Sex hormones regulate metainflammation in diet-induced obesity in mice.

Men have a statistically higher risk of metabolic and cardiovascular disease than premenopausal women, but the mechanisms mediating these differences are elusive. Chronic inflammation during obesity contributes to disease risk and is significantly more robust in males. Prior work demonstrated that compared with obese males, obese females have reduced proinflammatory adipose tissue macrophages (ATMs). Given the paucity of data on how sex hormones contribute to macrophage responses in obesity, we sought to understand the role of sex hormones in promoting obesity-induced myeloid inflammation. We used gonadectomy, estrogen receptor-deficient alpha chimeras, and androgen-insensitive mice to model sex hormone deficiency. These models were evaluated in diet-induced obesity conditions (high-fat diet [HFD]) and in vitro myeloid assays. We found that ovariectomy increased weight gain and adiposity. Ovariectomized females had increased ATMs and bone marrow myeloid colonies compared with sham-gonadectomized females. In addition, castrated males exposed to HFD had improved glucose tolerance, insulin sensitivity, and adiposity with fewer Ly6chi monocytes and bone marrow myeloid colonies compared with sham-gonadectomized males, although local adipose inflammation was enhanced. Similar findings were observed in androgen-insensitive mice; however, these mice had fewer CD11c+ ATMs, implying a developmental role for androgens in myelopoiesis and adipose inflammation. We concluded that gonadectomy results in convergence of metabolic and inflammatory responses to HFD between the sexes, and that myeloid estrogen receptor alpha contributes minimally to diet-induced inflammatory responses, whereas loss of androgen-receptor signaling improves metabolic and inflammatory outcomes. These studies demonstrate that sex hormones play a critical role in sex differences in obesity, metabolic dysfunction, and myeloid inflammation.

Stability of Saxitoxin in 50% Methanol Fecal Extracts and Raw Feces from Bowhead Whales (Balaena mysticetus).

In recent decades, harmful algal blooms (HABs) producing paralytic shellfish toxins (including saxitoxin, STX) have become increasingly frequent in the marine waters of Alaska, USA, subjecting Pacific Arctic and subarctic communities and wildlife to increased toxin exposure risks. Research on the risks of HAB toxin exposures to marine mammal health commonly relies on the sampling of marine mammal gastrointestinal (GI) contents to quantify HAB toxins, yet no studies have been published testing the stability of STX in marine mammal GI matrices. An understanding of STX stability in test matrices under storage and handling conditions is imperative to the integrity of toxin quantifications and conclusions drawn thereby. Here, STX stability is characterized in field-collected bowhead whale feces (stored raw in several treatments) and in fecal extracts (50% methanol, MeOH) over multiple time points. Toxin stability, as the percent of initial concentration (T0), was reported for each storage treatment and time point. STX was stable (mean 99% T0) in 50% MeOH extracts over the 8-week study period, and there was no significant difference in STX concentrations quantified in split fecal samples extracted in 80% ethanol (EtOH) and 50% MeOH. STX was also relatively stable in raw fecal material stored in the freezer (mean 94% T0) and the refrigerator (mean 93% T0) up to 8 weeks. STX degraded over time in the room-temperature dark, room-temperature light, and warm treatments to means of 48 ± 1.9, 38 ± 2.8, and 20 ± 0.7% T0, respectively, after 8 weeks (mean ± standard error; SE). Additional opportunistically analyzed samples frozen for ≤4.5 years also showed STX to be relatively stable (mean 97% T0). Mean percent of T0 was measured slightly above 100% in some extracts following some treatments, and (most notably) at some long-term frozen time points, likely due to evaporation from samples causing STX to concentrate, or variability between ELISA plates. Overall, these results suggest that long-term frozen storage of raw fecal samples and the analysis of extracts within 8 weeks of extraction in 50% MeOH is sufficient for obtaining accurate STX quantifications in marine mammal fecal material without concerns about significant degradation.

Desmopressin Administration and Impact on Hypertonic Saline Effectiveness in Intracranial Hemorrhage.

INTRODUCTION: Desmopressin improves hemostasis through the release of factor VIII, von Willebrand factor, and tissue plasminogen activator, and increases platelet adhesion. Neurocritical Care guidelines recommend consideration of desmopressin in antiplatelet-associated intracranial hemorrhage. Studies supporting its use have not evaluated the potential impact of desmopressin on serum sodium levels in patients receiving hypertonic saline therapy. The purpose of this study was to assess the impact of desmopressin on sodium levels and hypertonic saline effectiveness in intracranial hemorrhage. METHODS: This was a single center retrospective observational chart review. Patients were included in the desmopressin group if they were diagnosed with intracranial hemorrhage, administered desmopressin, and received hypertonic saline infusion. Patients in the hypertonic saline alone group were then matched 1:1 to the patients in the desmopressin group. The primary end point was the effect of desmopressin on reaching a sodium goal of 145-155 mEq/L. The secondary end points included intensive care unit and hospital length of stay, change in sodium, time to reach sodium goal, thrombotic events, mortality, and a composite of increased cerebral edema, hematoma expansion, midline shift, herniation, need for neurosurgical intervention, and neurologic decompensation. RESULTS: Of 112 patients screened, 25 patients met inclusion criteria for the desmopressin group, and 25 patients were matched with patients in the hypertonic saline alone group. The percentage of patients who reached goal sodium in the desmopressin group compared with hypertonic saline alone was similar (80% vs. 88%, respectively). There were no differences in the secondary end points. In the subgroup analysis, patients in the hypertonic saline group met the predefined sodium goal of 150-155 mEq/L within 48 h more often than those in the desmopressin group (82% vs. 60%, respectively, p = 0.042). CONCLUSIONS: The use of desmopressin in intracranial hemorrhage does not appear to negatively impact the ability for patients to reach goal sodium of 145-155 mEq/L. However, in patients with higher sodium goals, desmopressin may decrease hypertonic saline effectiveness.

Don't Ditch the Laptop Just Yet: A Direct Replication of Mueller and Oppenheimer's (2014) Study 1 Plus Mini Meta-Analyses Across Similar Studies.

In this direct replication of Mueller and Oppenheimer's (2014) Study 1, participants watched a lecture while taking notes with a laptop (n = 74) or longhand (n = 68). After a brief distraction and without the opportunity to study, they took a quiz. As in the original study, laptop participants took notes containing more words spoken verbatim by the lecturer and more words overall than did longhand participants. However, laptop participants did not perform better than longhand participants on the quiz. Exploratory meta-analyses of eight similar studies echoed this pattern. In addition, in both the original study and our replication, higher word count was associated with better quiz performance, and higher verbatim overlap was associated with worse quiz performance, but the latter finding was not robust in our replication. Overall, results do not support the idea that longhand note taking improves immediate learning via better encoding of information.

Stability of Domoic Acid in 50% Methanol Extracts and Raw Fecal Material from Bowhead Whales (Balaena mysticetus).

Domoic acid (DA), the toxin causing amnesic shellfish poisoning (ASP), is produced globally by some diatoms in the genus Pseudo-nitzschia. DA has been detected in several marine mammal species in the Alaskan Arctic, raising health concerns for marine mammals and subsistence communities dependent upon them. Gastrointestinal matrices are routinely used to detect Harmful Algal Bloom (HAB) toxin presence in marine mammals, yet DA stability has only been studied extensively in shellfish-related matrices. To address this knowledge gap, we quantified DA in bowhead whale fecal samples at multiple time points for two groups: (1) 50% methanol extracts from feces, and (2) raw feces stored in several conditions. DA concentrations decreased to 70 ± 7.1% of time zero (T0) in the 50% methanol extracts after 2 weeks, but remained steady until the final time point at 5 weeks (66 ± 5.7% T0). In contrast, DA concentrations were stable or increased in raw fecal material after 8 weeks of freezer storage (-20 °C), at room temperature (RT) in the dark, or refrigerated at 1 °C. DA concentrations in raw feces stored in an incubator (37 °C) or at RT in the light decreased to 77 ± 2.8% and 90 ± 15.0% T0 at 8 weeks, respectively. Evaporation during storage of raw fecal material is a likely cause of the increased DA concentrations observed over time with the highest increase to 126 ± 7.6% T0 after 3.2 years of frozen storage. These results provide valuable information for developing appropriate sample storage procedures for marine mammal fecal samples.

Comparing treatment outcomes and patient satisfaction among individuals presenting to psychiatric care with and without recent suicidal ideation.

OBJECTIVE: To compare pre- and posttreatment psychological functioning and patient satisfaction among patients with and without recent suicidal ideation receiving care at a partial hospital program. METHODS: Patients (N = 1295) completed (1) self-report measures of clinical severity, treatment beliefs, and patient satisfaction and (2) a clinician-administered suicidal ideation measure. RESULTS: At admission, patients with past-month ideation reported more severe psychopathology and functional impairment than those without past-month ideation; however, at discharge, both groups reported comparable psychological functioning. Additionally, although patients with past-month ideation reported lower expectations that treatment would be helpful, both groups ultimately reported comparable satisfaction with services. CONCLUSION: Individuals with recent suicidal ideation may present to care with more severe psychopathology and lower treatment expectations yet may experience comparable treatment benefits and report similar satisfaction with services as patients without recent ideation. Research is needed to identify treatment components that drive perceived benefits and symptom reduction among at-risk individuals.

Ice seals as sentinels for algal toxin presence in the Pacific Arctic and subarctic marine ecosystems.

Domoic acid (DA) and saxitoxin (STX)-producing algae are present in Alaskan seas, presenting exposure risks to marine mammals that may be increasing due to climate change. To investigate potential increases in exposure risks to four pagophilic ice seal species (Erignathus barbatus, bearded seals; Pusa hispida, ringed seals; Phoca largha, spotted seals; and Histriophoca fasciata, ribbon seals), this study analyzed samples from 998 seals harvested for subsistence purposes in western and northern Alaska during 2005-2019 for DA and STX. Both toxins were detected in bearded, ringed, and spotted seals, though no clinical signs of acute neurotoxicity were reported in harvested seals. Bearded seals had the highest prevalence of each toxin, followed by ringed seals. Bearded seal stomach content samples from the Bering Sea showed a significant increase in DA prevalence with time (logistic regression, p = .004). These findings are consistent with predicted northward expansion of DA-producing algae. A comparison of paired samples taken from the stomachs and colons of 15 seals found that colon content consistently had higher concentrations of both toxins. Collectively, these results suggest that ice seals, particularly bearded seals (benthic foraging specialists), are suitable sentinels for monitoring HAB prevalence in the Pacific Arctic and subarctic.

Reliability Testing of Augmented Reality Glasses Technology: Establishing the Evidence Base for Telewound Care.

PURPOSE: To test the fidelity and feasibility of using augmented reality glass (ARG) telehealth technology for comprehensive wound, ostomy, and continence (WOC) service delivery to underserved rural practice settings. DESIGN: Intrarater reliability design focusing on treatment integrity. SAMPLE AND SETTING: Adult patients in a tertiary care hospital and a rural long-term care setting who were scheduled for routine wound care consults. METHODS: Intra- and interrater reliability were assessed using a documentation-based wound assessment tool comprising 6 discrete assessment points. The wound teleassessment was first conducted by the telehealth "hub" WOC nurse remotely in collaboration with a bedside nurse wearing the ARG. The same hub WOC nurse then conducted an assessment at the bedside. Initial assessment points and treatment plans were compared to establish assessment and treatment intrarater reliability. A different WOC nurse, blinded to the first assessment, also conducted a bedside assessment and provided treatment recommendations, which were then compared to the hub WOC nurse's initial remotely ARG-generated treatment plan to establish treatment interrater reliability. RESULTS: Sixteen patients with 21 wounds were assessed. Six wound assessment components were included, yielding a total of 126 total observation points. Intrarater assessment reliability was 98%. Treatment plan interrater reliability was 100%. CONCLUSIONS: Results support further evaluation of ARG technology as a tool to enhance the delivery of wound care services in remote underserved settings. Implementation and evaluation of this technology on clinical and financial outcomes in multiple wound care delivery environments should be determined moving forward. Successful implementation should serve as a template to expand evidence-based WOC nursing care across the globe.

Dietary resistant starch prevents urinary excretion of vitamin D metabolites and maintains circulating 25-hydroxycholecalciferol concentrations in Zucker diabetic fatty rats.

BACKGROUND: Type 2 diabetes (T2D) is the leading cause of nephropathy in the United States. Renal complications of T2D include proteinuria and suboptimal serum 25-hydroxycholecalciferol (25D) concentrations. 25D is the major circulating form of vitamin D and renal reabsorption of the 25D-vitamin D-binding protein (DBP) complex via megalin-mediated endocytosis is believed to determine whether 25D can be activated to 1,25-dihydroxycholecalciferol (1,25D) or returned to circulation. We previously demonstrated that excessive urinary excretion of 25D-DBP and albuminuria occurred in rats with type 1 diabetes (T1D) and T2D. Moreover, feeding rats with T1D high-amylose maize partially resistant to digestion [resistant starch (RS)] prevented excretion of 25D-DBP without significantly affecting hyperglycemia. OBJECTIVE: We used Zucker diabetic fatty (ZDF) rats, a model of obesity-related T2D, to determine whether feeding RS could similarly prevent loss of vitamin D and maintain serum 25D concentrations. METHODS: Lean control Zucker rats (n = 8) were fed a standard semi-purified diet (AIN-93G) and ZDF rats were fed either the AIN-93G diet (n = 8) or the AIN-93G diet in which cornstarch was replaced with RS (550 g/kg diet; 35% resistant to digestion) (n = 8) for 6 wk. RESULTS: RS attenuated hyperglycemia by 41% (P < 0.01) and prevented urinary DBP excretion and albuminuria, which were elevated 3.0- (P < 0.01) and 3.6-fold (P < 0.01), respectively, in control diet-fed ZDF rats. Additionally, urinary excretion of 25D (P = 0.01) and 1,25D (P = 0.03) was higher (89% and 97%, respectively), whereas serum 25D concentrations were 31% lower (P < 0.001) in ZDF rats fed the control diet compared with RS-fed ZDF rats. Histopathologic scoring of the kidney revealed that RS attenuated diabetes-mediated damage by 21% (P = 0.12) despite an ∼50% decrease in megalin protein abundance. CONCLUSIONS: Taken together, these data provide evidence that suggests vitamin D balance can be maintained by dietary RS through nephroprotective actions in T2D, which are independent of vitamin D supplementation and renal expression of megalin.

Perspective taking as a transdiagnostic risk factor for interpersonal dysfunction.

OBJECTIVE: Numerous psychiatric populations have demonstrated reduced tendency to adopt others' perspectives relative to those without psychiatric illness; yet, the clinical implications of these deficits remain unclear. We examined whether impairments in perspective-taking are prospectively associated with symptom severity and functional outcomes in an acute psychiatric sample. We hypothesized that poorer perspective-taking would prospectively predict more severe depressive symptoms, functional impairment, and relationship problems. METHOD: Participants were 421 adults seeking psychiatric treatment at a partial hospital program. Participants completed the following self-report questionnaires at admission and discharge: Interpersonal Reactivity Index, Patient Health Questionnaire, Work and Social Adjustment Scale, and Behavior and Symptom Identification Scale. We conducted cross-lagged panel models to estimate directional effects. RESULTS: Consistent with hypotheses, more frequent perspective-taking was significantly and prospectively associated with less overall functional impairment (ß = -0.08, p = 0.04) and fewer relationship problems (ß = -0.11, p = 0.02). When modelled together, perspective-taking remained a significant and bidirectional predictor of relationship problems, but not overall functional impairment. Inconsistent with hypotheses, perspective-taking did not prospectively predict depressive symptoms. CONCLUSIONS: Results suggest that perspective-taking deficits are uniquely associated with relationship problems among adults with severe mental illness and highlight a potential target for future intervention.

Age and Sex as Determinants of Acute Domoic Acid Toxicity in a Mouse Model.

The excitatory neurotoxin domoic acid (DA) consistently contaminates food webs in coastal regions around the world. Acute exposure to the toxin causes Amnesic Shellfish Poisoning, a potentially lethal syndrome of gastrointestinal- and seizure-related outcomes. Both advanced age and male sex have been suggested to contribute to interindividual DA susceptibility. To test this, we administered DA doses between 0.5 and 2.5 mg/kg body weight to female and male C57Bl/6 mice at adult (7-9-month-old) and aged (25-28-month-old) life stages and observed seizure-related activity for 90 min, at which point we euthanized the mice and collected serum, cortical, and kidney samples. We observed severe clonic-tonic convulsions in some aged individuals, but not in younger adults. We also saw an association between advanced age and the incidence of a moderately severe seizure-related outcome, hindlimb tremors, and between advanced age and overall symptom severity and persistence. Surprisingly, we additionally report that female mice, particularly aged female mice, demonstrated more severe neurotoxic symptoms following acute exposure to DA than males. Both age and sex patterns were reflected in tissue DA concentrations as well: aged mice and females had generally higher concentrations of DA in their tissues at 90 min post-exposure. This study contributes to the body of work that can inform intelligent, evidence-based public health protections for communities threatened by more frequent and extensive DA-producing algal blooms.

The Influence of Maternal High Fat Diet During Lactation on Offspring Hematopoietic Priming.

Obesity and metabolic diseases are rising among women of reproductive age, increasing offspring metabolic risk. Maternal nutritional interventions during lactation present an opportunity to modify offspring outcomes. We previously demonstrated in mice that adult male offspring have metabolic impairments and increased adipose tissue macrophages (ATM) when dams are fed high fat diet (HFD) during the postnatal lactation window (HFD PN). We sought to understand the effect of HFD during lactation on early-life inflammation. HFD PN offspring were evaluated at postnatal day 16 to 19 for tissue weight and gene expression. Profiling of adipose tissue and bone marrow immune cells was conducted through lipidomics, in vitro myeloid colony forming unit assays, and flow cytometry. HFD PN mice had more visceral gonadal white adipose tissue (GWAT) and subcutaneous fat. Adipose tissue RNA sequencing demonstrated enrichment of inflammation, chemotaxis, and fatty acid metabolism and concordant changes in GWAT lipidomics. Bone marrow (BM) of both HFD PN male and female offspring had increased monocytes (CD45+Ly6G-CD11b+CD115+) and B cells (CD45+Ly6G-CD11b-CD19+). Similarly, serum from HFD PN offspring enhanced in vitro BM myeloid colonies in a toll-like receptor 4-dependent manner. We identified that male HFD PN offspring had increased GWAT pro-inflammatory CD11c+ ATMs (CD45+CD64+). Maternal exposure to HFD alters milk lipids enhancing adiposity and myeloid inflammation even in early life. Future studies are needed to understand the mechanisms driving this pro-inflammatory state of both BM and ATMs, the causes of the sexually dimorphic phenotypes, and the feasibility of intervening in this window to improve metabolic health.

Quality Improvement Intervention to Reduce Thirty-Day Hospital Readmission Rates Among Patients With Systemic Lupus Erythematosus.

OBJECTIVE: Systemic lupus erythematosus (SLE) has one of the highest 30-day hospital readmission rates among chronic diseases in the US. This quality improvement initiative developed and assessed the feasibility of a multidisciplinary postdischarge intervention to reduce 30-day readmission rates among SLE patients. METHODS: A retrospective study was performed using electronic health records of patients with SLE admitted to a university hospital prior to (nonintervention group) and after initiation of the study intervention (intervention group). The study population included patients with a diagnosis of SLE who were admitted to the hospital for any reason during an 8-month time period. The intervention involved sending a templated message at the time of discharge to the rheumatology clinic nurses, which prompted the nurses to call the patient to coordinate future visits and provide education. The primary outcome was the 30-day hospital readmission rate. Data were analyzed using a multivariate mixed binomial regression model. RESULTS: There were 59 hospitalizations in the nonintervention group and 73 hospitalizations in the intervention group during the 8-month study period. The 30-day readmission rate was 29% in the nonintervention group and 19% in the intervention group. The difference in readmission rates between the 2 groups was not statistically significant based on the multivariate model. CONCLUSION: Our study demonstrates the feasibility of implementing a multidisciplinary postdischarge intervention to reduce readmission rates for patients with SLE in a large academic medical center. Further investigation is warranted to determine if this approach reduces the unacceptably high hospital readmission rates among SLE patients.

Constitutive bone marrow adipocytes suppress local bone formation.

BM adipocytes (BMAd) are a unique cell population derived from BM mesenchymal progenitors and marrow adipogenic lineage precursors. Although they have long been considered to be a space filler within bone cavities, recent studies have revealed important physiological roles in hematopoiesis and bone metabolism. To date, the approaches used to study BMAd function have been confounded by contributions by nonmarrow adipocytes or by BM stromal cells. To address this gap in the field, we have developed a BMAd-specific Cre mouse model to deplete BMAds by expression of diphtheria toxin A (DTA) or by deletion of peroxisome proliferator-activated receptor gamma (Pparg). We found that DTA-induced loss of BMAds results in decreased hematopoietic stem and progenitor cell numbers and increased bone mass in BMAd-enriched locations, including the distal tibiae and caudal vertebrae. Elevated bone mass appears to be secondary to enhanced endosteal bone formation, suggesting a local effect caused by depletion of BMAd. Augmented bone formation with BMAd depletion protects mice from bone loss induced by caloric restriction or ovariectomy, and it facilitates the bone-healing process after fracture. Finally, ablation of Pparg also reduces BMAd numbers and largely recapitulates high-bone mass phenotypes observed with DTA-induced BMAd depletion.

Lipolysis of bone marrow adipocytes is required to fuel bone and the marrow niche during energy deficits.

To investigate roles for bone marrow adipocyte (BMAd) lipolysis in bone homeostasis, we created a BMAd-specific Cre mouse model in which we knocked out adipose triglyceride lipase (ATGL, Pnpla2 gene). BMAd-Pnpla2-/- mice have impaired BMAd lipolysis, and increased size and number of BMAds at baseline. Although energy from BMAd lipid stores is largely dispensable when mice are fed ad libitum, BMAd lipolysis is necessary to maintain myelopoiesis and bone mass under caloric restriction. BMAd-specific Pnpla2 deficiency compounds the effects of caloric restriction on loss of trabecular bone in male mice, likely due to impaired osteoblast expression of collagen genes and reduced osteoid synthesis. RNA sequencing analysis of bone marrow adipose tissue reveals that caloric restriction induces dramatic elevations in extracellular matrix organization and skeletal development genes, and energy from BMAd is required for these adaptations. BMAd-derived energy supply is also required for bone regeneration upon injury, and maintenance of bone mass with cold exposure.

Paralytic shellfish toxins in Alaskan Arctic food webs during the anomalously warm ocean conditions of 2019 and estimated toxin doses to Pacific walruses and bowhead whales.

Climate change-related ocean warming and reduction in Arctic sea ice extent, duration and thickness increase the risk of toxic blooms of the dinoflagellate Alexandrium catenella in the Alaskan Arctic. This algal species produces neurotoxins that impact marine wildlife health and cause the human illness known as paralytic shellfish poisoning (PSP). This study reports Paralytic Shellfish Toxin (PST) concentrations quantified in Arctic food web samples that include phytoplankton, zooplankton, benthic clams, benthic worms, and pelagic fish collected throughout summer 2019 during anomalously warm ocean conditions. PSTs (saxitoxin equivalents, STX eq.) were detected in all trophic levels with concentrations above the seafood safety regulatory limit (80 µg STX eq. 100 g-1) in benthic clams collected offshore on the continental shelf in the Beaufort, Chukchi, and Bering Seas. Most notably, toxic benthic clams (Macoma calcarea) were found north of Saint Lawrence Island where Pacific walruses (Odobenus rosmarus) are known to forage for a variety of benthic species, including Macoma. Additionally, fecal samples collected from 13 walruses harvested for subsistence purposes near Saint Lawrence Island during March to May 2019, all contained detectable levels of STX, with fecal samples from two animals (78 and 72 µg STX eq. 100 g-1) near the seafood safety regulatory limit. In contrast, 64% of fecal samples from zooplankton-feeding bowhead whales (n = 9) harvested between March and September 2019 in coastal waters of the Beaufort Sea near Utqiagvik (formerly Barrow) and Kaktovik were toxin-positive, and those levels were significantly lower than in walruses (max bowhead 8.5 µg STX eq. 100 g-1). This was consistent with the lower concentrations of PSTs found in regional zooplankton prey. Maximum ecologically-relevant daily toxin doses to walruses feeding on clams and bowhead whales feeding on zooplankton were estimated to be 21.5 and 0.7 µg STX eq. kg body weight-1 day-1, respectively, suggesting that walruses had higher PST exposures than bowhead whales. Average and maximum STX doses in walruses were in the range reported previously to cause illness and/or death in humans and humpback whales, while bowhead whale doses were well below those levels. These findings raise concerns regarding potential increases in PST/STX exposure risks and health impacts to Arctic marine mammals as ocean warming and sea ice reduction continue.

Obesity-induced inflammation: The impact of the hematopoietic stem cell niche.

Obesity and obesity-related diseases like type 2 diabetes (T2D) are prominent global health issues; therefore, there is a need to better understand the mechanisms underlying these conditions. The onset of obesity is characterized by accumulation of proinflammatory cells, including Ly6chi monocytes (which differentiate into proinflammatory macrophages) and neutrophils, in metabolic tissues. This shift toward chronic, low-grade inflammation is an obese-state hallmark and highly linked to metabolic disorders and other obesity comorbidities. The mechanisms that induce and maintain increased inflammatory myelopoiesis are of great interest, with a recent focus on how obesity affects more primitive hematopoietic cells. The hematopoietic system is constantly replenished by proper regulation of hematopoietic stem and progenitor (HSPC) pools in the BM. While early research suggests that chronic obesity promotes expansion of myeloid-skewed HSPCs, the involvement of the hematopoietic stem cell (HSC) niche in regulating obesity-induced myelopoiesis remains undefined. In this review, we explore the role of the multicellular HSC niche in hematopoiesis and inflammation, and the potential contribution of this niche to the hematopoietic response to obesity. This review further aims to summarize the potential HSC niche involvement as a target of obesity-induced inflammation and a driver of obesity-induced myelopoiesis.

Feather corticosterone does not correlate with environmental stressors or body condition in an endangered waterbird.

Physiological metrics are becoming popular tools for assessing individual condition and population health to inform wildlife management and conservation decisions. Corticosterone assays can provide information on how animals cope with individual and habitat-level stressors, and the recent development of feather assays is an exciting innovation that could yield important insights for conservation of wild birds. Due to the widespread enthusiasm for feather corticosterone as a potential bioindicator, studies are needed to assess the ability of this technique to detect meaningful differences in physiological stress across a variety of stressor types and intensities. We examined feather corticosterone from 144 individuals among the 13 known breeding populations of Hawaiian gallinule (Gallinula galeata sandvicensis), an endangered waterbird, on the island of O'ahu. These ecologically independent subpopulations are known to have low genetic connectivity and movement rates and differ largely across a number of important conditions, including level of predator management, human disturbance, proximity to urban development and conspecific population density. This system is well suited for assessing the performance of feather corticosterone as a bioindicator of different known habitat-level threats common to this and many other conservation-reliant species. We found no statistically significant relationship between feather corticosterone and level of predator control, level of human disturbance, gallinule population density, percent urban cover or body condition across all sites despite the substantial difference in stressor magnitude in our dataset. We did find that gallinules in habitats with larger population densities were in worse body condition. These findings suggest that feather corticosterone is not a consistent indicator of anthropogenic impacts on populations. Furthermore, they suggest that feather corticosterone may be a poor bioindicator of known habitat-level threats for Hawaiian gallinules and that it should be used with caution in other avian taxa of conservation concern.

G-CSF partially mediates effects of sleeve gastrectomy on the bone marrow niche.

Bariatric surgeries are integral to the management of obesity and its metabolic complications. However, these surgeries cause bone loss and increase fracture risk through poorly understood mechanisms. In a mouse model, vertical sleeve gastrectomy (VSG) caused trabecular and cortical bone loss that was independent of sex, body weight, and diet, and this loss was characterized by impaired osteoid mineralization and bone formation. VSG had a profound effect on the bone marrow niche, with rapid loss of marrow adipose tissue, and expansion of myeloid cellularity, leading to increased circulating neutrophils. Following VSG, circulating granulocyte-colony stimulating factor (G-CSF) was increased in mice, and was transiently elevated in a longitudinal study of humans. Elevation of G-CSF was found to recapitulate many effects of VSG on bone and the marrow niche. In addition to stimulatory effects of G-CSF on myelopoiesis, endogenous G-CSF suppressed development of marrow adipocytes and hindered accrual of peak cortical and trabecular bone. Effects of VSG on induction of neutrophils and depletion of marrow adiposity were reduced in mice deficient for G-CSF; however, bone mass was not influenced. Although not a primary mechanism for bone loss with VSG, G-CSF plays an intermediary role for effects of VSG on the bone marrow niche.

Granulocyte-derived TNFα promotes vascular and hematopoietic regeneration in the bone marrow.

Endothelial cells are a critical component of the bone marrow (BM) stromal network, which maintains and regulates hematopoietic cells. Vascular regeneration precedes, and is necessary for, successful hematopoietic stem cell (HSC) transplantation, the only cure for most hematopoietic diseases. Recent data suggest that mature hematopoietic cells regulate BM stromal-cell function. Whether a similar cross-talk regulates the BM vasculature is not known. Here we found that donor hematopoietic cells act on sinusoidal endothelial cells and induce host blood vessel and hematopoietic regeneration after BM transplantation in mice. Adoptive transfer of BM, but not peripheral, granulocytes prevented the death of mice transplanted with limited numbers of HSCs and accelerated recovery of host vessels and hematopoietic cells. Moreover, selective granulocyte ablation in vivo impaired vascular and hematopoietic regeneration after BM transplantation. Gene expression analyses indicated that granulocytes are the main source of the cytokine TNFα, whereas its receptor TNFR1 is selectively upregulated in regenerating blood vessels. In adoptive transfer experiments, wild type, but not Tnfa-/-, granulocytes induced vascular recovery, and wild-type granulocyte transfer did not prevent death or promote vascular regeneration in Tnfr1-/-; Tnfr2-/- mice. Thus, by delivering TNFα to endothelial cells, granulocytes promote blood vessel growth and hematopoietic regeneration. Manipulation of the cross-talk between granulocytes and endothelial cells may lead to new therapeutic approaches to improve blood vessel regeneration and increase survival and hematopoietic recovery after HSC transplantation.