). NPM protein is primarily located in the nucleus, but the recurrent NPMc+ mutation, which creates a nuclear export signal, is characterized by cytoplasmic localization and leukemogenic properties. Similarly, the NPM-MLF1 translocation product favors the partial cytoplasmic retention of NPM. Regardless of their common cellular distribution, NPM-MLF1 malignancies engender different effects on hematopoiesis compared to NPMc+ counterparts, highlighting possible aberrant nuclear function(s) of NPM in NPMc+ and NPM-MLF1 AML. We performed a proteomic analysis and found that NPM and NPM-MLF1 interact with various nuclear proteins including subunits of the chromatin remodeling complexes ISWI, NuRD and P/BAF. Accordingly, NPM and NPM-MLF1 are recruited to transcriptionally active or repressed genes along with NuRD subunits. Although the overall gene expression program in NPM knockdown cells is similar to that resulting from NPMc+, NPM-MLF1 expression differentially altered gene transcription regulated by NPM. The abnormal gene regulation imposed by NPM-MLF1 can be characterized by the enhanced recruitment of NuRD to gene regulatory regions. Thus, different mechanisms would orchestrate the dysregulation of NPM function in NPMc+- versus NPM1-MLF1-associated leukemia., Competing Interests: The authors have declared that no competing interests exist.

Learning the transmission history of alleles through a family or population plays an important role in evolutionary, demographic, and medical genetic studies. Most classical models of population genetics have attempted to do so under the assumption that the genealogy of a population is unavailable and that its idiosyncrasies can be described by a small number of parameters describing population size and mate choice dynamics. Large genetic samples have increased sensitivity to such modeling assumptions, and large-scale genealogical datasets become a useful tool to investigate realistic genealogies. However, analyses in such large datasets are often intractable using conventional methods. We present an efficient method to infer transmission paths of rare alleles through population-scale genealogies. Based on backward-time Monte Carlo simulations of genetic inheritance, we use an importance sampling scheme to dramatically speed up convergence. The approach can take advantage of available genotypes of subsets of individuals in the genealogy including haplotype structure as well as information about the mode of inheritance and general prevalence of a mutation or disease in the population. Using a high-quality genealogical dataset of more than three million married individuals in the Quebec founder population, we apply the method to reconstruct the transmission history of chronic atrial and intestinal dysrhythmia (CAID), a rare recessive disease. We identify the most likely early carriers of the mutation and geographically map the expected carrier rate in the present-day French-Canadian population of Quebec., (Copyright © 2018. Published by Elsevier Inc.)

According to evolutionary theory, mitochondria could be poisoned gifts that mothers transmit to their sons. This is because mutations harmful to males are expected to accumulate in the mitochondrial genome, the so-called 'mother's curse'. However, the contribution of the mother's curse to the mutation load in nature remains largely unknown and hard to predict, because compensatory mechanisms could impede the spread of deleterious mitochondria. Here we provide evidence for the mother's curse in action over 290 years in a human population. We studied a mutation causing Leber's hereditary optical neuropathy, a disease with male-biased prevalence and which has long been suspected to be maintained in populations by the mother's curse. Male carriers showed a low fitness relative to non-carriers and to females, mostly explained by their high rate of infant mortality. Despite poor male fitness, selection analysis predicted a slight (albeit non-significant) increase in frequency, which sharply contrasts with the 35.5% per-generation decrease predicted if mitochondrial DNA transmission had been through males instead of females. Our results are therefore even suggestive of positive selection through the female line that may exacerbate effects of the mother's curse. This study supports a contribution of the mother's curse to the reduction of male lifespan, uncovering a large fitness effect associated with a single mitochondrial variant.

Recent studies of the joint dynamics of ecological and evolutionary processes show that changes in genotype or phenotype distributions can affect population, community and ecosystem processes. Such eco-evolutionary dynamics are likely to occur in modern humans and may influence population dynamics. Here, we study contributions to population growth from detailed genealogical records of a contemporary human population. We show that evolutionary changes in women's age at first reproduction can affect population growth: 15.9% of variation in individual contribution to population growth over 108 years is explained by mean age at first reproduction and at least one-third of this variation (6.1%) is attributed to the genetic basis of this trait, which showed an evolutionary response to selection during the period studied. Our study suggests that eco-evolutionary processes have modulated the growth of contemporary human populations.

While longitudinal changes in biomarker levels and their impact on health have been characterized for individual markers, little is known about how overall marker profiles may change during aging and affect mortality risk. We implemented the recently developed measure of physiological dysregulation based on the statistical distance of biomarker profiles in the framework of the stochastic process model of aging, using data on blood pressure, heart rate, cholesterol, glucose, hematocrit, body mass index, and mortality in the Framingham original cohort. This allowed us to evaluate how physiological dysregulation is related to different aging-related characteristics such as decline in stress resistance and adaptive capacity (which typically are not observed in the data and thus can be analyzed only indirectly), and, ultimately, to estimate how such dynamic relationships increase mortality risk with age. We found that physiological dysregulation increases with age; that increased dysregulation is associated with increased mortality, and increasingly so with age; and that, in most but not all cases, there is a decreasing ability to return quickly to baseline physiological state with age. We also revealed substantial sex differences in these processes, with women becoming dysregulated more quickly but with men showing a much greater sensitivity to dysregulation in terms of mortality risk.

An increasing number of aging researchers believes that multi-system physiological dysregulation may be a key biological mechanism of aging, but evidence of this has been sparse. Here, we used biomarker data on nearly 33, 000 individuals from four large datasets to test for the presence of multi-system dysregulation. We grouped 37 biomarkers into six a priori groupings representing physiological systems (lipids, immune, oxygen transport, liver function, vitamins, and electrolytes), then calculated dysregulation scores for each system in each individual using statistical distance. Correlations among dysregulation levels across systems were generally weak but significant. Comparison of these results to dysregulation in arbitrary 'systems' generated by random grouping of biomarkers showed that a priori knowledge effectively distinguished the true systems in which dysregulation proceeds most independently. In other words, correlations among dysregulation levels were higher using arbitrary systems, indicating that only a priori systems identified distinct dysregulation processes. Additionally, dysregulation of most systems increased with age and significantly predicted multiple health outcomes including mortality, frailty, diabetes, heart disease, and number of chronic diseases. The six systems differed in how well their dysregulation scores predicted health outcomes and age. These findings present the first unequivocal demonstration of integrated multi-system physiological dysregulation during aging, demonstrating that physiological dysregulation proceeds neither as a single global process nor as a completely independent process in different systems, but rather as a set of system-specific processes likely linked through weak feedback effects. These processes--probably many more than the six measured here--are implicated in aging., (© 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)