Entire Human Lifespan Research Articles

Social Isolation as a Precursor to Academic Downturn and Vice Versa

Research in the fields of social science and public health indicates the vital role of social interaction and relationships in promoting mental well-being across the entire human lifespan and education is no exception. Academics ,with its power of inquiring about the universe’s hymn to the patterns of subatomic beings , go beyond the confines of textbooks, Academics can be comprehended as a banyan tree with ever growing branches. Each branch has nuances , differentiating it in the most miniscule ways. As leaves sprout out of innumerable nodes , it ingeniously represents the evolving nature of academics. Wherein each discovery or invention creates a ripple effect in academics. While I have only experienced the finance and business side of academics , The surrealness of penetrating the boundaries of education stays alive in me. For approximately 3 years , I have dedicated time and effort into dissecting my patterns of studying , results , and conducting research - primary and secondary- between Isolation and its effect on academics and learning experiences. Although the relation may seem one dimensional , it delves deeper into the studies of psychology and academics. This project has been intellectually stimulating for me. Furthermore , this research explains the effects of social isolation and how it profoundly impacts learning.

Monitoring Blood Glucose in Mouse Offspring after Intracytoplasmic sperm injection - Embryo Transfer.

Human lifespan is considerably long, while mouse models can simulate the entire human lifespan in a relatively short period, with one year of mouse life roughly equivalent to 40 human years. Intracytoplasmic sperm injection (ICSI) is a commonly used assisted reproductive technology in clinical practice. However, given its relatively recent emergence about 30 years ago, the long-term effects of this technique on human development remain unclear. In this study, we established the ICSI combined with embryo transfer (ET) method using a mouse model. The results demonstrated that normal mouse sperm, after undergoing in vitro culture and subsequent ICSI, exhibited a fertilization rate of 89.57% and a two-cell rate of 87.38%. Following ET, the birth rate of offspring was approximately 42.50%. Furthermore, as the mice aged, fluctuations in glucose metabolism levels were observed, which may be associated with the application of the ICSI technique. These findings signify that the mouse ICSI-ET technique provides a valuable platform for evaluating the impact of sperm abnormalities on embryo development and their long-term effects on offspring health, particularly concerning glucose metabolism. This study provides important insights for further research on the potential effects of the ICSI technique on human development, emphasizing the necessity for in-depth investigation into the long-term implications of this technology.

Acute Myeloid Leukemia (AML) from Older HSCs Is Resistant to Chemotherapy and Has an Altered DNA Damage Response

Acute myeloid leukemia (AML) is an aggressive malignancy that leads to the accumulation of immature myeloid precursors, resulting in progressive marrow failure and death. AML arises from the hematopoietic stem cell (HSC), either directly or through an early myeloid precursor. HSCs must survive for the entire human lifespan to provide the 200+ billion blood cells that are produced daily. They are subjected to the entirety of the aging process. Further, while AML is diagnosed in every age range, it disproportionately affects older patients, with a median age at diagnosis of 68. Older age, typically defined as 60 years of age or older, is a powerful, poor prognostic factor. Clinical trials show an estimated 5-year survival of less than 10% in these patients. Ten-year survival is even worse with one study estimating 2.4% of patients over 60 years of age alive at ten years when treated with chemotherapy. Importantly, this poor outcome is the result of disease that is significantly more resistant to therapy. Even though this clinical data is well known the underlying mechanisms of therapy resistance in older AML are unknown. To address this, we generated genetically identical AML cells from fetal, 12-week-old (Young) or 24-month-old (Old) murine HSCs. Retroviral vectors were used to express the oncogenic MLL-ENL fusion protein and NRas G12D. AML was confirmed by morphology, immunophenotype and all AML cells were lethal when injected into syngeneic recipients. Old AML cells demonstrated reduced autophagy, decreased NAD levels and impaired mitochondria consistent with a significant effect of biological aging. When treated with DNA damaging chemotherapy, Old AML cells were significantly more resistant than either Young or Fetal cells to both cytarabine and the anthracycline doxorubicin. To examine the DNA damage response AML cells were treated with doxorubicin and stained for the early DNA damage marker gH2AX. Old AML cells generated significantly more gH2AX than either Fetal or Young AML cells (Figure 1). We next examined the induction of p53 in response to treatment and in contrast to the gH2AX results Old AML cells induced the least amount of p53 in response to doxorubicin treatment (Figure 2). This data demonstrates that Old AML cells were more adept at recognizing DNA damage but least likely to induce p53 in response to it suggesting a difference in DNA repair. To better understand these differences RNA sequencing was performed and differentially expressed genes (DEGs) identified. When Fetal and Young AML cells were compared, no DEGs reached the false discovery threshold for significance, demonstrating that Fetal and Young AMLs have highly similar gene expression profiles. In contrast, when Old AML cells were compared to either Young or Fetal cells, hundreds of highly significant DEGs were identified, and KEGG pathway enrichment analysis revealed that several DNA repair pathways were significantly upregulated in Old AML. These include base excision repair (FDR p= 8.60E-06), mismatch repair (FDR p=3.26E-05), and nucleotide excision repair (FDR p= 0.00043). To further validate these pathways, the Beat AML TCGA dataset was assessed for the prognostic effect of increased expression of key genes in these pathways. Patients with increased expression of these genes had a trend toward worse survival (p=0.07) consistent with these pathways being clinically relevant. These data suggest that AML arising in older patients may overexpress DNA damage repair pathways leading to chemotherapy resistance and poor outcomes. Additional work on ways to increase sensitivity to Old AML cells is in progress.

Biochemical Mechanisms of Beneficial Effects of Beta-Alanine Supplements on Cognition.

Using nutritional interventions to cure and manage psychiatric disorders is a promising tool. In this regard, accumulating documents support strong relationships between the diet and brain health throughout the lifespan. Evidence from animal and human studies demonstrated that β-alanine (Beta-alanine; BA), a natural amino acid, provides several benefits in fight against cognitive decline promoting mental health. This review summarizes and reports state-of-the-art evidence on how BA affects cognitive health and argues existence of potential unrevealed biochemical mechanisms and signaling cascades. There is a growing body of evidence showing that BA supplement has a significant role in mental health mediating increase of the cell carnosine and brain-derived neurotrophic factor (BDNF) content. BDNF is one of the most studied neurotrophins in the mammalian brain, which activates several downstream functional cascades via the tropomyosin-related kinase receptor type B (TrkB). Activation of TrkB induces diverse processes, such as programmed cell death and neuronal viability, dendritic branching growth, dendritic spine formation and stabilization, synaptic development, cognitive-related processes, and synaptic plasticity. Carnosine exerts its main effect via its antioxidant properties. This critical antioxidant also scavenges hypochlorous acid (HOCl), another toxic species produced in mammalian cells. Carnosine regulates transcription of hundreds of genes related to antioxidant mechanisms by increasing expression of the nuclear erythroid 2-related factor 2 (Nrf2) and translocating Nrf2 to the nucleus. Another major protective effect of carnosine on the central nervous system (CNS) is related to its anti-glycating, anti-aggregate activities, anti-inflammatory, metal ion chelator activity, and regulation of pro-inflammatory cytokine secretion. These effects could be associated with the carnosine ability to form complexes with metal ions, particularly with zinc (Zn2+). Thus, it seems that BA via BDNF and carnosine mechanisms may improve brain health and cognitive function over the entire human lifespan.

Transcription factor-based direct conversion of human fibroblasts to functional astrocytes.

SummaryAstrocytes are emerging key players in neurological disorders. However, their role in disease etiology is poorly understood owing to inaccessibility of primary human astrocytes. Pluripotent stem cell-derived cells fail to mimic age and due to their clonal origin do not mimic genetic heterogeneity of patients. In contrast, direct conversion constitutes an attractive approach to generate human astrocytes that capture age and genetic diversity. We describe efficient direct conversion of human fibroblasts to functional induced astrocytes (iAs). Expression of the minimal combination Sox9 and Nfib generates iAs with molecular, phenotypic, and functional properties resembling primary human astrocytes. iAs could be obtained by conversion of fibroblasts covering the entire human lifespan. Importantly, iAs supported function of induced neurons obtained through direct conversion from the same fibroblast population. Fibroblast-derived iAs will become a useful tool to elucidate the biology of astrocytes and complement current in vitro models for studies of late-onset neurological disorders.

From Alpha Diversity to Zzz: Interactions among sleep, the brain, and gut microbiota in the first year of life.

Sleep disorders have been linked to alterations of gut microbiota composition in adult humans and animal models, but it is unclear how this link develops. With longitudinal assessments in 162 healthy infants, we present a so far unrecognized sleep-brain-gut interrelationship. First, we report a link between sleep habits and gut microbiota: daytime sleep is associated with bacterial diversity, and nighttime sleep fragmentation and variability are linked with bacterial maturity and enterotype. Second, we demonstrate a sleep-brain-gut link: bacterial diversity and enterotype are associated with sleep neurophysiology. Third, we show that the sleep-brain-gut link is relevant in development: sleep habits and bacterial markers predict behavioral-developmental outcomes. Our results demonstrate the dynamic interplay between sleep, gut microbiota, and the maturation of brain and behavior during infancy, which aligns with the newly emerging concept of a sleep-brain-gut axis. Importantly, sleep and gut microbiota represent promising health targets since both can be modified non-invasively. As many adult diseases root in early childhood, leveraging protective factors of adequate sleep and age-appropriate gut microbiota in infancy could constitute a health promoting factor across the entire human lifespan.

The Impact of Physical Exercise on the Hippocampus in Physiological Condition and Ageing-Related Decline: Current Evidence from Animal and Human Studies.

Physical exercise (PE), notoriously, promotes a state of general well-being, throughout the entire human lifespan. Moreover, maintaining an adequate and regular PE habit results in a powerful preventive factor towards many diseases and may also help in managing existing pathological conditions. PE induces structural and functional changes in various parts of the body, determining biological and psychological benefits. Additionally, in the elderly, PE might represent a remarkable tool reducing cognitive impairments related to the normal aging processes and it has also been found to have an impact on neurodegenerative diseases such as Alzheimer's disease. The present review aims to provide an overview of PE effects on the hippocampus, since it is one of the brain regions most susceptible to aging and, therefore, involved in diseases characterized by cognitive impairment.

In This Issue

See article, p. 434.Ficlatuzumab is a first-in-class monoclonal antibody that blocks oncogenic MET signaling by blocking its ligand HGF. Here Wang et al. report on the safety and efficacy of ficlatuzumab combination with cytarabine in 17 patients with relapsed/refractory acute myeloid leukemia. Nine of the patients (53%) achieved a complete remission. Progression-free survival was 31.2 months, and median overall survival has not been reached. These outcomes compare favorably to historical data but remain to be validated in larger, randomized trials. Phosphoproteomic analysis identified S6 and MET phosphorylation as molecular correlates of response. Ras and GTPase gene expression signature was higher in prospective responders, whereas prospective nonresponders had elevated interferon and Myc signature.See article, p. 450.Human T-cell leukemia virus type-1 (HTLV-1) infection can progress to adult T-cell leukemia/lymphoma (ATL). To elucidate determinants of HTLV-1–driven oncogenesis, Koya et al. characterize circulating blood cells of healthy donors, HTLV-1 carriers, and patients with ATL by genome sequencing and CITE-seq combined with TCR-seq and BCR-seq. This high-dimensional single-cell analysis identifies Treg phenotype as a hallmark of premalignant clonal outgrowth. As the neoplastic clones progress to ATL, their expansion is accompanied by a proportional expansion of the myeloid compartment and immunosuppressive phenotypes including PD-L1 upregulation. The study delineates a new mechanism of PD-L1 acquisition by protein transfer from ATL to nonmalignant cells.See article, p. 468.Immunologic consequences of cell death contribute to clinical efficacy of certain chemotherapeutics, and identification of immunogenic drugs is essential for their optimal clinical use alone and in combination with immunotherapy. In this work, Gulla et al. have shown that a specific anti–multiple myeloma (MM) immunity occurs upon cell death induced by the proteasome inhibitor bortezomib, leading to immunologic memory and long-term clinical response. Intrinsic activation of STING followed by a viral mimicry state further contributes to the immunogenic effect, and combination of bortezomib with a STING agonist potentiates tumor cell–immune microenvironment interplay. These findings invite a deeper characterization of the immunologic effects of anti-MM agents and inform novel chemo-immunotherapy combinations.See article, p. 484.To obtain insight into the etiology of childhood leukemia, Brandsma et al. determined mutation burden of leukemic blasts and normal hematopoietic stem and progenitor cells (HSPC) from pediatric acute myeloid leukemia (pAML) patients and healthy age-matched controls. Integrating these data with available adult cohorts, they established a baseline of HSPC mutation accrual over the entire human lifespan. A subset of pediatric leukemia cases falling above the baseline harbored more genetic driver events and associated with better survival. The mutation pattern, characteristic of cells with high proliferation and oxidative stress, suggests a more committed progenitor as a cell of origin in this pAML subset.See article, p. 500.While the most frequent drivers of clonal hematopoiesis have been characterized previously, mutations in these genes are not present in about half of clonal hematopoiesis cases. By identifying recurrent mutations in the blood of large numbers of healthy people, Beauchamp et al. discover additional genes likely to drive clonal hematopoiesis and thus regulating hematopoietic stem cell (HSC) expansion. Modeling ZBTB33 mutations in mouse HSCs, the authors observe that the edited cells expand and have a competitive advantage compared with control cells. Cells with Zbtb33 mutations also have altered intron retention, potentially connecting ZBTB33 to RNA splicing, a commonly mutated pathway in clonal hematopoiesis and myelodysplastic syndromes.See article, p. 518.Romine et al. characterize acute myeloid leukemia (AML) sensitivity to BET inhibitors (BETi) by two orthogonal approaches: ex vivo drug screening of genetically defined primary AML samples, and genome-wide CRISPR screens of BETi-sensitive and BETi-resistant cells. Both identify loss of monocytic differentiation regulators as drivers of BETi resistance. BETi-resistant AML cells express low levels of myeloid markers; conversely, forced myeloid differentiation sensitizes AML cells to BETi. CRISPR dropout screens in BETi-resistant cells reveal BCL2 and CDK4/6 as targetable vulnerabilities to overcome BETi resistance. Moreover, monocytic AML refractory to BCL2 inhibition, an unmet clinical challenge, shows preclinical responses to combined Bcl2 and BETi.See article, p. 532.Binding of tyrosine kinase inhibitors (TKI) by plasma proteins, most notably alpha-1-acid glycoprotein (AGP), can dramatically reduce TKI bioavailability and thus clinical potency. In this work, Young et al. characterize AGP impact on staurosporine-derived TKI (STS-TKI) activity against FLT3-mutated acute myeloid leukemia (AML). Under physiologic conditions and drug concentrations, AGP quenches STS-TKI activity to subtherapeutic levels due to high-affinity drug–protein interactions. To overcome this, the authors screen for drugs restoring TKI activity in the presence of AGP, identifying mifepristone. In an in vivo model, mifepristone coadministration restores midostaurin clearance of AML cells. These results suggest a combinatorial approach for unlocking TKI activity to potentiate therapeutic responses in FLT3-mutated AML.

Protein posttranslational modification (PTM) by glycation: Role in lens aging and age-related cataractogenesis

Crystallins, the most prevalent lens proteins, have no turnover throughout the entire human lifespan. These long-lived proteins are susceptible to post-synthetic modifications, including oxidation and glycation, which are believed to be some of the primary mechanisms for age-related cataractogenesis. Thanks to high glutathione (GSH) and ascorbic acid (ASA) levels as well as low oxygen content, the human lens is able to maintain its transparency for several decades. Aging accumulates substantial changes in the human lens, including a decreased glutathione concentration, increased reactive oxygen species (ROS) formation, impaired antioxidative defense capacity, and increased redox-active metal ions, which induce glucose and ascorbic acid degradation and protein glycation. The glycated lens crystallins are either prone to UVA mediated free radical production or they attract metal ion binding, which can trigger additional protein oxidation and modification. This vicious cycle is expected to be exacerbated with older age or diabetic conditions. ASA serves as an antioxidant in the human lens under reducing conditions to protect the human lens from damage, but ASA converts to the pro-oxidative role and causes lens protein damage by ascorbylation in high oxidation or enriched redox-active metal ion conditions. This review is dedicated in honor of Dr. Frank Giblin, a great friend and superb scientist, whose pioneering and relentless work over the past 45 years has provided critical insight into lens redox regulation and glutathione homeostasis during aging and cataractogenesis.

DNA Methylation Biomarkers in Aging and Age-Related Diseases.

Recent research efforts provided compelling evidence of genome-wide DNA methylation alterations in aging and age-related disease. It is currently well established that DNA methylation biomarkers can determine biological age of any tissue across the entire human lifespan, even during development. There is growing evidence suggesting epigenetic age acceleration to be strongly linked to common diseases or occurring in response to various environmental factors. DNA methylation based clocks are proposed as biomarkers of early disease risk as well as predictors of life expectancy and mortality. In this review, we will summarize key advances in epigenetic clocks and their potential application in precision health. We will also provide an overview of progresses in epigenetic biomarker discovery in Alzheimer’s, type 2 diabetes, and cardiovascular disease. Furthermore, we will highlight the importance of prospective study designs to identify and confirm epigenetic biomarkers of disease.

KENDALA GURU PAUD MENGEMBANGKAN SENTRA MEMBACA DAN MENULIS (STUDI KASUS DI JAKARTA TIMUR 2018)

Early childhood is the important stage entire human life-span. Early writing and reading in early childhood is the one of critical aspect to develop. Teachers should improve the environment which support to the children in literacy. The objective of this study is to describe the obstacles of early childhood teachers to develop reading and writing center for the children. This study used qualitative method which involved 27 early childhood teachers in East Jakarta. Purpossive sampling method was used, while data analyze used Miles and Huberman technique to data reduction, data display, and verification. This study revealed the experience of early childhood teacher obstacles to develop reading and writing center. It include the obstacle of preparing media of reading and writing, difficultes to manage play environment, improve library center, creating an appropriate book for children, and developing media for listening activities.

Single-cell whole-genome sequencing reveals the functional landscape of somatic mutations in B lymphocytes across the human lifespan.

Accumulation of mutations in somatic cells has been implicated as a cause of aging since the 1950s. However, attempts to establish a causal relationship between somatic mutations and aging have been constrained by the lack of methods to directly identify mutational events in primary human tissues. Here we provide genome-wide mutation frequencies and spectra of human B lymphocytes from healthy individuals across the entire human lifespan using a highly accurate single-cell whole-genome sequencing method. We found that the number of somatic mutations increases from <500 per cell in newborns to >3,000 per cell in centenarians. We discovered mutational hotspot regions, some of which, as expected, were located at Ig genes associated with somatic hypermutation (SHM). B cell-specific mutation signatures associated with development, aging, or SHM were found. The SHM signature strongly correlated with the signature found in human B cell tumors, indicating that potential cancer-causing events are already present even in B cells of healthy individuals. We also identified multiple mutations in sequence features relevant to cellular function (i.e., transcribed genes and gene regulatory regions). Such mutations increased significantly during aging, but only at approximately one-half the rate of the genome average, indicating selection against mutations that impact B cell function. This full characterization of the landscape of somatic mutations in human B lymphocytes indicates that spontaneous somatic mutations accumulating with age can be deleterious and may contribute to both the increased risk for leukemia and the functional decline of B lymphocytes in the elderly.

Impact of Apolipoprotein E gene polymorphism during normal and pathological conditions of the brain across the lifespan.

The central nervous system (CNS) is the cellular substrate for the integration of complex, dynamic, constant, and simultaneous interactions among endogenous and exogenous stimuli across the entire human lifespan. Numerous studies on aging-related brain diseases show that some genes identified as risk factors for some of the most common neurodegenerative diseases - such as the allele 4 of APOE gene (APOE4) for Alzheimer’s disease (AD) - have a much earlier neuro-anatomical and neuro-physiological impact. The impact of APOE polymorphism appears in fact to start as early as youth and early-adult life. Intriguingly, though, those same genes associated with aging-related brain diseases seem to influence different aspects of the brain functioning much earlier actually, that is, even from the neonatal periods and earlier. The APOE4, an allele classically associated with later-life neurodegenerative disorders as AD, seems in fact to exert a series of very early effects on phenomena of neuroplasticity and synaptogenesis that begin from the earliest periods of life such as the fetal ones.We reviewed some of the findings supporting the hypothesis that APOE polymorphism is an early modifier of various neurobiological aspects across the entire human lifespan - from the in-utero to the centenarian life - during both normal and pathological conditions of the brain.

Telomeres Increasingly Develop Aberrant Structures in Aging Humans.

Telomeres progressively shorten with age, and it has been proposed that critically short and dysfunctional telomeres contribute to aging and aging-associated diseases in humans. For many years it was thought that telomere erosion was strictly a consequence of the "end replication problem," or the inability of replicative polymerases to completely duplicate linear DNA ends. It is becoming increasingly evident, however, that telomere shortening of cultured human cells is also caused because of other replication defects in telomeric repeats, those that cause fragile telomeres and other aberrant telomeric structures that can be detected on metaphase chromosomes. Whether these replication defects contribute to telomere erosion also in human tissues is currently unknown. By analyzing peripheral blood mononuclear cells from a total of 35 healthy subjects ranging in age from 23 to 101 years, we demonstrated that telomeres increasingly display aberrant structures with advancing donor age. Although the percentages of fragile telomeres increased only until adulthood, the percentages of chromosomes displaying sister telomere loss and sister telomere chromatid fusions increased consistently throughout the entire human life span. Our data, therefore, suggest that telomeric replication defects other than the end replication problem contribute to aging-associated telomere erosion in humans.

Toward Antitumor Immunity and Febrile Infections: Gamma/Delta (γδ) T Cells Hypothesis

Retrospective as well as prospective clinical studies indicate that episodes of high fever as a typical reaction to an acute infection during the entire human life span are inversely related to cancer incidence. Laboratory data aimed at discovering why fever incidents appear beneficial in lowering the risk of cancer remain rudimentary at best. Several hypotheses have been presented thus far, and recent debates have pointed to the effect of fever on innate and adaptive immune functions. In this paper we focus on a particular mode of adaptive immune functioning that involves a type of T cells carrying a receptor composed of gamma/delta chain heterodimer (γδ T-cell receptor; γδ TCR). We present an argument for a key role of infectious fever in the recruitment and enhancement of immune antitumor competence of γδ T cells during the life span of a human being. The unique physiology of γδ T lymphocytes indicating a possible cellular link between innate and adaptive immunity—including modes of antigen recognition as well their presence in tissues prone to infections, metabolic stress, and neoplastic development—makes them a target for exploration in the context of fever and cancer risk, and for future cancer immunotherapy.

Newborn susceptibility to infection vs. disease depends on complex in vivo interactions of host and pathogen.

The burden of newborn infectious disease has long been recognized as the highest across the entire human life span. The precise underlying cause is unfortunately still far from clear. A substantial body of data derived mostly from in vitro experimentation indicates "lower" host immune responses in early vs. adult life and is briefly summarized within this review. However, emerging data derived mostly from in vivo experimentation reveal that the newborn host also exhibits an exuberant immune and inflammatory response following infection when compared to the adult. In this context, it is important to emphasize that "infection" does not equate "infectious disease," as for many infections it is the host response to the infection that causes disease. This simple insight readily arranges existing evidence into cause-effect relationships that explain much of the increase in clinical suffering from infection in early life. We here briefly summarize the evidence in support of this paradigm and highlight the important implications it has for efforts to ameliorate the suffering and dying from infection in early life.

Age-dependent expression ofDNMT1andDNMT3Bin PBMCs from a large European population enrolled in the MARK-AGE study

SummaryAging is associated with alterations in the content and patterns of DNA methylation virtually throughout the entire human lifespan. Reasons for these variations are not well understood. However, several lines of evidence suggest that the epigenetic instability in aging may be traced back to the alteration of the expression of DNA methyltransferases. Here, the association of the expression of DNA methyltransferases DNMT1 and DNMT3B with age has been analysed in the context of the MARK‐AGE study, a large‐scale cross‐sectional study of the European general population. Using peripheral blood mononuclear cells, we assessed the variation of DNMT1 and DNMT3B gene expression in more than two thousand age‐stratified women and men (35–75 years) recruited across eight European countries. Significant age‐related changes were detected for both transcripts. The level of DNMT1 gradually dropped with aging but this was only observed up to the age of 64 years. By contrast, the expression of DNMT3B decreased linearly with increasing age and this association was particularly evident in females. We next attempted to trace the age‐related changes of both transcripts to the influence of different variables that have an impact on changes of their expression in the population, including demographics, dietary and health habits, and clinical parameters. Our results indicate that age affects the expression of DNMT1 and DNMT3B as an almost independent variable in respect of all other variables evaluated.

No turnover in lens lipids for the entire human lifespan.

Lipids are critical to cellular function and it is generally accepted that lipid turnover is rapid and dysregulation in turnover results in disease (Dawidowicz 1987; Phillips et al., 2009; Liu et al., 2013). In this study, we present an intriguing counter-example by demonstrating that in the center of the human ocular lens, there is no lipid turnover in fiber cells during the entire human lifespan. This discovery, combined with prior demonstration of pronounced changes in the lens lipid composition over a lifetime (Hughes et al., 2012), suggests that some lipid classes break down in the body over several decades, whereas others are stable. Such substantial changes in lens cell membranes may play a role in the genesis of age-related eye disorders. Whether long-lived lipids are present in other tissues is not yet known, but this may prove to be important in understanding the development of age-related diseases.

The Relationship between “Protection of” and “Violence Against” Infants and Young Children: The U.S. Experience, 1940–2005

Between 1940 and 2005, in the United States, the rate of unnatural death declined about 75 percent in infant and young child boys and girls; a remarkable indicator of successful child protection. During this same period, the rate of reported homicide in infant boys increased 64.0 percent, in infant girls increased 43.5 percent, in young child boys increased 333.3 percent, and in young child girls increased 300.0 percent, a dismal and disturbing indicator of failed child protection. Can these simultaneously encouraging and discouraging observations be reconciled? The four categories of unnatural death, homicide, suicide, motor vehicle accident (MVA), and non-MVA, are mutually exclusive classifications. Correlations between the four categories of unnatural death among U.S. men and woman in all age groups for the years 1940 through 2005 were calculated. A negative correlation between homicide and non-MVA death rates was shown for all age groups, encompassing the entire human lifespan, in both genders. This consistently observed negative correlation was only observed between homicide and non-MVA death rates, and was not demonstrated between other causes of unnatural deaths. Moreover, this negative correlation was strongest (less than −0.7) in infants and young children. These observations are consistent with the suggestion that as the rate of unnatural death in infants and young children dramatically declined, society gave greater scrutiny to those fewer occurring unnatural deaths and demonstrated an increasing propensity to assign blame for those fewer deaths.

Knowledge-Guided Robust MRI Brain Extraction for Diverse Large-Scale Neuroimaging Studies on Humans and Non-Human Primates

Accurate and robust brain extraction is a critical step in most neuroimaging analysis pipelines. In particular, for the large-scale multi-site neuroimaging studies involving a significant number of subjects with diverse age and diagnostic groups, accurate and robust extraction of the brain automatically and consistently is highly desirable. In this paper, we introduce population-specific probability maps to guide the brain extraction of diverse subject groups, including both healthy and diseased adult human populations, both developing and aging human populations, as well as non-human primates. Specifically, the proposed method combines an atlas-based approach, for coarse skull-stripping, with a deformable-surface-based approach that is guided by local intensity information and population-specific prior information learned from a set of real brain images for more localized refinement. Comprehensive quantitative evaluations were performed on the diverse large-scale populations of ADNI dataset with over 800 subjects (55∼90 years of age, multi-site, various diagnosis groups), OASIS dataset with over 400 subjects (18∼96 years of age, wide age range, various diagnosis groups), and NIH pediatrics dataset with 150 subjects (5∼18 years of age, multi-site, wide age range as a complementary age group to the adult dataset). The results demonstrate that our method consistently yields the best overall results across almost the entire human life span, with only a single set of parameters. To demonstrate its capability to work on non-human primates, the proposed method is further evaluated using a rhesus macaque dataset with 20 subjects. Quantitative comparisons with popularly used state-of-the-art methods, including BET, Two-pass BET, BET-B, BSE, HWA, ROBEX and AFNI, demonstrate that the proposed method performs favorably with superior performance on all testing datasets, indicating its robustness and effectiveness.