Microglia Require CD4 T Cells to Complete the Fetal-to-Adult Transition.

The brain is a site of relative immune privilege. Although CD4 T cells have been reported in the central nervous system, their presence in the healthy brain remains controversial, and their function remains largely unknown. We used a combination of imaging, single cell, and surgical approaches to identify a CD69+ CD4 T cell population in both the mouse and human brain, distinct from circulating CD4 T cells. The brain-resident population was derived through in situ differentiation from activated circulatory cells and was shaped by self-antigen and the peripheral microbiome. Single-cell sequencing revealed that in the absence of murine CD4 T cells, resident microglia remained suspended between the fetal and adult states. This maturation defect resulted in excess immature neuronal synapses and behavioral abnormalities. These results illuminate a role for CD4 T cells in brain development and a potential interconnected dynamic between the evolution of the immunological and neurological systems. VIDEO ABSTRACT.

Titration of RAS alters senescent state and influences tumour initiation.

Oncogenic RAS-induced senescence (OIS) is an autonomous tumour suppressor mechanism associated with premalignancy1,2. Achieving this phenotype typically requires a high level of oncogenic stress, yet the phenotype provoked by lower oncogenic dosage remains unclear. Here we develop oncogenic RAS dose-escalation models in vitro and in vivo, revealing a RAS dose-driven non-linear continuum of downstream phenotypes. In a hepatocyte OIS model in vivo, ectopic expression of NRAS(G12V) does not induce tumours, in part owing to OIS-driven immune clearance3. Single-cell RNA sequencing analyses reveal distinct hepatocyte clusters with typical OIS or progenitor-like features, corresponding to high and intermediate levels of NRAS(G12V), respectively. When titred down, NRAS(G12V)-expressing hepatocytes become immune resistant and develop tumours. Time-series monitoring at single-cell resolution identifies two distinct tumour types: early-onset aggressive undifferentiated and late-onset differentiated hepatocellular carcinoma. The molecular signature of each mouse tumour type is associated with different progenitor features and enriched in distinct human hepatocellular carcinoma subclasses. Our results define the oncogenic dosage-driven OIS spectrum, reconciling the senescence and tumour initiation phenotypes in early tumorigenesis.

Senescence-induced endothelial phenotypes underpin immune-mediated senescence surveillance.

Senescence is a stress-responsive tumor suppressor mechanism associated with expression of the senescence-associated secretory phenotype (SASP). Through the SASP, senescent cells trigger their own immune-mediated elimination, which if evaded leads to tumorigenesis. Senescent parenchymal cells are separated from circulating immunocytes by the endothelium, which is targeted by microenvironmental signaling. Here we show that SASP induces endothelial cell NF-κB activity and that SASP-induced endothelial expression of the canonical NF-κB component Rela underpins senescence surveillance. Using human liver sinusoidal endothelial cells (LSECs), we show that SASP-induced endothelial NF-κB activity regulates a conserved transcriptional program supporting immunocyte recruitment. Furthermore, oncogenic hepatocyte senescence drives murine LSEC NF-κB activity in vivo. Critically, we show two distinct endothelial pathways in senescence surveillance. First, endothelial-specific loss of Rela prevents development of Stat1-expressing CD4+ T lymphocytes. Second, the SASP up-regulates ICOSLG on LSECs, with the ICOS-ICOSLG axis contributing to senescence cell clearance. Our results show that the endothelium is a nonautonomous SASP target and an organizing center for immune-mediated senescence surveillance.

Evolution of sex differences in cooperation can be explained by trade-offs with dispersal.

Explaining the evolution of sex differences in cooperation remains a major challenge. Comparative studies highlight that offspring of the more philopatric sex tend to be more cooperative within their family groups than those of the more dispersive sex but we do not understand why. The leading "Philopatry hypothesis" proposes that the more philopatric sex cooperates more because their higher likelihood of natal breeding increases the direct fitness benefits of natal cooperation. However, the "Dispersal trade-off hypothesis" proposes that the more dispersive sex cooperates less because preparations for dispersal, such as extra-territorial prospecting, trade-off against natal cooperation. Here, we test both hypotheses in cooperatively breeding white-browed sparrow weavers (Plocepasser mahali), using a novel high-resolution automated radio-tracking method. First, we show that males are the more dispersive sex (a rare reversal of the typical avian sex difference in dispersal) and that, consistent with the predictions of both hypotheses, females contribute substantially more than males to cooperative care while within the natal group. However, the Philopatry hypothesis cannot readily explain this female-biased cooperation, as females are not more likely than males to breed within their natal group. Instead, our radio-tracking findings support the Dispersal trade-off hypothesis: males conduct pre-dispersal extra-territorial prospecting forays at higher rates than females and prospecting appears to trade-off against natal cooperation. Our findings thus highlight that the evolution of sex differences in cooperation could be widely attributable to trade-offs between cooperation and dispersal; a potentially general explanation that does not demand that cooperation yields direct fitness benefits.

Mothers in a cooperatively breeding bird increase investment per offspring at the pre-natal stage when they will have more help with post-natal care.

In many cooperative societies, including our own, helpers assist with the post-natal care of breeders' young and may thereby benefit the post-natal development of offspring. Here, we present evidence of a novel mechanism by which such post-natal helping could also have beneficial effects on pre-natal development: By lightening post-natal maternal workloads, helpers may allow mothers to increase their pre-natal investment per offspring. We present the findings of a decade-long study of cooperatively breeding white-browed sparrow-weaver, Plocepasser mahali, societies. Within each social group, reproduction is monopolized by a dominant breeding pair, and non-breeding helpers assist with nestling feeding. Using a within-mother reaction norm approach to formally identify maternal plasticity, we demonstrate that when mothers have more female helpers, they decrease their own post-natal investment per offspring (feed their nestlings at lower rates) but increase their pre-natal investment per offspring (lay larger eggs, which yield heavier hatchlings). That these plastic maternal responses are predicted by female helper number, and not male helper number, implicates the availability of post-natal helping per se as the likely driver (rather than correlated effects of group size), because female helpers feed nestlings at substantially higher rates than males. We term this novel maternal strategy "maternal front-loading" and hypothesize that the expected availability of post-natal help either allows or incentivizes helped mothers to focus maternal investment on the pre-natal phase, to which helpers cannot contribute directly. The potential for post-natal helping to promote pre-natal development further complicates attempts to identify and quantify the fitness consequences of helping.

Pioglitazone does not enhance exogenous glucose oxidation or metabolic clearance rate during aerobic exercise in men under acute high-altitude exposure.

Insulin insensitivity decreases exogenous glucose oxidation and metabolic clearance rate (MCR) during aerobic exercise in unacclimatized lowlanders at high altitude (HA). Whether use of an oral insulin sensitizer before acute HA exposure enhances exogenous glucose oxidation is unclear. This study investigated the impact of pioglitazone (PIO) on exogenous glucose oxidation and glucose turnover compared with placebo (PLA) during aerobic exercise at HA. With the use of a randomized crossover design, native lowlanders (n = 7 males, means ± SD, age: 23 ± 6 yr, body mass: 84 ± 11 kg) consumed 145 g (1.8 g/min) of glucose while performing 80 min of steady-state (1.43 ± 0.16 V̇o2 L/min) treadmill exercise at HA (460 mmHg; [Formula: see text] 96.6 mmHg) following short-term (5 days) use of PIO (15 mg oral dose per day) or PLA (microcrystalline cellulose pill). Substrate oxidation and glucose turnover were determined using indirect calorimetry and stable isotopes ([13C]glucose and 6,6-[2H2]glucose). Exogenous glucose oxidation was not different between PIO (0.31 ± 0.03 g/min) and PLA (0.32 ± 0.09 g/min). Total carbohydrate oxidation (PIO: 1.65 ± 0.22 g/min, PLA: 1.68 ± 0.32 g/min) or fat oxidation (PIO: 0.10 ± 0.0.08 g/min, PLA: 0.09 ± 0.07 g/min) was not different between treatments. There was no treatment effect on glucose rate of appearance (PIO: 2.46 ± 0.27, PLA: 2.43 ± 0.27 mg/kg/min), disappearance (PIO: 2.19 ± 0.17, PLA: 2.20 ± 0.22 mg/kg/min), or MCR (PIO: 1.63 ± 0.37, PLA: 1.73 ± 0.40 mL/kg/min). Results from this study indicate that PIO is not an effective intervention to enhance exogenous glucose oxidation or MCR during acute HA exposure. Lack of effect with PIO suggests that the etiology of glucose metabolism dysregulation during acute HA exposure may not result from insulin resistance in peripheral tissues.NEW & NOTEWORTHY Short-term (5 days) use of the oral insulin sensitizer pioglitazone does not alter circulating glucose or insulin responses to enhance exogenous glucose oxidation during steady-state aerobic exercise in young healthy men under simulated acute (8 h) high-altitude (460 mmHg) conditions. These results indicate that dysregulations in glucose metabolism in native lowlanders sojourning at high altitude may not be due to insulin resistance at peripheral tissue.

Blunt Cerebrovascular Injury Complications in Aging Adults: A National Trauma Database Study.

INTRODUCTION: Blunt cerebrovascular injury (BCVI) is defined as a nonpenetrating injury to the carotid or vertebral arteries which can be highly morbid. Because BCVI is rare, most studies have been devoted to triaging trauma patients for BCVI identification, with little data available regarding the complications these patients experience after initial evaluation. Here, we analyze the association of complications during admission for BCVI patients. METHODS: The National Trauma Databank was queried from 2007 to 2014 for adults ≥65 y old. Demographics, incidence of BCVI, and injury data were evaluated using univariate analysis. Rates of inpatient complications due to acutely acquired infections and strokes were evaluated using univariate and multivariable analysis. RESULTS: We identified 666,815 non-BCVI and 552 BCVI patients. Patients with a BCVI were typically male, White, younger (65-75-y-old), had three or more comorbidities, and had Medicare insurance. BCVI patients had a mild head injury upon arrival at the emergency department and experienced a motor vehicle accident/fall. The median length of stay in the intensive care unit, days spent on a ventilator, and presence of polytrauma were higher among BCVI patients. BCVI patients had increased odds of experiencing a stroke and pneumonia as complications while admitted compared to their non-BCVI counterparts. CONCLUSIONS: Postinjury, patients who suffered a BCVI had higher odds of stroke and pneumonia than patients who did not experience a BCVI. Additional studies are needed to determine the modifiable risk factors associated with BCVIs among aging adults.

Adjusting the Split: Examining Complications After Emergency Exploratory Laparotomy in Older Adults.

INTRODUCTION: Older adults experience higher rates of complications after an emergency exploratory laparotomy (EEL). To better understand the shift to an aging population in the United States, identifying how age may influence these complications in older patients is important. The current standard age category for older adult patients is ≥65. We analyzed postlaparotomy complications using a lower age split. METHODS: A retrospective analysis was done on patients who required an EEL from October 2015 to December 2019 at an academic medical center. Patient demographics and hospital course variables were collected. Differences in complications in patients aged ≥/<55 y and ≥/<65 y were measured using univariate and multivariable analyses. RESULTS: A total of 481 patients were reviewed. Both patient groups of ≥55 and ≥65 were typically male, White, had 3+ comorbidities, Medicare insurance, were retired, and presented in extremis to the emergency department. Patients aged ≥55 y had significant rates of pulmonary complications and inpatient mortality (odds ratio 2.2, 2.7, respectively). Patients aged ≥65 y had significant rates of genitourinary and cardiac complications (odds ratio 2.3, 1.8, respectively). CONCLUSIONS: Patients aged ≥55 y undergoing EEL had higher odds of experiencing pulmonary complications and death during their index hospitalizations, which was not present with the standard ≥/<65-y-old patient analysis. Those aged ≥65 y experienced index genitourinary and cardiac complications. The ≥/<55 age split has a unique set of complications that should be considered. Given the increased odds of inpatient mortality and types of complications in patients aged ≥55 y, the current age split for older adults should be reconsidered.

Identifying Factors Associated With Code Status Changes After Emergency General Surgery.

INTRODUCTION: Surgical emergencies are time sensitive. Identifying patients who may benefit from preoperative goals of care discussions is critical to ensuring that operative intervention aligns with the patient's values. We sought to identify patient factors associated with acute changes in a patient's goals using code status change (CSC) as proxy. METHODS: A retrospective analysis of single-institution data for patients undergoing urgent laparotomy was performed. Patients were stratified based on whether a postoperative CSC occurred. Parametric, nonparametric, and regression analyses were used to identify variables associated with CSC. RESULTS: Of 484 patients, 13.8% (n = 67) had a postoperative CSC. Patients with postoperative CSC were older (65 versus 60 years, P < 0.001). Odds of CSC were significantly higher in patients who were transferred between facilities (odds ratio [OR] 2.1), had a higher Charlson Comorbidity Index (3-4: OR 3.9, 5+: OR 6.8), and had a higher quick sequential organ failure assessment score (2: OR 5.0; 3: OR 38.7). Patients with anemia (OR 1.9) and active cancer (OR 3.0) had higher odds of CSC. CONCLUSIONS: Timely intervention in emergency general surgery may result in high-risk interventions and subsequent complications that do not align with a patient's goals and values. Our analysis identified a subset of patients who undergo surgery and have a postoperative CSC leading to transition to comfort-focused care. In these patients, a pause in clinical momentum may help ensure operative intervention remains goal concordant.

Adenosine 2A Receptor Agonism Improves Survival in Extracorporeal Cardiopulmonary Resuscitation.

INTRODUCTION: Despite resuscitation advances including extracorporeal cardiopulmonary resuscitation (ECPR), freedom from neurologic and myocardial insult after cardiac arrest remains unlikely. We hypothesized that adenosine 2A receptor (A2AR) agonism, which attenuates reperfusion injury, would improve outcomes in a porcine model of ECPR. METHODS: Adult swine underwent 20 min of circulatory arrest followed by defibrillation and 6 h of ECPR. Animals were randomized to receive saline vehicle or A2AR agonist (ATL1223 or Regadenoson) infusion during extracorporeal membrane oxygenation. Animals were weaned off extracorporeal membrane oxygenation and monitored for 24 h. Clinical and biochemical end points were compared. RESULTS: The administration of A2AR agonists increased survival (P = 0.01) after cardiac arrest compared to vehicle. Markers of neurologic damage including S100 calcium binding protein B and glial fibrillary acidic protein were significantly lower with A2AR agonist treatment. CONCLUSIONS: In a model of cardiac arrest treated with ECPR, A2AR agonism increased survival at 24 h and reduced neurologic damage suggesting A2AR activation may be a promising therapeutic target after cardiac arrest.

Exposure Effects of Environmentally Relevant Concentrations of the Tricyclic Antidepressant Amitriptyline in Early Life Stage Zebrafish.

Antidepressants are one of the most globally prescribed classes of pharmaceuticals, and drug target conservation across phyla means that nontarget organisms may be at risk from the effects of exposure. Here, we address the knowledge gap for the effects of chronic exposure (28 days) to the tricyclic antidepressant amitriptyline (AMI) on fish, including for concentrations with environmental relevance, using zebrafish (Danio rerio) as our experimental model. AMI was found to bioconcentrate in zebrafish, was readily transformed to its major active metabolite nortriptyline, and induced a pharmacological effect (downregulation of the gene encoding the serotonin transporter; slc6a4a) at environmentally relevant concentrations (0.03 µg/L and above). Exposures to AMI at higher concentrations accelerated the hatch rate and reduced locomotor activity, the latter of which was abolished after a 14 day period of depuration. The lack of any response on the features of physiology and behavior we measured at concentrations found in the environment would indicate that AMI poses a relatively low level of risk to fish populations. The pseudopersistence and likely presence of multiple drugs acting via the same mechanism of action, however, together with a global trend for increased prescription rates, mean that this risk may be underestimated using current ecotoxicological assessment paradigms.

The phylogeny and evolutionary ecology of hoverflies (Diptera: Syrphidae) inferred from mitochondrial genomes.

Hoverflies (Diptera: Syrphidae) are a diverse group of pollinators and a major research focus in ecology, but their phylogenetic relationships remain incompletely known. Using a genome skimming approach we generated mitochondrial genomes for 91 species, capturing a wide taxonomic diversity of the family. To reduce the required amount of input DNA and overall cost of the library construction, sequencing and assembly was conducted on mixtures of specimens, which raises the problem of chimera formation of mitogenomes. We present a novel chimera detection test based on gene tree incongruence, but identified only a single mitogenome of chimeric origin. Together with existing data for a final set of 127 taxa, phylogenetic analysis on nucleotide and amino acid sequences using Maximum Likelihood and Bayesian Inference revealed a basal split of Microdontinae from all other syrphids. The remainder consists of several deep clades assigned to the subfamily Eristalinae in the current classification, including a clade comprising the subfamily Syrphinae (plus Pipizinae). These findings call for a re-definition of subfamilies, but basal nodes had insufficient support to fully justify such action. Molecular-clock dating placed the origin of the Syrphidae crown group in the mid-Cretaceous while the Eristalinae-Syrphinae clade likely originated near the K/Pg boundary. Transformation of larval life history characters on the tree suggests that Syrphidae initially had sap feeding larvae, which diversified greatly in diet and habitat association during the Eocene and Oligocene, coinciding with the diversification of angiosperms and the evolution of various insect groups used as larval host, prey, or mimicry models. Mitogenomes proved to be a powerful phylogenetic marker for studies of Syrphidae at subfamily and tribe levels, allowing dense taxon sampling that provided insight into the great ecological diversity and rapid evolution of larval life history traits of the hoverflies.

Deficiency of the ywhaz gene, involved in neurodevelopmental disorders, alters brain activity and behaviour in zebrafish.

Genetic variants in YWHAZ contribute to psychiatric disorders such as autism spectrum disorder and schizophrenia, and have been related to an impaired neurodevelopment in humans and mice. Here, we have used zebrafish to investigate the mechanisms by which YWHAZ contributes to neurodevelopmental disorders. We observed that ywhaz expression was pan-neuronal during developmental stages and restricted to Purkinje cells in the adult cerebellum, cells that are described to be reduced in number and size in autistic patients. We then performed whole-brain imaging in wild-type and ywhaz CRISPR/Cas9 knockout (KO) larvae and found altered neuronal activity and connectivity in the hindbrain. Adult ywhaz KO fish display decreased levels of monoamines in the hindbrain and freeze when exposed to novel stimuli, a phenotype that can be reversed with drugs that target monoamine neurotransmission. These findings suggest an important role for ywhaz in establishing neuronal connectivity during development and modulating both neurotransmission and behaviour in adults.

Relationship between burning mouth disorder and gastroesophageal reflux disease: A scoping review.

OBJECTIVE: This study aims to provide a scoping review and attempts to uncover the possible association between burning mouth disorder and gastroesophageal reflux disease. METHODS: PubMed, EMBASE, Web of Science, the Cochrane Library, Ovid, Scopus, and a search platform (EBSCOhost) were searched from their inception to August 22, 2023. RESULTS: After screening 2795 records, 18 articles were included in the final review, comprising cross-sectional studies (n = 9), case-control studies (n = 5), case reports (n = 2), case series (n = 1), and experimental study (n = 1). The prevalence of gastroesophageal reflux disease and its extraesophageal manifestations of laryngopharyngeal reflux in burning mouth patients was reported 3.39%-23.4% and 50%-93.8%, respectively, while oral burning was reported in 9%-45% of patients with gastroesophageal reflux disease. In case-control studies, gastroesophageal reflux disease was more prevalent in patients with burning mouth disorder compared with controls. Burning mouth would be resolved after antireflux therapy in laryngopharyngeal reflux patients in case series. PH value and saliva alternation might be the possible mechanisms. CONCLUSION: The possibility of the correlation between burning mouth disorder and gastroesophageal reflux disease still needs to be clearly demonstrated through better-conducted studies. The link between them is worth to be explored in future research.

Differential RNA Transcriptome in Ustekinumab Responders vs Non-Responders.

Despite numerous available psoriasis treatments, no "one size fits all" regimen provides complete disease control without side effects, logistical obstacles, and/or expense. Despite increasingly efficacious drugs, only 20-25% of patients treated with biologic therapies achieve completely clear skin (PASI 100) and even fewer achieve this if they have experienced failures of multiple biologics.

Development of a therapeutic anti-HtrA1 antibody and the identification of DKK3 as a pharmacodynamic biomarker in geographic atrophy.

Genetic polymorphisms in the region of the trimeric serine hydrolase high-temperature requirement 1 (HTRA1) are associated with increased risk of age-related macular degeneration (AMD) and disease progression, but the precise biological function of HtrA1 in the eye and its contribution to disease etiologies remain undefined. In this study, we have developed an HtrA1-blocking Fab fragment to test the therapeutic hypothesis that HtrA1 protease activity is involved in the progression of AMD. Next, we generated an activity-based small-molecule probe (ABP) to track target engagement in vivo. In addition, we used N-terminomic proteomic profiling in preclinical models to elucidate the in vivo repertoire of HtrA1-specific substrates, and identified substrates that can serve as robust pharmacodynamic biomarkers of HtrA1 activity. One of these HtrA1 substrates, Dickkopf-related protein 3 (DKK3), was successfully used as a biomarker to demonstrate the inhibition of HtrA1 activity in patients with AMD who were treated with the HtrA1-blocking Fab fragment. This pharmacodynamic biomarker provides important information on HtrA1 activity and pharmacological inhibition within the ocular compartment.

Psychiatric Emergencies in Los Angeles County During, and After, Initial COVID-19 Societal Restrictions: An Interrupted Time-Series Analysis.

Emergency department (ED) visits for psychiatric care in the US reportedly declined during the COVID-19 pandemic. This work, however, does not control for strong temporal patterning in visits before the pandemic and does not examine a potential "rebound" in demand for psychiatric care following the relaxation of initial societal restrictions. Here, we examine COVID-19-related perturbations in psychiatric care during and after the 1st stage of societal restrictions in the largest safety-net hospital in Los Angeles. We retrieved psychiatric ED visit data (98,888 total over 156 weeks, Jan 2018 to Dec 2020) from Los Angeles County + USC Medical Center. We applied interrupted time series methods to identify and control for autocorrelation in psychiatric ED visits before examining their relation with the 1st stage of societal restrictions (i.e., March 13 to May 8, 2020), as well as the subsequent "rebound" period of relaxed restrictions (i.e., after May 8, 2020). Psychiatric ED visits fell by 78.13 per week (i.e., 12%) during the 1st stage of societal restrictions (SD = 23.99, p < 0.01). Reductions in ED visits for alcohol use, substance use, and (to a lesser extent) anxiety disorders accounted for the overall decline. After the 1st stage of societal restrictions, however, we observe no "rebound" above expected values in psychiatric ED visits overall (coef = - 16.89, SD = 20.58, p = 0.41) or by diagnostic subtype. This pattern of results does not support speculation that, at the population level, foregoing ED care during initial societal restrictions subsequently induced a psychiatric "pandemic" of urgent visits.

Social dominance and rainfall predict telomere dynamics in a cooperative arid-zone bird.

In many vertebrate societies dominant individuals breed at substantially higher rates than subordinates, but whether this hastens ageing remains poorly understood. While frequent reproduction may trade off against somatic maintenance, the extraordinary fecundity and longevity of some social insect queens highlight that breeders need not always suffer more rapid somatic deterioration than their nonbreeding subordinates. Here, we used extensive longitudinal assessments of telomere dynamics to investigate the impact of dominance status on within-individual age-related changes in somatic integrity in a wild social bird, the white-browed sparrow-weaver (Plocepasser mahali). Dominant birds, who monopolise reproduction, had neither shorter telomeres nor faster telomere attrition rates over the long-term (1-5 years) than their subordinates. However, over shorter (half-year) time intervals dominants with shorter telomeres showed lower rates of telomere attrition (and evidence suggestive of telomere lengthening), while the same was not true among subordinates. Dominants may therefore invest more heavily in telomere length regulation (and/or somatic maintenance more broadly); a strategy that could mitigate the long-term costs of reproductive effort, leaving their long-term telomere dynamics comparable to those of subordinates. Consistent with the expectation that reproduction entails short-term costs to somatic integrity, telomere attrition rates were most severe for all birds during the breeding seasons of wetter years (rainfall is the key driver of reproductive activity in this arid-zone species). Our findings suggest that, even in vertebrate societies in which dominants monopolise reproduction, dominants may experience long-term somatic integrity trajectories indistinguishable from those of their nonreproductive subordinates.

Exogenous Oncostatin M induces Cardiac Dysfunction, Musculoskeletal Atrophy, and Fibrosis.

Musculoskeletal diseases such as muscular dystrophy, cachexia, osteoarthritis, and rheumatoid arthritis impair overall physical health and reduce survival. Patients suffer from pain, dysfunction, and dysmobility due to inflammation and fibrosis in bones, muscles, and joints, both locally and systemically. The Interleukin-6 (IL-6) family of cytokines, most notably IL-6, is implicated in musculoskeletal disorders and cachexia. Here we show elevated circulating levels of OSM in murine pancreatic cancer cachexia and evaluate the effects of the IL-6 family member, Oncostatin M (OSM), on muscle and bone using adeno-associated virus (AAV) mediated over-expression of murine OSM in wildtype and IL-6 deficient mice. Initial studies with high titer AAV-OSM injection yielded high circulating OSM and IL-6, thrombocytosis, inflammation, and 60% mortality without muscle loss within 4 days. Subsequently, to mimic OSM levels in cachexia, a lower titer of AAV-OSM was used in wildtype and Il6 null mice, observing effects out to 4 weeks and 12 weeks. AAV-OSM caused muscle atrophy and fibrosis in the gastrocnemius, tibialis anterior, and quadriceps of the injected limb, but these effects were not observed on the non-injected side. In contrast, OSM induced both local and distant trabecular bone loss as shown by reduced bone volume, trabecular number, and thickness, and increased trabecular separation. OSM caused cardiac dysfunction including reduced ejection fraction and reduced fractional shortening. RNA-sequencing of cardiac muscle revealed upregulation of genes related to inflammation and fibrosis. None of these effects were different in IL-6 knockout mice. Thus, OSM induces local muscle atrophy, systemic bone loss, tissue fibrosis, and cardiac dysfunction independently of IL-6, suggesting a role for OSM in musculoskeletal conditions with these characteristics, including cancer cachexia.

Perfect Chirality with Imperfect Polarization.

Unidirectional (chiral) emission of light from a circular dipole emitter into a waveguide is only possible at points of perfect circular polarization (C points), with elliptical polarizations yielding a lower directional contrast. However, there is no need to restrict engineered systems to circular dipoles, and with an appropriate choice of dipole unidirectional emission is possible for any elliptical polarization. Using elliptical dipoles, rather than circular, typically increases the size of the area suitable for chiral interactions (in an exemplary mode by a factor ∼30), while simultaneously increasing coupling efficiencies. We propose illustrative schemes to engineer the necessary elliptical transitions in both atomic systems and quantum dots.