Broadly effective metabolic and immune recovery with C5 inhibition in CHAPLE disease.

Complement hyperactivation, angiopathic thrombosis and protein-losing enteropathy (CHAPLE disease) is a lethal disease caused by genetic loss of the complement regulatory protein CD55, leading to overactivation of complement and innate immunity together with immunodeficiency due to immunoglobulin wasting in the intestine. We report in vivo human data accumulated using the complement C5 inhibitor eculizumab for the medical treatment of patients with CHAPLE disease. We observed cessation of gastrointestinal pathology together with restoration of normal immunity and metabolism. We found that patients rapidly renormalized immunoglobulin concentrations and other serum proteins as revealed by aptamer profiling, re-established a healthy gut microbiome, discontinued immunoglobulin replacement and other treatments and exhibited catch-up growth. Thus, we show that blockade of C5 by eculizumab effectively re-establishes regulation of the innate immune complement system to substantially reduce the pathophysiological manifestations of CD55 deficiency in humans.

The Plasma Proteome Fingerprint Associated with Circulating Carotenoids and Retinol in Older Adults.

BACKGROUND: Although diets rich in carotenoids are associated with reduced risks of cardiovascular disease, age-related macular degeneration, disability, and other adverse aging outcomes, the underlying biological mechanisms are not fully elucidated. OBJECTIVES: To characterize the plasma proteome fingerprint associated with circulating carotenoid and retinol concentrations in older adults. METHODS: In 728 adults ≥65 y participating in the Invecchiare in Chianti (InCHIANTI) Study, plasma α-carotene, ß-carotene, ß-cryptoxanthin, lutein, zeaxanthin, and lycopene were measured using HPLC. The SOMAscan assay was used to measure 1301 plasma proteins. Multivariable linear regression models were used to examine the relationship of individual carotenoids and retinol with plasma proteins. A false discovery rate approach was used to deal with multiple comparisons using a q-value < 0.05. RESULTS: Plasma ß-carotene, ß-cryptoxanthin, lutein, zeaxanthin, and lycopene were associated with 85, 39, 4, 2, and 5 plasma proteins, respectively, in multivariable linear regression models adjusting for potential confounders (q < 0.05). No proteins were associated with α-carotene or retinol. Two or more carotenoids were positively associated with ferritin, 6-phosphogluconate dehydrogenase (decarboxylating), hepcidin, thrombospondin-2, and choline/ethanolamine kinase. The proteins associated with circulating carotenoids were related to energy metabolism, sirtuin signaling, inflammation and oxidative stress, iron metabolism, proteostasis, innate immunity, and longevity. CONCLUSIONS: The plasma proteomic fingerprint associated with elevated circulating carotenoids in older adults provides insight into the mechanisms underlying the protective role of carotenoids on health.

Prior psychosocial profile and perceived impact of the COVID-19 pandemic: insights from the Baltimore Longitudinal Study of Aging.

Stress, social isolation, and changes in health behaviors during the COVID-19 pandemic period may have a lasting influence on health. Here, the correlation between current or prior demographic, social and health related characteristics, including psychosocial factors with perceived impact of the COVID-19 pandemic assessed by questionnaire during the early pandemic period is evaluated among 770 participants of the Baltimore Longitudinal Study of Aging. In multinomial logistic regression models participants with higher pre-pandemic personal mastery, a construct related to self-efficacy, were more likely to report "both positive and negative" impact of the pandemic than a solely "negative" impact (OR: 2.17, 95% CI: 1.29-3.65). Higher perceived stress and frequent contact with family prior to the pandemic were also associated with pandemic impact. These observations highlight the relevance of psychosocial factors in the COVID-19 pandemic experience and identify characteristics that may inform interventions in future public health crises.

Colchicine's effects on metabolic and inflammatory molecules in adults with obesity and metabolic syndrome: results from a pilot randomized controlled trial.

OBJECTIVE: Recent clinical trials have demonstrated that colchicine may have metabolic and cardiovascular and benefits in at-risk patients; however, the mechanisms through which colchicine may improve outcomes are still unclear. We sought to examine colchicine's effects on circulating inflammatory and metabolic molecules in adults with obesity and metabolic syndrome (MetS). METHODS: Blood samples were collected pre- and post-intervention during a double-blind randomized controlled trial in which 40 adults with obesity and MetS were randomized to colchicine 0.6 mg or placebo twice-daily for 3 months. Serum samples were analyzed for 1305 circulating factors using the SomaScan Platform. The Benjamini-Hochberg procedure was used to adjust the false discovery rate (FDR) for multiple testing. RESULTS: At baseline, age (48.0 ± 13.8 vs. 44.7 ± 10.3 years) and BMI (39.8 ± 6.4 vs. 41.8 ± 8.2 kg/m2) were not different between groups. After controlling for the FDR, 34 molecules were significantly changed by colchicine. Colchicine decreased concentrations of multiple inflammatory molecules, including C-reactive protein, interleukin 6, and resistin, in addition to vascular-related proteins (e.g., oxidized low-density lipoprotein receptor, phosphodiesterase 5A). Conversely, relative to placebo, colchicine significantly increased concentrations of eight molecules including secreted factors associated with metabolism and anti-thrombosis. CONCLUSIONS: In adults with obesity, colchicine significantly affected concentrations of proteins involved in the innate immune system, endothelial function and atherosclerosis, uncovering new mechanisms behind its cardiometabolic effects. Further research is warranted to investigate whether colchicine's IL-6 suppressive effects may be beneficial in COVID-19.

A Plasma Proteomic Signature of Skeletal Muscle Mitochondrial Function.

Although mitochondrial dysfunction has been implicated in aging, physical function decline, and several age-related diseases, an accessible and affordable measure of mitochondrial health is still lacking. In this study we identified the proteomic signature of muscular mitochondrial oxidative capacity in plasma. In 165 adults, we analyzed the association between concentrations of plasma proteins, measured using the SOMAscan assay, and skeletal muscle maximal oxidative phosphorylation capacity assessed as post-exercise phosphocreatine recovery time constant (τPCr) by phosphorous magnetic resonance spectroscopy. Out of 1301 proteins analyzed, we identified 87 proteins significantly associated with τPCr, adjusting for age, sex, and phosphocreatine depletion. Sixty proteins were positively correlated with better oxidative capacity, while 27 proteins were correlated with poorer capacity. Specific clusters of plasma proteins were enriched in the following pathways: homeostasis of energy metabolism, proteostasis, response to oxidative stress, and inflammation. The generalizability of these findings would benefit from replication in an independent cohort and in longitudinal analyses.

Impact of Influenza A Virus Infection on the Proteomes of Human Bronchoepithelial Cells from Different Donors.

Susceptibility to influenza A virus is determined by a balance of viral and host factors. The genetic background of the host contributes to the severity of disease, but the influenza-related proteomes of cells from different individuals have not been compared. We used high-resolution mass spectrometry to identify proteins in normal human bronchial epithelial (NHBE) cells isolated from three different donors. Infection of each NHBE cell culture with influenza A/California/07/2009 (H1N1) resulted in expression of viral proteins and a variety of host proteins, including interferons, interferon-stimulated genes, and secreted chemokines/cytokines. The expression level of viral proteins corresponded to the level of host proteins that support influenza infection (i.e., pro-viral proteins); however, production of infectious virus was inversely related to the levels of antiviral proteins, suggesting that a balance of pro-viral proteins and the antiviral response controls virus replication. In summary, our results demonstrate that expression levels of pro-viral as well as antiviral factors are different for each donor and suggest that relative quantitation of these factors may provide a way to identify individuals or population groups who are susceptible to severe influenza disease.

Comparative Efficacy of Monoclonal Antibodies That Bind to Different Epitopes of the 2009 Pandemic H1N1 Influenza Virus Neuraminidase.

UNLABELLED: Antibodies against the neuraminidase (NA) of influenza virus correlate with resistance against disease, but the effectiveness of antibodies against different NA epitopes has not been compared. In the present study, we evaluated the in vitro and in vivo efficacies of four monoclonal antibodies (MAbs): HF5 and CD6, which are specific to two different epitopes in the NA of 2009 pandemic H1N1 (pH1N1) virus, and 4E9 and 1H5, which are specific to a conserved epitope in the NA of both H1N1 and H5N1 viruses. In the in vitro assays, HF5 and CD6 inhibited virus spread and growth more effectively than 4E9 and 1H5, with HF5 being the most effective inhibitor. When administered prophylactically at 5 mg/kg of body weight, HF5 and CD6 protected ~90 to 100% of DBA/2 mice against lethal wild-type pH1N1 virus challenge; however, at a lower dose (1 mg/kg), HF5 protected ~90% of mice, whereas CD6 protected only 25% of mice. 4E9 and 1H5 were less effective than HF5 and CD6, as indicated by the partial protection achieved even at doses as high as 15 mg/kg. When administered therapeutically, HF5 protected a greater proportion of mice against lethal pH1N1 challenge than CD6. However, HF5 quickly selected pH1N1 virus escape mutants in both prophylactic and therapeutic treatments, while CD6 did not. Our findings confirm the important role of NA-specific antibodies in immunity to influenza virus and provide insight into the properties of NA antibodies that may serve as good candidates for therapeutics against influenza. IMPORTANCE: Neuraminidase (NA) is one of the major surface proteins of influenza virus, serving as an important target for antivirals and therapeutic antibodies. The impact of NA-specific antibodies on NA activity and virus replication is likely to depend on where the antibody binds. Using in vitro assays and the mouse model, we compared the inhibitory/protective efficacy of four mouse monoclonal antibodies (MAbs) that bind to different sites within the 2009 pandemic H1N1 (pH1N1) virus NA. The ability of each MAb to protect mice against lethal pH1N1 infection corresponded to its ability to inhibit NA activity in vitro; however, the MAb that was the most effective inhibitor of NA activity selected pH1N1 escape variants in vivo. One of the tested MAbs, which binds to a conserved region in the NA of pH1N1 virus, inhibited NA activity but did not result in escape variants, highlighting its suitability for development as a therapeutic agent.

Sequencing and characterization of the complete mitochondrial genomes of three Pneumocystis species provide new insights into divergence between human and rodent Pneumocystis.

Pneumocystis jirovecii is an important opportunistic pathogen associated with AIDS and other immunodeficient conditions. Currently, very little is known about its nuclear and mitochondrial genomes. In this study, we sequenced the complete mitochondrial genome (mtDNA) of this organism and its closely related species Pneumocystis carinii and Pneumocystis murina by a combination of sequencing technologies. Our study shows that P. carinii and P. murina mtDNA share a nearly identical number and order of genes in a linear configuration, whereas P. jirovecii has a circular mtDNA containing nearly the same set of genes but in a different order. Detailed studies of the mtDNA terminal structures of P. murina and P. carinii suggest a unique replication mechanism for linear mtDNA. Phylogenetic analysis supports a close association of Pneumocystis species with Taphrina, Saitoella, and Schizosaccharomyces, and divergence within Pneumocystis species, with P. murina and P. carinii being more closely related to each other than either is to P. jirovecii. Comparative analysis of four complete P. jirovecii mtDNA sequences in this study and previously reported mtDNA sequences for diagnosing and genotyping suggests that the current diagnostic and typing methods can be improved using the complete mtDNA data. The availability of the complete P. jirovecii mtDNA also opens the possibility of identifying new therapeutic targets.

The emotional states and associated behavioral responses (flexible-adaptive behaviors vs. inflexible-maladaptive behaviors) of cancer patients during the SARS-CoV-2 outbreak: A multi-center cross-sectional study in Italy.

OBJECTIVE: Distress during SARS-CoV-2 outbreak affected also cancer patients' well-being. Aim of this study was to investigate patient' reactions and behavior (flexible-adaptive vs. inflexible-maladaptive) during the SARS-CoV-2 outbreak. METHODS: A cross-sectional survey was designed with a self-report questionnaire, "the ImpACT questionnaire," developed for the study. Regression analysis was performed on data. RESULTS: Four hundred and forty five cancer patients from 17 Italian regions participated in the study. 79.8% of participants were female (mean age of 58 years). 92.6% of participants reported feeling vulnerable to COVID-19 contagion; 75.6% reported helpless, 62.7% sad, 60.4% anxious, and 52.0% anger. Avoidance of thinking about coronavirus is the principal maladaptive behavior that emerged. Participants who reported feeling anxious were more likely to have fear of staff being infected with COVID-19 (OR = 3.01; 95% CI = 1.49-6.30) and to have disrupted sleep due to worry (OR = 2.42; 95% CI = 1.23-4.83). Younger participants reported more anxiety (OR = 0.97; 95% CI = 0.94-1.00); men reported feeling calm more than women (OR = 2.60; 95% CI = 1.27-5.43). CONCLUSIONS: Majority of cancer patients reported serious concerns regarding SARS-CoV-2 infection; reliable information and psychological support must be offers to respond to these needs.

Cross-sectional analysis of healthy individuals across decades: Aging signatures across multiple physiological compartments.

The study of age-related biomarkers from different biofluids and tissues within the same individual might provide a more comprehensive understanding of age-related changes within and between compartments as these changes are likely highly interconnected. Understanding age-related differences by compartments may shed light on the mechanism of their reciprocal interactions, which may contribute to the phenotypic manifestations of aging. To study such possible interactions, we carried out a targeted metabolomic analysis of plasma, skeletal muscle, and urine collected from healthy participants, age 22-92 years, and identified 92, 34, and 35 age-associated metabolites, respectively. The metabolic pathways that were identified across compartments included inflammation and cellular senescence, microbial metabolism, mitochondrial health, sphingolipid metabolism, lysosomal membrane permeabilization, vascular aging, and kidney function.

Association of Plasma Markers of Alzheimer's Disease, Neurodegeneration, and Neuroinflammation with the Choroid Plexus Integrity in Aging.

The choroid plexus (CP) is a vital brain structure essential for cerebrospinal fluid (CSF) production. Moreover, alterations in the CP's structure and function are implicated in molecular conditions and neuropathologies including multiple sclerosis, Alzheimer's disease, and stroke. Our goal is to provide the first characterization of the association between variation in the CP microstructure and macrostructure/volume using advanced magnetic resonance imaging (MRI) methodology, and blood-based biomarkers of Alzheimer's disease (Aß42/40 ratio; pTau181), neuroinflammation and neuronal injury (GFAP; NfL). We hypothesized that plasma biomarkers of brain pathology are associated with disordered CP structure. Moreover, since cerebral microstructural changes can precede macrostructural changes, we also conjecture that these differences would be evident in the CP microstructural integrity. Our cross-sectional study was conducted on a cohort of 108 well-characterized individuals, spanning 22-94 years of age, after excluding participants with cognitive impairments and non-exploitable MR imaging data. Established automated segmentation methods were used to identify the CP volume/macrostructure using structural MR images, while the microstructural integrity of the CP was assessed using our advanced quantitative high-resolution MR imaging of longitudinal and transverse relaxation times (T1 and T2). After adjusting for relevant covariates, positive associations were observed between pTau181, NfL and GFAP and all MRI metrics. These associations reached significance (p<0.05) except for CP volume vs. pTau181 (p=0.14), CP volume vs. NfL (p=0.35), and T2 vs. NFL (p=0.07). Further, negative associations between Aß42/40 and all MRI metrics were observed but reached significance only for Aß42/40 vs. T2 (p=0.04). These novel findings demonstrate that reduced CP macrostructural and microstructural integrity is positively associated with blood-based biomarkers of AD pathology, neurodegeneration/neuroinflammation and neurodegeneration. Degradation of the CP structure may co-occur with AD pathology and neuroinflammation ahead of clinically detectable cognitive impairment, making the CP a potential structure of interest for early disease detection or treatment monitoring.

A unified metric of human immune health.

Immunological health has been challenging to characterize but could be defined as the absence of immune pathology. While shared features of some immune diseases and the concept of immunologic resilience based on age-independent adaptation to antigenic stimulation have been developed, general metrics of immune health and its utility for assessing clinically healthy individuals remain ill defined. Here we integrated transcriptomics, serum protein, peripheral immune cell frequency and clinical data from 228 patients with 22 monogenic conditions impacting key immunological pathways together with 42 age- and sex-matched healthy controls. Despite the high penetrance of monogenic lesions, differences between individuals in diverse immune parameters tended to dominate over those attributable to disease conditions or medication use. Unsupervised or supervised machine learning independently identified a score that distinguished healthy participants from patients with monogenic diseases, thus suggesting a quantitative immune health metric (IHM). In ten independent datasets, the IHM discriminated healthy from polygenic autoimmune and inflammatory disease states, marked aging in clinically healthy individuals, tracked disease activities and treatment responses in both immunological and nonimmunological diseases, and predicted age-dependent antibody responses to immunizations with different vaccines. This discriminatory power goes beyond that of the classical inflammatory biomarkers C-reactive protein and interleukin-6. Thus, deviations from health in diverse conditions, including aging, have shared systemic immune consequences, and we provide a web platform for calculating the IHM for other datasets, which could empower precision medicine.

Proteomic Mediators of Overall Cardiovascular Health on All-Cause Mortality.

Measures of cardiovascular health (CVH) assessed by a combination of behavioral and biological factors has shown protective associations with all-cause mortality. The mechanisms underlying these associations have not been fully elucidated. In this study, we characterized the plasma proteomics profile of CVH and tested whether specific proteins mediated the associations between CVH and all-cause mortality in participants of the InCHIANTI study. Of the 1301 proteins tested, 92 proteins were associated with CVH (22 positively, 70 negatively). Proteins most strongly associated with CVH included leptin (LEP), fatty acid binding protein 3 (FABP3), Angiopoietin-2 (ANGPT2), and growth-differential factor 15 (GDF15). Of the 92 CVH-associated proteins, 33 proteins significantly mediated the associations between CVH and all-cause mortality, with percent mediation ranging from 5 to 30%. The most significant mediating proteins were GDF15 and insulin-like growth factor 2 (IGFBP2). Proteins associated with better CVH were enriched for proteins that reflect the suppression of the complement coagulation and GH/IGF pathways.

Human Metabolome Reference Database in a Biracial Cohort across the Adult Lifespan.

As one of the OMICS in systems biology, metabolomics defines the metabolome and simultaneously quantifies numerous metabolites that are final or intermediate products and effectors of upstream biological processes. Metabolomics provides accurate information that helps determine the physiological steady state and biochemical changes during the aging process. To date, reference values of metabolites across the adult lifespan, especially among ethnicity groups, are lacking. The "normal" reference values according to age, sex, and race allow the characterization of whether an individual or a group deviates metabolically from normal aging, encompass a fundamental element in any study aimed at understanding mechanisms at the interface between aging and diseases. In this study, we established a metabolomics reference database from 20-100 years of age from a biracial sample of community-dwelling healthy men and women and examined metabolite associations with age, sex, and race. Reference values from well-selected healthy individuals can contribute to clinical decision-making processes of metabolic or related diseases.

Cerebrospinal fluid exploratory proteomics and ketamine metabolite pharmacokinetics in human volunteers after ketamine infusion.

Ketamine is a treatment for both refractory depression and chronic pain syndromes. In order to explore ketamine's potential mechanism of action and whether ketamine or its metabolites cross the blood brain barrier, we examined the pharmacokinetics of ketamine and its metabolites-norketamine (NK), dehydronorketamine (DHNK), and hydroxynorketamines (HNKs)-in cerebrospinal fluid (CSF) and plasma, as well as in an exploratory proteomic analysis in the CSF of nine healthy volunteers who received ketamine intravenously (0.5 mg/kg IV). We found that ketamine, NK, and (2R,6R;2S,6S)-HNK readily crossed the blood brain barrier. Additionally, 354 proteins were altered in the CSF in at least two consecutive timepoints (p < 0.01). Proteins in the classes of tyrosine kinases, cellular adhesion molecules, and growth factors, including insulin, were most affected, suggesting an interplay of altered neurotransmission, neuroplasticity, neurogenesis, synaptogenesis, and neural network functions following ketamine administration.

Multiomics integration of 22 immune-mediated monogenic diseases reveals an emergent axis of human immune health.

Monogenic diseases are often studied in isolation due to their rarity. Here we utilize multiomics to assess 22 monogenic immune-mediated conditions with age- and sex-matched healthy controls. Despite clearly detectable disease-specific and "pan-disease" signatures, individuals possess stable personal immune states over time. Temporally stable differences among subjects tend to dominate over differences attributable to disease conditions or medication use. Unsupervised principal variation analysis of personal immune states and machine learning classification distinguishing between healthy controls and patients converge to a metric of immune health (IHM). The IHM discriminates healthy from multiple polygenic autoimmune and inflammatory disease states in independent cohorts, marks healthy aging, and is a pre-vaccination predictor of antibody responses to influenza vaccination in the elderly. We identified easy-to-measure circulating protein biomarker surrogates of the IHM that capture immune health variations beyond age. Our work provides a conceptual framework and biomarkers for defining and measuring human immune health.

Proteins in the pathway from high red blood cell width distribution to all-cause mortality.

BACKGROUND: The pathophysiological mechanisms underlying the association between red blood cell distribution width (RDW) and all-cause mortality are unknown. We conducted a data-driven discovery investigation to identify plasma proteins that mediate the association between RDW and time to death in community-dwelling adults. METHODS: At baseline, 962 adults (women, 54·4%; age range, 21-98 years) participated in the InCHIANTI, "Aging in the Chianti Area" study, and proteomics data were generated from their plasma specimens. Of these, 623 participants had proteomics data available at the 9-year follow-up. For each visit, a total of 1301 plasma proteins were measured using SOMAscan technology. Complete data on vital status were available up to the 15-year follow-up period. Protein-specific exponential distribution accelerated failure time, and linear regression analyses adjusted for possible covariates were used for mortality and mediation analyses, respectively (survival data analysis). FINDINGS: Baseline values of EGFR, GHR, NTRK3, SOD2, KLRF1, THBS2, TIMP1, IGFBP2, C9, APOB, and LRP1B mediated the association between baseline RDW and all-cause mortality. Changes in IGFBP2 and C7 over 9 years mediated the association between changes in RDW and 6-year all-cause mortality. INTERPRETATION: Cellular senescence may contribute to the association between RDW and mortality. FUNDING: This study was funded by grants from the National Institutes of Health (NIH) and the National Institute on Aging (NIA) contract and was supported by the Intramural Research Program of the NIA, NIH. The InCHIANTI study was supported as a 'targeted project' by the Italian Ministry of Health and in part by the U.S. NIA.

Plasma Growth and Differentiation Factor 15 Predict Longitudinal Changes in Bone Parameters in Women, but Not in Men.

Bone fragility can progress with aging, but biomarkers to detect emerging osteopenia have not been fully elucidated. Growth/differentiation factor 15 (GDF-15) has pleiotropic roles in a broad range of age-related conditions, but its association with osteopenia is unknown. We examined the relationship between plasma GDF-15 levels and rate of change in bone parameters over 9 years of follow-up in 596 adults in the InCHIANTI study (baseline age, 65-94 years; women, 52.4%; mean follow-up, 7.0 ± 3.0 years). Plasma GDF-15 concentrations were measured using the 1.3k HTS SOMAscan assay. Eight bone parameters were measured in the right tibia by peripheral quantitative computed tomography; total bone density, trabecular bone density, medullary plus trabecular bone density, cortical bone density, total bone area, cortical bone area, medullary bone area, and minimum moment of inertia (mMOI). We ran sex-specific linear mixed-effect models with random intercepts and slopes adjusted for age, age-squared, education, body mass index, the rate of change in weight, smoking, sedentary behavior, cross-sectional areas of calf muscles and fat, 25-hydroxyvitamin D, parathyroid hormone, calcium, diabetes mellitus, and follow-up time. We found a significant association of "baseline GDF-15 × time" in models predicting cortical bone density and the mMOI in women, suggesting that the rates of decline in these bone parameters increased with higher GDF-15 (false discovery rate <0.05). Higher plasma levels GDF-15 predicted an accelerated decline in bone parameters in women, but was less associated in men. Furthermore studies are needed to understand the mechanisms underlying these sex differences.

Effects of colchicine on lipolysis and adipose tissue inflammation in adults with obesity and metabolic syndrome.

OBJECTIVE: The aim of this study was to examine whether colchicine's anti-inflammatory effects would improve measures of lipolysis and distribution of leukocyte populations in subcutaneous adipose tissue (SAT). METHODS: A secondary analysis was conducted for a double-blind, randomized, placebo-controlled pilot study in which 40 adults with obesity and metabolic syndrome (MetS) were randomized to colchicine 0.6 mg or placebo twice daily for 3 months. Non-insulin-suppressible (l0 ), insulin-suppressible (l2 ), and maximal (l0 +l2 ) lipolysis rates were calculated by minimal model analysis. Body composition was determined by dual-energy x-ray absorptiometry. SAT leukocyte populations were characterized by flow cytometry analysis from biopsied samples obtained before and after the intervention. RESULTS: Colchicine treatment significantly decreased l2 and l0 +l2 versus placebo (p < 0.05). These changes were associated with a significant reduction in markers of systemic inflammation, including high-sensitivity C-reactive protein, resistin, and circulating monocytes and neutrophils (p < 0.01). Colchicine did not significantly alter SAT leukocyte population distributions (p > 0.05). CONCLUSIONS: In adults with obesity and MetS, colchicine appears to improve insulin regulation of lipolysis and reduce markers of systemic inflammation independent of an effect on local leukocyte distributions in SAT. Further studies are needed to better understand the mechanisms by which colchicine affects adipose tissue metabolic pathways in adults with obesity and MetS.

Characterization of the meiosis-specific recombinase Dmc1 of pneumocystis.

The life cycle of Pneumocystis, which causes life-threatening pneumonia in immunosuppressed patients, remains poorly defined. In the present study, we have identified and characterized an orthologue of dmc1, a gene specific for meiotic recombination in yeast, in 3 species of Pneumocystis. dmc1 is a single-copy gene that is transcribed as ∼1.2-kb messenger RNA, which encodes a protein of 336-337 amino acids. Pneumocystis Dmc1 was 61%-70% identical to those from yeast. Confocal microscopy results indicated that the expression of Dmc1 is primarily confined to the cyst form of Pneumocystis. By sequence analysis of 2 single-copy regions of the human Pneumocystis jirovecii genome, we can infer multiple recombination events, which are consistent with meiotic recombination in this primarily haploid organism. Taken together, these studies support the occurrence of a sexual phase in the life cycle of Pneumocystis.