Distinct longevity mechanisms across and within species and their association with aging.

Lifespan varies within and across species, but the general principles of its control remain unclear. Here, we conducted multi-tissue RNA-seq analyses across 41 mammalian species, identifying longevity signatures and examining their relationship with transcriptomic biomarkers of aging and established lifespan-extending interventions. An integrative analysis uncovered shared longevity mechanisms within and across species, including downregulated Igf1 and upregulated mitochondrial translation genes, and unique features, such as distinct regulation of the innate immune response and cellular respiration. Signatures of long-lived species were positively correlated with age-related changes and enriched for evolutionarily ancient essential genes, involved in proteolysis and PI3K-Akt signaling. Conversely, lifespan-extending interventions counteracted aging patterns and affected younger, mutable genes enriched for energy metabolism. The identified biomarkers revealed longevity interventions, including KU0063794, which extended mouse lifespan and healthspan. Overall, this study uncovers universal and distinct strategies of lifespan regulation within and across species and provides tools for discovering longevity interventions.

Reduced expression of MYC increases longevity and enhances healthspan.

MYC is a highly pleiotropic transcription factor whose deregulation promotes cancer. In contrast, we find that Myc haploinsufficient (Myc(+/-)) mice exhibit increased lifespan. They show resistance to several age-associated pathologies, including osteoporosis, cardiac fibrosis, and immunosenescence. They also appear to be more active, with a higher metabolic rate and healthier lipid metabolism. Transcriptomic analysis reveals a gene expression signature enriched for metabolic and immune processes. The ancestral role of MYC as a regulator of ribosome biogenesis is reflected in reduced protein translation, which is inversely correlated with longevity. We also observe changes in nutrient and energy sensing pathways, including reduced serum IGF-1, increased AMPK activity, and decreased AKT, TOR, and S6K activities. In contrast to observations in other longevity models, Myc(+/-) mice do not show improvements in stress management pathways. Our findings indicate that MYC activity has a significant impact on longevity and multiple aspects of mammalian healthspan.

CD4 receptor diversity represents an ancient protection mechanism against primate lentiviruses.

Infection with human and simian immunodeficiency viruses (HIV/SIV) requires binding of the viral envelope glycoprotein (Env) to the host protein CD4 on the surface of immune cells. Although invariant in humans, the Env binding domain of the chimpanzee CD4 is highly polymorphic, with nine coding variants circulating in wild populations. Here, we show that within-species CD4 diversity is not unique to chimpanzees but found in many African primate species. Characterizing the outermost (D1) domain of the CD4 protein in over 500 monkeys and apes, we found polymorphic residues in 24 of 29 primate species, with as many as 11 different coding variants identified within a single species. D1 domain amino acid replacements affected SIV Env-mediated cell entry in a single-round infection assay, restricting infection in a strain- and allele-specific fashion. Several identical CD4 polymorphisms, including the addition of N-linked glycosylation sites, were found in primate species from different genera, providing striking examples of parallel evolution. Moreover, seven different guenons (Cercopithecus spp.) shared multiple distinct D1 domain variants, pointing to long-term trans-specific polymorphism. These data indicate that the HIV/SIV Env binding region of the primate CD4 protein is highly variable, both within and between species, and suggest that this diversity has been maintained by balancing selection for millions of years, at least in part to confer protection against primate lentiviruses. Although long-term SIV-infected species have evolved specific mechanisms to avoid disease progression, primate lentiviruses are intrinsically pathogenic and have left their mark on the host genome.

Lost in translation: Therapeutic Alliance as a mediator in the relationship between teletherapy and marital satisfaction.

The global impact of the SARS-COV-2 pandemic necessitated a rapid shift to online/teletherapy psychotherapy services. While research suggests the feasibility and efficacy of teletherapy, there is limited investigation into couple teletherapy's impact on satisfaction and therapeutic alliance. This study aimed to address this gap by examining changes in couple satisfaction during tele- and in-person therapy sessions over 12 sessions and exploring whether therapeutic alliance development mediates these changes. Using growth curve modeling in a sample of 416 couples, it found that teletherapy participants initially reported higher couple satisfaction, but improvement in this domain was slower than in-person therapy recipients. The development of the therapeutic alliance mediated this effect via two indirect paths. Implications include the need for focused attention on alliance development in teletherapy and more empirically-informed approaches in couple teletherapy.

Adverse Childhood Experiences Predict Diurnal Cortisol Throughout Gestation.

OBJECTIVE: Adverse childhood experiences (ACEs) are associated with negative prenatal and perinatal health outcomes and may, via these pathways, have intergenerational effects on child health and development. We examine the impact of ACEs on maternal salivary cortisol, a key measure of prenatal biology previously linked with pregnancy-related health outcomes. METHODS: Leveraging assessments across three trimesters, we used linear mixed-effects models to analyze the influence of ACEs on maternal prenatal diurnal cortisol patterns in a diverse cohort of pregnant women (analytic sample, n = 207). Covariates included comorbid prenatal depression, psychiatric medications, and sociodemographic factors. RESULTS: Maternal ACEs were significantly associated with flatter diurnal cortisol slopes (i.e., less steep decline), after adjusting for covariates, with effects consistent across gestation (estimate = 0.15, standard error = 0.06, p = .008). CONCLUSIONS: ACEs experienced before pregnancy may have a robust and lasting influence on maternal prenatal hypothalamic-pituitary-adrenal activity throughout gestation, a key biological marker associated with perinatal and child health outcomes. The findings suggest one route of intergenerational transmission of early adverse experiences and underscore the potential value of assessing prepregnancy adverse experiences for promoting perinatal and maternal and child health.

Cadmium reduces growth of male fetuses by impairing development of the placental vasculature and reducing expression of nutrient transporters.

In utero exposure to the toxic metal cadmium (Cd) alters fetoplacental growth in rodents and has been inversely associated with birth weight and infant size in some birth cohorts. Moreover, studies suggest that Cd may have differential effects on growth and development according to offspring sex. The purpose of the current study was to evaluate changes in male and female fetoplacental development following a single injection of saline (5 ml/kg ip) or cadmium chloride (CdCl2, 2.5, 5 mg/kg, ip) on gestational day (GD) 9. By GD18, no changes in fetal or placental weights were observed after treatment with 2.5 mg/kg CdCl2. By comparison, the weight and length of male fetuses and their placentas were reduced following treatment with 5 mg/kg CdCl2 whereas no change was observed in females. In addition, the area of maternal and fetal blood vessels as well as the expression of the glucose transporters, Glut1 and Glut3, and the endothelial marker, CD34, were reduced in the placentas of CdCl2-treated male offspring compared to females. Interestingly, the placentas of females accumulated 80% more Cd than males after CdCl2 (5 mg/kg) administration. Female placentas also had higher concentrations of zinc and the zinc transporter Znt1 compared to males which may explain the limited changes in fetal growth observed following CdCl2 treatment. Taken together, disruption of vasculature development and reduced expression of glucose transporters in the placenta provide potential mechanisms underlying reduced fetal growth in male offspring despite the greater accumulation of Cd in female placentas.

Transient early life growth hormone exposure permanently alters brain, muscle, liver, macrophage, and adipocyte status in long-lived Ames dwarf mice.

The exceptional longevity of Ames dwarf (DF) mice can be abrogated by a brief course of growth hormone (GH) injections started at 2 weeks of age. This transient GH exposure also prevents the increase in cellular stress resistance and decline in hypothalamic inflammation characteristic of DF mice. Here, we show that transient early-life GH treatment leads to permanent alteration of pertinent changes in adipocytes, fat-associated macrophages, liver, muscle, and brain that are seen in DF mice. Ames DF mice, like Snell dwarf and GHRKO mice, show elevation of glycosylphosphatidylinositol specific phospholipase D1 in liver, neurogenesis in brain as indicated by BDNF and DCX proteins, muscle production of fibronectin type III domain-containing protein 5 (a precursor of irisin), uncoupling protein 1 as an index of thermogenic capacity in brown and white fat, and increase in fat-associated anti-inflammatory macrophages. In each case, transient exposure to GH early in life reverts the DF mice to the levels of each protein seen in littermate control animals, in animals evaluated at 15-18 months of age. Thus, many of the traits seen in long-lived mutant mice, pertinent to age-related changes in inflammation, neurogenesis, and metabolic control, are permanently set by early-life GH levels.

Risk Assessment for Hepatobiliary Toxicity Liabilities in Drug Development.

Risk assessment of hepatobiliary toxicities represents one of the greatest challenges and, more often than not, one of the most rewarding activities in which toxicologic pathologists can partake, and often times lead. This is in part because each liver toxicity picture is a bit different, informed by a broad range and diversity of relevant data, and also in part because the heavily relied upon animal models are imperfect regarding predictivity of hepatic effects in humans. Following identification and characterization of a hepatotoxicity hazard, typically in nonclinical toxicology studies, a holistic and integrated assessment of liver-relevant endpoints is conducted that typically incorporates ADME (absorption, distribution, metabolism, and excretion) information (ideally, including extensive transporter data, exposure margins, and possibly concentration of parent/metabolite at region of injury), target expression/function, in silico prediction data, in vitro hepatocyte data, liver/circulating biomarkers, and importantly, species specificity of any of these data. Of course, a thorough understanding, developed in close partnership with clinical colleagues, of the anticipated liver disease status of intended patient populations is paramount to hepatic risk assessment. This is particularly important since the likelihood of translatable determinant hepatic events observed in nonclinical models to occur in humans has been reasonably well established.

Protective role of the placental efflux transporter BCRP/ABCG2 in the relationship between prenatal cadmium exposure, placenta weight, and size at birth.

BACKGROUND AND AIM: Placental efflux transporter proteins, such as BCRP, reduce the placental and fetal toxicity of environmental contaminants but have received little attention in perinatal environmental epidemiology. Here, we evaluate the potential protective role of BCRP following prenatal exposure to cadmium, a metal that preferentially accumulates in the placenta and adversely impacts fetal growth. We hypothesized that individuals with a reduced function polymorphism in ABCG2, the gene encoding BCRP, would be most vulnerable to the adverse impacts of prenatal cadmium exposure, notably, smaller placental and fetal size. METHODS: We measured cadmium in maternal urine samples at each trimester and in term placentas from UPSIDE-ECHO study participants (NY, USA; n = 269). We fit adjusted multivariable linear regression and generalized estimating equation models to examine log-transformed urinary and placental cadmium concentrations in relation to birthweight, birth length, placental weight, and fetoplacental weight ratio (FPR) and stratified models by ABCG2 Q141K (C421A) genotype. RESULTS: Overall 17% of participants expressed the reduced-function ABCG2 C421A variant (AA or AC). Placental cadmium concentrations were inversely associated with placental weight (ß = -19.55; 95%CI: -37.06, -2.04) and trended towards higher FPR (ß = 0.25; 95%CI: -0.01, 0.52) with stronger associations in 421A variant infants. Notably, higher placental cadmium concentrations in 421A variant infants were associated with reduced placental weight (ß = -49.42; 95%CI: 98.87, 0.03), and higher FPR (ß = 0.85, 95%CI: 0.18, 1.52), while higher urinary cadmium concentration was associated with longer birth length (ß = 0.98; 95%CI: 0.37, 1.59), lower ponderal index (ß = -0.09; 95%CI: 0.15, -0.03), and higher FPR (ß = 0.42; 95%CI: 0.14, 0.71). CONCLUSIONS: Infants with reduced function ABCG2 polymorphisms may be particularly vulnerable to the developmental toxicity of cadmium as well as other xenobiotics that are BCRP substrates. Additional work examining the influence of placental transporters in environmental epidemiology cohorts is warranted.

Prenatal perfluoroalkyl substances exposure and maternal sex steroid hormones across pregnancy.

BACKGROUND: Poly- and perfluoroalkyl substances (PFAS) are ubiquitous and persistent environmental contaminants that may act as endocrine disruptors in utero, but the specific endocrine pathways are unknown. OBJECTIVE: We examined associations between maternal serum PFAS and sex steroid hormones at three time points during pregnancy. METHODS: Pregnant women participating in the Understanding Pregnancy Signals and Infant Development (UPSIDE) study contributed biospecimens, questionnaire, and medical record data in each trimester (n = 285). PFAS (including perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorohexane sulfonic acid (PFHxS), perfluorononanoic acid (PFNA) and perfluorodecanoic acid (PFDA)) were analyzed in second-trimester serum samples by high-performance liquid chromatography and tandem mass spectrometry (LC-MS/MS). Total testosterone [TT], free testosterone [fT], estrone [E1], estradiol [E2], and estriol [E3]) were measured by LC-MS/MS in serum samples from each trimester. Linear mixed models with random intercepts were used to examine associations between log-transformed PFAS concentrations and hormone levels, adjusting for covariates, and stratifying by fetal sex. Results are presented as the mean percentage difference (Δ%) in hormone levels per ln-unit increase in PFAS concentration. RESULTS: In adjusted models, PFHxS was associated with higher TT (%Δ = 20.0, 95%CI: 1.7, 41.6), particularly among women carrying male fetuses (%Δ = 15.3, 95%CI: 1.2, 30.7); this association strengthened as the pregnancy progressed. PFNA (%Δ = 7.9, 95%CI: 3.4, 12.5) and PFDA (%Δ = 7.2, 95%CI: 4.9, 9.7) were associated with higher fT, with associations again observed only in women carrying male fetuses. PFHxS was associated with higher levels of E2 and E3 in women carrying female fetuses (%Δ = 13.2, 95%CI: 0.5, 29.1; %Δ = 17.9, 95%CI: 3.2, 34.8, respectively). No associations were observed for PFOS and PFOA. CONCLUSION: PFHxS, PFNA, and PFDA may disrupt androgenic and estrogenic pathways in pregnancy in a sex-dependent manner.

Per- and polyfluoroalkyl substances, gestational weight gain, postpartum weight retention and body composition in the UPSIDE cohort.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals found in drinking water and consumer products, resulting in ubiquitous human exposure. PFAS have been linked to endocrine disruption and altered weight gain across the lifespan. A limited and inconsistent body of research suggests PFAS may impact gestational weight gain (GWG) and postpartum body mass index (BMI), which are important predictors of overall infant and maternal health, respectively. METHODS: In the Understanding Pregnancy Signals and Infant Development (UPSIDE/UPSIDE-MOMs) study (n = 243; Rochester, NY), we examined second trimester serum PFAS (PFOS: perfluorooctanesulfonic acid, PFOA: perfluorooctanoic acid, PFNA: perfluorononanoic acid, PFHxS: perfluorohexanesulfonic acid, PFDA: perfluorodecanoic acid) in relation to GWG (kg, and weekly rate of gain) and in the postpartum, weight retention (PPWR (kg) and total body fat percentage (measured by bioelectrical impedance)). We fit multivariable linear regression models examining these outcomes in relation to log-transformed PFAS in the whole cohort as well as stratified by maternal pre-pregnancy BMI (< 25 vs. = > 25 kg/m2), adjusting for demographics and lifestyle factors. We used weighted quantile sum regression to find the combined influence of the 5 PFAS on GWG, PPWR, and body fat percentage. RESULTS: PFOA and PFHxS were inversely associated with total GWG (PFOA: ß = -1.54 kg, 95%CI: -2.79, -0.30; rate ß = -0.05 kg/week, 95%CI: -0.09, -0.01; PFHxS: ß = -1.59 kg, 95%CI: -3.39, 0.21; rate ß = -0.05 kg/week, 95%CI: -0.11, 0.01) and PPWR at 6 and 12 months (PFOA 6 months: ß = -2.39 kg, 95%CI: -4.17, -0.61; 12 months: ß = -4.02 kg, 95%CI: -6.58, -1.46; PFHxS 6 months: ß = -2.94 kg, 95%CI: -5.52, -0.35; 12 months: ß = -5.13 kg, 95%CI: -8.34, -1.93). PFOA was additionally associated with lower body fat percentage at 6 and 12 months (ß = -1.75, 95%CI: -3.17, -0.32; ß = -1.64, 95%CI: -3.43, 0.16, respectively) with stronger associations observed in participants with higher pre-pregnancy BMI. The PFAS mixture was inversely associated with weight retention at 12 months (ß = -2.030, 95%CI: -3.486, -0.573) amongst all participants. CONCLUSION: PFAS, in particular PFOA and PFHxS, in pregnancy are associated with altered patterns of GWG and postpartum adiposity with potential implications for fetal development and long-term maternal cardiometabolic health.

Associations between neighborhood stress and maternal sex steroid hormones in pregnancy.

BACKGROUND: Neighborhood stressors (e.g., crime and deprivation) have been associated with adverse pregnancy outcomes including preterm birth and low birth weight. A potential mechanism is disruption of maternal endocrine pathways. While stress hormones (e.g., cortisol) have received much attention, other relevant hormones, including sex steroids, have been overlooked. METHODS: Pregnant women in the Understanding Pregnancy Signals and Infant Development (UPSIDE) study contributed biospecimens, questionnaires, and medical record data (n = 262). In each trimester, maternal serum total testosterone [TT], estrone, estradiol, and estriol were measured using LC/MS-MS and serum free testosterone was measured by equilibrium dialysis. In the third trimester, participants reported on neighborhood stress over the last year through the validated City Stress Inventory. We examined two subscales: 11-item neighborhood disorder (e.g., vacant buildings, crime) and 7-item exposure to violence (personal experiences of violence). Composite scores were calculated and examined categorically (quartile (Q) for neighborhood disorder and any/none for exposure to violence). We fitted linear mixed models examining associations between neighborhood stressors and sex steroid hormones across pregnancy as well as trimester-specific linear regression models, all adjusting for confounders. Secondarily, we stratified by fetal sex. Results are presented as percentage change (∆%) and 95% confidence interval (CI) in hormones. RESULTS: Most participants (73%) reported one or more exposures to neighborhood disorder; 22% reported any exposure to violence. In adjusted models, neighborhood disorder was associated with higher TT across pregnancy (Q2: %∆= 37.3, 95%CI: 13.2, 66.5; Q3: %∆= 22.2, 95%CI: 1.2, 47.5; and Q4: %∆= 25.7, 95%CI: 1.6, 55.3), with the strongest associations observed in the third trimester (Q2: %∆= 38.0, 95%CI: 10.6, 72.1; Q3: %∆= 29.2, 95%CI: 4.4, 59.9; and Q4: %∆=33.4, 95%CI: 4.9, 69.6). In stratified models, neighborhood disorder was associated with higher TT among women carrying male fetuses (%∆ range: 48.2-84.8). Exposure to violence was not associated with any hormones. CONCLUSION: Neighborhood disorder is associated with higher maternal testosterone levels, which may have implications for maternal and child health. Additional research is needed to understand the mechanisms by which neighborhood stress impacts endocrine physiology.

Interprofessional relationships and their impact on resident hospitalizations in nursing homes: A qualitative study.

AIM: The aim of this study is to explore experiences and perspectives of nurses and providers (e.g., physicians, medical directors, fellows, and nurse practitioners) on reducing preventable hospitalizations of nursing home (NH) residents in relation to interprofessional relationship and hospitalization decision-making process. BACKGROUND: Preventable NH resident hospitalization continues to be a pressing public health issue. Studies show that improved interprofessional relationship may help reduce hospitalization, yet research on communication processes and interactions among different NH staff remains limited. METHODS: This is a qualitative descriptive study. Two focus groups were held with fourteen nurses and thirteen in-depth, qualitative interviews were conducted with providers from two Chicagoland NHs. Focus group sessions and interviews were transcribed, coded, and analyzed for common themes based on qualitative description method. RESULTS: All study participants agreed that providers have the ultimate responsibility for hospitalization decisions. However, nurses believed they could influence those decisions, depending on provider characteristics, trust, and resident conditions. Nurses and providers differed in the way they experienced and conveyed emotions, and differed in key elements affecting hospitalization decisions such as structural or environmental factors (e.g., lacking staff and equipment at the facility, poor communication between the NH and hospitals) and interpersonal factors (e.g., characteristics of effective nurses or providers and the effective interactions between them). CONCLUSIONS: Interpersonal factors, including perceived competence, respect, and trust, may influence NH hospitalization decisions and be targeted for reducing preventable hospitalizations of residents.

Call me maybe? In-person vs. teletherapy outcomes among married couples.

ABSTRACTObjective: The objective of this study was to investigate the effectiveness of teletherapy compared to in-person couple therapy in outcomes such as couple satisfaction, sexual satisfaction, and the therapeutic alliance.Method: Data from 1157 married clients seeking couple therapy were examined. Individual growth curve models were used to analyze changes in the aforementioned outcomes, with teletherapy as a predictor. The study also examined client age and clinic type as moderators.Results: The results indicated that overall, teletherapy is as effective as in-person therapy in improving outcomes. However, there were notable differences in the development of the therapeutic alliance. The alliance improved at twice the rate in in-person therapy as in teletherapy. Clinic type was also found to be a moderator of changes in sexual satisfaction. Clients in group and private practices reported improvements in sexual satisfaction; whereas clients seen in training clinics reported decreases in sexual satisfaction.Conclusion: The study concludes that although teletherapy may be a viable alternative to in-person couple therapy, there are nevertheless differences in the development of the therapeutic alliance that warrant care and further investigation. The setting of the therapy also plays a role in the effectiveness of therapy, although not specific to therapy modality.

A case report of granulomatous lymphomatoid papulosis.

Lymphomatoid papulosis is a chronic CD30-positive cutaneous lymphoproliferative disorder that is characterized by recurring red-brown necrotic papules. It exhibits a wide spectrum of histopathologic findings and is often associated with cutaneous T-cell lymphomas. Six different histological subtypes have been classified by the WHO, but there is limited understanding regarding rare histopathologic variants. We describe a 51-year-old man who presented with recurring, necrotic papules for 6 years that progressed to involve the face, scalp, trunk, axilla, and scrotum. Histopathology demonstrated sarcoidal granulomas, along with a CD30-positive T cell infiltrate which demonstrated clonality by T cell receptor gamma gene rearrangement. A diagnosis of lymphomatoid papulosis associated with granulomas was established based on the clinical and histopathologic presentation. The clinical understanding of granulomatous lymphomatoid papulosis is limited in the available literature and more awareness of this histopathologic variant is required for accurate classification of this disorder.

Effects of Small Molecule Ligands on ACKR3 Receptors.

Chemokines such as stromal derived factor 1 and their G protein coupled receptors are well-known regulators of the development and functions of numerous tissues. C-X-C motif chemokine ligand 12 (CXCL12) has two receptors: C-X-C chemokine motif receptor 4 (CXCR4) and atypical chemokine receptor 3 (ACKR3). ACKR3 has been described as an atypical "biased" receptor because it does not appear to signal through G proteins and, instead, signals solely through the ß-arrestin pathway. In support of this conclusion, we have shown that ACKR3 is unable to signal through any of the known mammalian G α isoforms and have generated a comprehensive map of the G α activation by CXCL12/CXCR4. We also synthesized a series of small molecule ligands which acted as selective agonists for ACKR3 as assessed by their ability to recruit ß-arrestin to the receptor. Using select point mutations, we studied the molecular characteristics that determine the ability of small molecules to activate ACKR3 receptors, revealing a key role for the deeper binding pocket composed of residues in the transmembrane domains of ACKR3. The development of more selective ACKR3 ligands should allow us to better appreciate the unique roles of ACKR3 in the CXCL12/CXCR4/ACKR3-signaling axis and better understand the structural determinants for ACKR3 activation. SIGNIFICANCE STATEMENT: We are interested in the signaling produced by the G protein coupled receptor atypical chemokine receptor 3 (ACKR3), which signals atypically. In this study, novel selective ligands for ACKR3 were discovered and the site of interactions between these small molecules and ACKR3 was defined. This work will help to better understand the unique signaling roles of ACKR3.

High Dimensional Multiomics Reveals Unique Characteristics of Early Plasma Administration in Polytrauma Patients With TBI.

OBJECTIVES: The authors sought to identify causal factors that explain the selective benefit of prehospital administration of thawed plasma (TP) in traumatic brain injury (TBI) patients using mediation analysis of a multiomic database. BACKGROUND: The Prehospital Air Medical Plasma (PAMPer) Trial showed that patients with TBI and a pronounced systemic response to injury [defined as endotype 2 (E2)], have a survival benefit from prehospital administration of TP. An interrogation of high dimensional proteomics, lipidomics and metabolomics previously demonstrated unique patterns in circulating biomarkers in patients receiving prehospital TP, suggesting that a deeper analysis could reveal causal features specific to TBI patients. METHODS: A novel proteomic database (SomaLogic Inc., aptamer-based assay, 7K platform) was generated using admission blood samples from a subset of patients (n=149) from the PAMPer Trial. This proteomic dataset was combined with previously reported metabolomic and lipidomic datasets from these same patients. A 2-step analysis was performed to identify factors that promote survival in E2-TBI patients who had received early TP. First, features were selected using both linear and multivariate-latent-factor regression analyses. Then, the selected features were entered into the causal mediation analysis. RESULTS: Causal mediation analysis of observable features identified 16 proteins and 41 lipids with a high proportion of mediated effect (>50%) to explain the survival benefit of early TP in E2-TBI patients. The multivariate latent-factor regression analyses also uncovered 5 latent clusters of features with a proportion effect >30%, many in common with the observable features. Among the observable and latent features were protease inhibitors known to inhibit activated protein C and block fibrinolysis (SERPINA5 and CPB2), a clotting factor (factor XI), as well as proteins involved in lipid transport and metabolism (APOE3 and sPLA(2)-XIIA). CONCLUSIONS: These findings suggest that severely injured patients with TBI process exogenous plasma differently than those without TBI. The beneficial effects of early TP in E2-TBI patients may be the result of improved blood clotting and the effect of brain protective factors independent of coagulation.

Placental Iron Content Is Lower than Previously Estimated and Is Associated with Maternal Iron Status in Women at Greater Risk of Gestational Iron Deficiency and Anemia.

BACKGROUND: Based on limited data, it is estimated that the placenta retains 90 mg of iron. Little is known about determinants of placental iron content. Animal data indicate that the placenta prioritizes iron for its own needs, but this hypothesis has not been evaluated in humans. OBJECTIVES: To characterize placental iron content and placental iron concentration (p[Fe]) in pregnant women at risk of iron insufficiency and identify determinants of p[Fe]. METHODS: Placentas were collected from 132 neonates born to teens carrying singletons (≤18 y) and 101 neonates born to 48 women carrying multiples (20-46 y). Maternal and neonatal iron status indicators [hemoglobin, serum ferritin (SF), soluble transferrin receptor (sTfR), serum iron, total body iron (TBI)] and hormones (erythropoietin, hepcidin) were measured. p[Fe] was measured using inductively coupled plasma-mass spectrometry. Correlation analyses and mixed-effects models were constructed to identify determinants of p[Fe]. RESULTS: Mean placental iron content was 23 mg per placenta (95% CI: 15, 33 mg) in the multiples and 40 mg (95% CI: 31, 51 mg) in the teens (P = 0.03). Mean p[Fe] did not differ between the cohorts. p[Fe] was higher in anemic (175 µg/g; 95% CI: 120, 254 µg/g) compared with nonanemic (46 µg/g; 95% CI: 26, 82 µg/g) women carrying multiples (P = 0.009), but did not differ between anemic (62 µg/g; 95% CI: 40, 102 µg/g) and nonanemic (73 µg/g; 95% CI: 56, 97 µg/g) teens. In women carrying multiples, low maternal iron status [lower SF (P = 0.002) and lower TBI (P = 0.01)] was associated with higher p[Fe], whereas in teens, improved iron status [lower sTfR (P = 0.03) and higher TBI (P = 0.03)] was associated with higher p[Fe]. CONCLUSIONS: Placental iron content was ∼50% lower than previously estimated. p[Fe] is significantly associated with maternal iron status. In women carrying multiples, poor maternal iron status was associated with higher p[Fe], whereas in teens, improved iron status was associated with higher p[Fe]. More data are needed to understand determinants of p[Fe] and the variable iron partitioning in teens compared with mature women.

Rapamycin, Acarbose and 17α-estradiol share common mechanisms regulating the MAPK pathways involved in intracellular signaling and inflammation.

BACKGROUND: Rapamycin (Rapa), acarbose (ACA), and 17α-estradiol (17aE2, males only) have health benefits that increase lifespan of mice. Little is known about how these three agents alter the network of pathways downstream of insulin/IGF1 signals as well as inflammatory/stress responses. RESULTS: ACA, Rapa, and 17aE2 (in males, but not in females) oppose age-related increases in the MEK1- ERK1/2-MNK1/2 cascade, and thus reduce phosphorylation of eIF4E, a key component of cap-dependent translation. In parallel, these treatments (in both sexes) reduce age-related increases in the MEK3-p38MAPK-MK2 pathway, to decrease levels of the acute phase response proteins involved in inflammation. CONCLUSION: Each of three drugs converges on the regulation of both the ERK1/2 signaling pathway and the p38-MAPK pathway. The changes induced by treatments in ERK1/2 signaling are seen in both sexes, but the 17aE2 effects are male-specific, consistent with the effects on lifespan. However, the inhibition of age-dependent p38MAPK pathways and acute phase responses is triggered in both sexes by all three drugs, suggesting new approaches to prevention or reversal of age-related inflammatory changes in a clinical setting independent of lifespan effects.

signatureSearch: environment for gene expression signature searching and functional interpretation.

signatureSearch is an R/Bioconductor package that integrates a suite of existing and novel algorithms into an analysis environment for gene expression signature (GES) searching combined with functional enrichment analysis (FEA) and visualization methods to facilitate the interpretation of the search results. In a typical GES search (GESS), a query GES is searched against a database of GESs obtained from large numbers of measurements, such as different genetic backgrounds, disease states and drug perturbations. Database matches sharing correlated signatures with the query indicate related cellular responses frequently governed by connected mechanisms, such as drugs mimicking the expression responses of a disease. To identify which processes are predominantly modulated in the GESS results, we developed specialized FEA methods combined with drug-target network visualization tools. The provided analysis tools are useful for studying the effects of genetic, chemical and environmental perturbations on biological systems, as well as searching single cell GES databases to identify novel network connections or cell types. The signatureSearch software is unique in that it provides access to an integrated environment for GESS/FEA routines that includes several novel search and enrichment methods, efficient data structures, and access to pre-built GES databases, and allowing users to work with custom databases.