Strain dropouts reveal interactions that govern the metabolic output of the gut microbiome.

The gut microbiome is complex, raising questions about the role of individual strains in the community. Here, we address this question by constructing variants of a complex defined community in which we eliminate strains that occupy the bile acid 7α-dehydroxylation niche. Omitting Clostridium scindens (Cs) and Clostridium hylemonae (Ch) eliminates secondary bile acid production and reshapes the community in a highly specific manner: eight strains change in relative abundance by >100-fold. In single-strain dropout communities, Cs and Ch reach the same relative abundance and dehydroxylate bile acids to a similar extent. However, Clostridium sporogenes increases >1,000-fold in the ΔCs but not ΔCh dropout, reshaping the pool of microbiome-derived phenylalanine metabolites. Thus, strains that are functionally redundant within a niche can have widely varying impacts outside the niche, and a strain swap can ripple through the community in an unpredictable manner, resulting in a large impact on an unrelated community-level phenotype.

GSDMB is increased in IBD and regulates epithelial restitution/repair independent of pyroptosis.

Gasdermins are a family of structurally related proteins originally described for their role in pyroptosis. Gasdermin B (GSDMB) is currently the least studied, and while its association with genetic susceptibility to chronic mucosal inflammatory disorders is well established, little is known about its functional relevance during active disease states. Herein, we report increased GSDMB in inflammatory bowel disease, with single-cell analysis identifying epithelial specificity to inflamed colonocytes/crypt top colonocytes. Surprisingly, mechanistic experiments and transcriptome profiling reveal lack of inherent GSDMB-dependent pyroptosis in activated epithelial cells and organoids but instead point to increased proliferation and migration during in vitro wound closure, which arrests in GSDMB-deficient cells that display hyper-adhesiveness and enhanced formation of vinculin-based focal adhesions dependent on PDGF-A-mediated FAK phosphorylation. Importantly, carriage of disease-associated GSDMB SNPs confers functional defects, disrupting epithelial restitution/repair, which, altogether, establishes GSDMB as a critical factor for restoration of epithelial barrier function and the resolution of inflammation.

Depletion of complement factor 3 delays the neuroinflammatory response to intracortical microelectrodes.

The neuroinflammatory response to intracortical microelectrodes (IMEs) used with brain-machine interfacing (BMI) applications is regarded as the primary contributor to poor chronic performance. Recent developments in high-plex gene expression technologies have allowed for an evolution in the investigation of individual proteins or genes to be able to identify specific pathways of upregulated genes that may contribute to the neuroinflammatory response. Several key pathways that are upregulated following IME implantation are involved with the complement system. The complement system is part of the innate immune system involved in recognizing and eliminating pathogens - a significant contributor to the foreign body response against biomaterials. Specifically, we have identified Complement 3 (C3) as a gene of interest because it is the intersection of several key complement pathways. In this study, we investigated the role of C3 in the IME inflammatory response by comparing the neuroinflammatory gene expression at the microelectrode implant site between C3 knockout (C3-/-) and wild-type (WT) mice. We have found that, like in WT mice, implantation of intracortical microelectrodes in C3-/- mice yields a dramatic increase in the neuroinflammatory gene expression at all post-surgery time points investigated. However, compared to WT mice, C3 depletion showed reduced expression of many neuroinflammatory genes pre-surgery and 4 weeks post-surgery. Conversely, depletion of C3 increased the expression of many neuroinflammatory genes at 8 weeks and 16 weeks post-surgery, compared to WT mice. Our results suggest that C3 depletion may be a promising therapeutic target for acute, but not chronic, relief of the neuroinflammatory response to IME implantation. Additional compensatory targets may also be required for comprehensive long-term reduction of the neuroinflammatory response for improved intracortical microelectrode performance.

Amniotic fluid gamma-glutamyl transferase for prediction of biliary atresia in cases of non-visualisation of the fetal gallbladder: a retrospective study using a validated analytical platform and local reference range.

INTRODUCTION: The level of amniotic fluid gamma-glutamyl transferase (AFGGT) may help identify biliary atresia (BA) in cases of non-visualisation of the fetal gallbladder (NVFGB). This study aimed to validate a serum/plasma matrix-based gamma-glutamyl transferase (GGT) assay for amniotic fluid (AF) samples, establish a local gestational age-specific AFGGT reference range, and evaluate the efficacy of AFGGT for predicting fetal BA in pregnancies with NVFGB using the constructed reference range. METHODS: The analytical performance of a serum/plasma matrix-based GGT assay on AF samples was evaluated using a Cobas c502 analyser. Amniotic fluid gamma-glutamyl transferase levels in confirmed euploid singleton pregnancies (16+0 to 22+6 weeks of gestation) were determined using the same analyser to establish a local gestational age-specific reference range (the 2.5th to 97.5th percentiles). This local reference range was used to determine the positive predictive value (PPV) and negative predictive value (NPV) of AFGGT level <2.5th percentile for identifying fetal BA in euploid pregnancies with NVFGB. RESULTS: The serum/plasma matrix-based GGT assay was able to reliably and accurately determine GGT levels in AF samples. Using the constructed local gestational age-specific AFGGT reference range, the NPV and PPV of AFGGT level <2.5th percentile for predicting fetal BA in pregnancies with NVFGB were 100% and 25% (95% confidence interval=0, 53), respectively. CONCLUSION: In pregnancies with NVFGB, AFGGT level ≥2.5th percentile likely excludes fetal BA. Although AFGGT level <2.5th percentile is not diagnostic of fetal BA, fetuses with AFGGT below this level should be referred for early postnatal investigation.

MBOAT7-driven lysophosphatidylinositol acylation in adipocytes contributes to systemic glucose homeostasis.

We previously demonstrated that antisense oligonucleotide-mediated knockdown of Mboat7, the gene encoding membrane bound O-acyltransferase 7, in the liver and adipose tissue of mice promoted high fat diet-induced hepatic steatosis, hyperinsulinemia, and systemic insulin resistance. Thereafter, other groups showed that hepatocyte-specific genetic deletion of Mboat7 promoted striking fatty liver and NAFLD progression in mice but does not alter insulin sensitivity, suggesting the potential for cell autonomous roles. Here, we show that MBOAT7 function in adipocytes contributes to diet-induced metabolic disturbances including hyperinsulinemia and systemic insulin resistance. We generated Mboat7 floxed mice and created hepatocyte- and adipocyte-specific Mboat7 knockout mice using Cre-recombinase mice under the control of the albumin and adiponectin promoter, respectively. Here, we show that MBOAT7 function in adipocytes contributes to diet-induced metabolic disturbances including hyperinsulinemia and systemic insulin resistance. The expression of Mboat7 in white adipose tissue closely correlates with diet-induced obesity across a panel of ∼100 inbred strains of mice fed a high fat/high sucrose diet. Moreover, we found that adipocyte-specific genetic deletion of Mboat7 is sufficient to promote hyperinsulinemia, systemic insulin resistance, and mild fatty liver. Unlike in the liver, where Mboat7 plays a relatively minor role in maintaining arachidonic acid-containing PI pools, Mboat7 is the major source of arachidonic acid-containing PI pools in adipose tissue. Our data demonstrate that MBOAT7 is a critical regulator of adipose tissue PI homeostasis, and adipocyte MBOAT7-driven PI biosynthesis is closely linked to hyperinsulinemia and insulin resistance in mice.

Long-term trends in the incidence and management of shoulder dystocia in a tertiary obstetric unit in Hong Kong.

INTRODUCTION: Because there have been changes in the management of macrosomic pregnancies and shoulder dystocia in the past decade, this study was conducted to compare the incidences of shoulder dystocia and perinatal outcomes between the periods of 2000-2009 and 2010-2019. METHODS: This retrospective study was conducted in a tertiary obstetric unit. All cases of shoulder dystocia were identified using the hospital's electronic database. The incidences, maternal and fetal characteristics, obstetric management methods, and perinatal outcomes were compared between the two study periods. RESULTS: The overall incidence of shoulder dystocia decreased from 0.23% (134/58 326) in 2000-2009 to 0.16% (108/65 683) in 2010-2019 (P=0.009), mainly because of the overall decline in the proportion of babies with macrosomia (from 3.3% to 2.3%; P<0.001). The improved success rates of the McRoberts' manoeuvre (from 31.3% to 47.2%; P=0.012) and posterior arm extraction (from 52.9% to 92.3%; P=0.042) allowed a greater proportion of affected babies to be delivered within 2 minutes (from 59.0% to 79.6%; P=0.003). These changes led to a significant reduction in the proportion of fetuses with low Apgar scores: <5 at 1 minute of life (from 13.4% to 5.6%; P=0.042) and <7 at 5 minutes of life (from 11.9% to 4.6%; P=0.045). CONCLUSION: More proactive management of macrosomic pregnancies and enhanced training in the acute management of shoulder dystocia led to significant improvements in shoulder dystocia incidence and perinatal outcomes from 2000-2009 to 2010-2019.

User perceptions of COVID-19 telemedicine testing services, disease risk, and pandemic preparedness: findings from a private clinic in Hong Kong.

INTRODUCTION: During the coronavirus disease 2019 (COVID-19) pandemic, telemedicine has been regarded as a method for providing safe access to healthcare. Here, we explored the experiences of individuals using telemedicine in Hong Kong during the COVID-19 pandemic to understand their risk perceptions and preparedness measures. METHODS: We conducted a cross-sectional online survey of telemedicine users of private clinic-based COVID-19 testing services from 6 April to 11 May 2020. All users were invited to complete an anonymous online survey regarding COVID-19 risk perception and preparedness measures. The results of the survey were compared with the findings of a previous territory-wide survey. RESULTS: In total, 141 of 187 telemedicine users agreed to participate; the response rate was 75.4%. Of the participants, 95.1% (116/122) believed that telemedicine consultations were useful. Nearly half of the participants (49.0%) agreed or strongly agreed that telemedicine consultations were appropriate during the COVID-19 pandemic. Most participants believed that telemedicine consultations could perform the functions of 'health protection, promotion and disease prevention' (73.6%) and 'diagnosis' (64.0%). Concerning the choice of telemedicine provider, almost all participants (99.2%) were willing to consult medical doctors; more than half of the participants (54.1%) were willing to consult registered nurses, but only 13.1% were willing to consult non-clinical staff who had been trained to provide telemedicine services. CONCLUSION: The use of telemedicine for screening and patient education can be encouraged during the COVID-19 pandemic in Hong Kong.

Descriptive analysis of poisoning cases involving attention deficit hyperactivity disorder medications in Hong Kong.

INTRODUCTION: The number of poisoning cases involving attention deficit hyperactivity disorder (ADHD) medications has reportedly risen with their increased use. However, there is limited relevant evidence from Asia. We analysed the characteristics of poisoning events involving these medications in Hong Kong. METHODS: We retrieved data regarding ADHD medication-related poisoning cases from the Hong Kong Poison Information Centre and conducted a descriptive analysis of the demographic information and poisoning information including sources of cases, exposure reason, exposure location, and outcome. The HKPIC data were linked with the Hospital Authority Clinical Data Analysis and Reporting System (CDARS) via de-identified Accident and Emergency numbers of public hospitals to investigate clinical characteristics. We also retrieved ADHD medication prescription records from the CDARS, then compared trends between poisoning cases and ADHD medication use. RESULTS: We identified 72 poisoning cases involving ADHD medications between 2009 and 2019, of which approximately 70% occurred in the affected individual's residence; most were intentional poisoning events (65.3%). No statistically significant association was observed between ADHD medication prescription trends and poisoning events involving ADHD medications. Of the 66 cases (91.7%) successfully linked to CDARS, 40 (60.6%) occurred in individuals with ADHD (median age: 14 years); 26 (39.4%) occurred in individuals who lacked ADHD (median age: 33 years) but displayed higher rates of other mental disorders including depression and anxiety. CONCLUSION: No significant correlation was evident between ADHD medication prescriptions and poisoning events involving ADHD medications. However, medication management and caregiver education must be emphasised to prevent potential poisoning events.

Macrophage-Hypoxia-Inducible Factor-1α Signaling in Carotid Artery Stenosis.

Macrophages play crucial and diverse roles in the pathogenesis of inflammatory vascular diseases. Macrophages are the principal innate immune cells recruited to arterial walls to govern vascular homeostasis by modulating the proliferation of vascular smooth muscle cells, the reorganization of extracellular matrix components, the elimination of dead cells, and the restoration of normal blood flow. However, chronic sterile inflammation within the arterial walls draws inflammatory macrophages into intimal/neointimal regions that may contribute to disease pathogenesis. In this context, the accumulation and aberrant activation of macrophages in the neointimal regions govern the progression of inflammatory arterial wall diseases. Herein, we report that myeloid-hypoxia-inducible factor-1α (HIF1α) deficiency attenuates vascular smooth muscle cells and macrophage abundance in stenotic arteries and abrogates carotid neointima formation in vivo. The integrated transcriptomics, Gene Set Enrichment Analysis, metabolomics, and target gene evaluation showed that HIF1α represses oxidative phosphorylation, tricarboxylic acid cycle, fatty acid metabolism, and c-MYC signaling pathways while promoting inflammatory, glycolytic, hypoxia response gene expression in stenotic artery macrophages. At the molecular level, proinflammatory agents utilized STAT3 signaling pathways to elevate HIF1α expression in macrophages. Collectively, this study uncovers that macrophage-HIF1α deficiency restrains the pathogenesis of carotid artery stenosis by rewiring inflammatory and metabolic signaling pathways in macrophages.

BHLHE40 promotes macrophage pro-inflammatory gene expression and functions.

Macrophages are the principal innate immune cells that populate all major organs and provide the first line of cellular defense against infections and/or injuries. The immediate and early-responding macrophages must mount a robust pro-inflammatory response to protect the host by eliminating deleterious agents. The effective pro-inflammatory macrophage response requires the activation of complex transcriptional programs that modulate the dynamic regulation of inflammatory and metabolic gene expression. Therefore, transcription factors that govern pro-inflammatory and metabolic gene expression play an essential role in shaping the macrophage inflammatory response. Herein, we identify the basic helix-loop-helix family member e40 (BHLHE40), as a critical transcription factor that promotes broad pro-inflammatory and glycolytic gene expression by elevating HIF1α levels in macrophages. Our in vivo studies revealed that myeloid-BHLHE40 deficiency significantly attenuates macrophage and neutrophil recruitment to the site of inflammation. Our integrated transcriptomics and gene set enrichment analysis (GSEA) studies show that BHLHE40 deficiency broadly curtails inflammatory signaling pathways, hypoxia response, and glycolytic gene expression in macrophages. Utilizing complementary gain- and loss-of-function studies, our analyses uncovered that BHLHE40 promotes LPS-induced HIF1α mRNA and protein expression in macrophages. More importantly, forced overexpression of oxygen stable form of HIF1α completely reversed attenuated pro-inflammatory and glycolytic gene expression in BHLHE40-deficient macrophages. Collectively, these results demonstrate that BHLHE40 promotes macrophage pro-inflammatory gene expression and functions by elevating HIF1α expression in macrophages.

Role of pre-operative ureteral stent on outcomes of retrograde intra-renal surgery (RIRS): systematic review and meta-analysis of 3831 patients and comparison of Asian and non-Asian cohorts.

PURPOSE: To evaluate the outcomes of pre-stented (PS) versus non-pre-stented (NPS) patients who have undergone retrograde intrarenal surgery (RIRS) for renal calculi with subgroup analysis of Asian and non-Asian cohorts. METHODS: Protocol is registered in PROSPERO, CRD42021261123. Eligible studies identified from four electronic databases. Meta-analysis was done to enumerate the outcomes of RIRS in between PS and NPS. Secondary sub-analysis was done to look for differences in outcomes in Asian and non-Asian cohorts. RESULTS: Fourteen studies involving 3831 patients (4 prospective, 10 retrospective studies) were included. PS patients experienced higher success rates of ureteral access sheath (UAS) insertion than NPS (RR 1.09, 95% CI 1.05-1.13, p < 0.00001). PS patients had lower risk of ureteral injuries from UAS placement (RR 0.69, 95% CI 0.50-0.96, p = 0.03). No significant differences in intra- and postoperative complications between two groups were found. Stone-free rate (SFR) outcomes for residual fragment (RF) cut-off of < 1 mm and < 4 mm favoured the PS patients (RR 1.10, 95% CI 1.04-1.17, p = 0.002 for < 4 mm, RR1.10, 95% CI 1.02-1.19, p = 0.02 for < 1 mm). In the subgroup analysis, PS Asian patients had similar SFR as NPS patients for SFR(< 4 mm) but non-Asian population showed better outcomes in the PS patients for SFR(< 4 mm) (RR 1.31, 95% CI 1.13-1.52, p = 0.0005). CONCLUSIONS: This meta-analysis suggests that pre-stenting results in a higher success for UAS placement, minimising intraoperative ureteric injury, with higher overall SFR for any RF cut-off in PS cohorts. In non-Asian cohort, significant differences occurred at SFR < 4 mm but not for SFR < 1 mm. No difference was seen in our Asian cohort for any SFR cut-off in both PS and NPS patients.

Systematic review and meta-analysis of ketamine-associated uropathy.

INTRODUCTION: This systematic review and meta-analysis focused on the literature regarding ketamine-associated uropathy to summarise its clinical manifestations, the results of urological assessments, and current management. METHODS: A literature search was conducted using keywords and MeSH terms related to ketamine abuse, urinary tracts, and urological examinations. Databases including Embase, MEDLINE, and the Cochrane Central Register of Controlled Trials were searched up to 26 June 2020. RESULTS: In total, 1365 articles were retrieved; 45 articles (4921 patients) were included in the analysis of patient demographics, clinical manifestations, examination results, and treatments. Frequency was the most common manifestation (pooled prevalence 77.1%, 95% confidence interval [CI]=56.9%-92.2%), followed by urgency (69.9%, 95% CI=48.8%-87.3%) and suprapubic pain (60.4%, 95% CI=35.3%-82.9%). Upper urinary tract involvement was less common; the pooled prevalence of hydronephrosis was 30.2% (95% CI=22.0%-39.2%). Further workup revealed a pooled functional bladder capacity of 95.23 mL (95% CI=63.57-126.88 mL), pooled voided volume of 113.31 mL (95% CI=59.44- 167.19 mL), and pooled maximum urine flow rate of 8.69 mL/s (95% CI=5.54-11.83 mL/s). Cystoscopic examinations and bladder biopsy revealed frequent urothelial denudation, inflammatory changes, and inflammatory cell infiltration. Treatments included oral medications for symptomatic relief, intravesical therapy, and surgery (eg, hydrodistension and bladder reconstruction), but ketamine abstinence was necessary for improvement. CONCLUSION: Ketamine-associated uropathy frequently involves frequency, urgency, and suprapubic pain; upper urinary tract involvement is less common. Affected patients showed reductions in bladder capacity and urine flow rate. Endoscopic and histological analyses often revealed cystitis. Despite variations in treatment, ketamine abstinence is important for all patients with ketamine-associated uropathy.

Recommendations for the management of advanced and metastatic renal cell carcinoma: joint consensus statements from the Hong Kong Urological Association and the Hong Kong Society of Uro-Oncology.

INTRODUCTION: Kidney cancer, primarily renal cell carcinoma (RCC), ranks among the top 10 most common malignancies in the male population of Hong Kong. In 2019, members of two medical societies in Hong Kong formed an expert panel to establish a set of consensus statements for the management of metastatic RCC. On 22 June 2021, the same panel met to review recent evidence and reassess their positions regarding the management of advanced and metastatic RCC, with the aim of providing recommendations for physicians in Hong Kong. PARTICIPANTS: The panel included 12 experts (6 clinical oncologists and 6 urologists) who had extensive experience managing patients with RCC in Hong Kong. EVIDENCE: The panel reviewed randomised controlled trials, observational studies, systematic reviews/meta-analyses, and international clinical guidelines to address key clinical questions that were identified before the meeting. CONSENSUS PROCESS: In total, 15 key clinical questions were identified before the meeting, covering the surgical and systemic treatment of advanced or metastatic clear cell, sarcomatoid, and non-clear cell RCCs. At the meeting, the panellists voted on these questions, then discussed relevant evidence and practical considerations. CONCLUSIONS: The treatment landscape for advanced and metastatic RCC continues to evolve. More immune checkpoint inhibitor (ICI)-based combination regimens will be indicated for the treatment of metastatic clear cell RCC. There is increasing evidence concerning the benefit of adjuvant ICI treatment for resected advanced RCC. This article summarises recent evidence and expert insights regarding a series of key clinical questions about the management of advanced and metastatic RCC.

Characterization of the mid-coronal plane method for measurement of radiographic change in knee joint space width across different levels of image parallax.

OBJECTIVE: Radiographic measurement of the change in knee joint space width (ΔJSW) is often affected by image parallax, which causes an apparent exaggeration of JSW due to projectional differences. This issue with parallax (quantified by intermargin distance) can in part be addressed with a novel mid-coronal plane (MCP) measurement method. The objectives of the study were to determine 1) accuracy and 2) reproducibility of the MCP method, and 3) compare the MCP method to that used in the Osteoarthritis Initiative (OAI) for different categories of parallax. METHODS: Posteroanterior radiographs (n = 70) with known JSW were digitally reconstructed from CT images of cadaver knees and used to determine the accuracy of ΔJSW using the MCP method for parallax categories of None, Mild/Moderate, and Severe. Reproducibility was determined from pairs of clinical radiographs selected from the OAI (n = 170). The MCP method was also compared to the OAI methodology. Both reproducibility and agreement were characterized by Bland-Altman analysis and intraclass correlation coefficients (ICC). RESULTS: The MCP method was accurate to 0.11 mm in cases with no parallax, and 0.18 mm across all categories of parallax for medial and lateral compartments. Reproducibility of the MCP method was graded "excellent" (ICC 0.98, 95% CI [0.98, 0.99]). The MCP results agreed very well with the OAI (ICC 0.92, 95% CI [0.89, 0.94]), with mean absolute differences between methods increasing with increasing parallax. CONCLUSION: The MCP method is an accurate, reproducible alternative to the OAI method for multi-center clinical trials where subject and X-ray beam positioning may be variable.

Kruppel-like factor 6 promotes macrophage inflammatory and hypoxia response.

Macrophages are the professional phagocytes that protect the host from infection or injury. Tissue microenvironment at the site of injury and inflammation is characterized by low oxygen concentration and poor supply of nutrients. The responding macrophages have to advance against oxygen and nutrient gradients to reach the site of inflammation to perform host protection, and tissue repair functions. Thus, evolution has fashioned macrophages to orchestrate a coordinated inflammatory and hypoxic gene program to mount an effective immune response. Here, we discovered that Kruppel-like factor 6 (KLF6) governs macrophage functions by promoting inflammatory and hypoxic response gene programming. Our in vivo studies revealed that myeloid-KLF6-deficient mice were highly resistant to endotoxin-induced systemic inflammatory response syndrome symptomatology and mortality. Using complementary gain- and loss-of-function studies, we observed that KLF6 overexpression elevate and KLF6 deficiency attenuate inducible HIF1α expression in macrophages. Our integrated transcriptomics and gene set enrichment analysis studies uncovered that KLF6 deficiency attenuates broad inflammatory and glycolytic gene expression in macrophages. More importantly, overexpression of oxygen stable HIF1α reversed attenuated proinflammatory and glycolytic gene expression in KLF6-deficient macrophages. Collectively, our studies uncovered that KLF6 govern inflammatory and hypoxic response by regulating HIF1α expression in macrophage.

CITED2 limits pathogenic inflammatory gene programs in myeloid cells.

Monocyte-derived macrophages are the major innate immune cells that provide the first line of cellular defense against infections or injuries. These recruited macrophages at the site of inflammation are exposed to a broad range of cytokines that categorically incite a robust pro-inflammatory response. However, macrophage pro-inflammatory activation must be under exquisite control to avert unbridled inflammation. Thus, endogenous mechanisms must exist that rigorously preserve macrophage quiescence and yet, allow nimble pro-inflammatory macrophage response with precise spatiotemporal control. Herein, we identify the CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl-terminal domain 2 (CITED2) as a critical intrinsic negative regulator of inflammation, which broadly attenuates pro-inflammatory gene programs in macrophages. Our in vivo studies revealed that myeloid-CITED2 deficiency significantly heightened macrophages and neutrophils recruitment to the site of inflammation. Our integrated transcriptomics and gene set enrichment analysis (GSEA) studies uncovered that CITED2 deficiency broadly enhances NFκB targets, IFNγ/IFNα responses, and inflammatory response gene expression in macrophages. Using complementary gain- and loss-of-function studies, we observed that CITED2 overexpression attenuate and CITED2 deficiency elevate LPS-induced NFκB transcriptional activity and NFκB-p65 recruitment to target gene promoter in macrophages. More importantly, blockade of NFκB signaling completely reversed elevated pro-inflammatory gene expression in macrophages. Collectively, our findings show that CITED2 restrains NFκB activation and curtails broad pro-inflammatory gene programs in myeloid cells.

Ecological Transitions in Grouping Benefits Explain the Paradox of Environmental Quality and Sociality.

Both benign and harsh environments promote the evolution of sociality. This paradox-societies occur in environments of such contrasting quality-may be explained by the different types of benefits that individuals receive from grouping: resource defense benefits that derive from group-defended critical resources versus collective action benefits that result from social cooperation among group members. Here, we investigate cooperative behavior in the burying beetle Nicrophorus nepalensis along an elevational gradient where environmental quality (climate and competition) varies with altitude. We show that climate (temperature) and competition (both intra- and interspecific) independently and synergistically influence sociality via different grouping benefits that vary along the gradient. At low elevations where interspecific competition for resources is intense, groups gain from the collective action benefit of increased interspecific competitive ability. In contrast, pairs have higher fitness at intermediate elevations where intraspecific competition for resources is greatest because resource defense is the key grouping benefit. However, groups and pairs have similar fitness at high elevations, suggesting that there is no grouping benefit in such physiologically challenging environments. Our results demonstrate that sociality is favored for different reasons under a range of environmental conditions, perhaps explaining why animal societies occur in environments of such contrasting quality.

Androgen Deprivation Induces Transcriptional Reprogramming in Prostate Cancer Cells to Develop Stem Cell-Like Characteristics.

Enzalutamide, an antiandrogen, is approved for therapy of castration resistant prostate cancer. Clinical applications have shown that approximately 30% of patients acquire resistance after a short period of treatment. However, the molecular mechanisms underlying this resistance is not completely understood. To identify transcriptomic signatures associated with acquisition of drug resistance we profiled gene expression of paired enzalutamide sensitive and resistant human prostate cancer LNCaP (lymph node carcinoma of the prostate) and C4-2B cells. Overlapping genes differentially regulated in the enzalutamide resistant cells were ranked by Ingenuity Pathway Analysis and their functional validation was performed using ingenuity knowledge database followed by confirmation to correlate transcript with protein expression. Analysis revealed that genes associated with cancer stem cells, such as POU5F1 (OCT4), SOX2, NANOG, BMI1, BMP2, CD44, SOX9, and ALDH1 were markedly upregulated in enzalutamide resistant cells. Amongst the pathways enriched in the enzalutamide-resistant cells were those associated with RUNX2, hedgehog, integrin signaling, and molecules associated with elastic fibers. Further examination of a patient cohort undergoing ADT and its comparison with no-ADT group demonstrated high expression of POU5F1 (OCT4), ALDH1, and SOX2 in ADT specimens, suggesting that they may be clinically relevant therapeutic targets. Altogether, our approach exhibits the potential of integrative transcriptomic analyses to identify critical genes and pathways of antiandrogen resistance as a promising approach for designing novel therapeutic strategies to circumvent drug resistance.

Resolving the Paradox of Environmental Quality and Sociality: The Ecological Causes and Consequences of Cooperative Breeding in Two Lineages of Birds.

Cooperatively breeding animals occur in virtually every ecosystem on earth. Comparative and biogeographic studies suggest that both benign and harsh-as well as stable and fluctuating-environments can favor the evolution of cooperative breeding behavior. The fact that cooperative societies occur in environments of such contrasting quality creates a paradox of environmental quality and sociality. The dual benefits framework-which leads to the prediction that the ecological consequences of sociality (e.g., range size) vary depending on the benefits that individuals of each species receive by forming social groups-offers a potential resolution to this paradox. Here we use a case study of two avian lineages, starlings (Sturnidae) and hornbills (Bucerotidae), in which environmental unpredictability appears to have opposite effects on the evolution of cooperation to test the dual benefits framework. Consistent with previous work, harsh and unpredictable environments promote cooperative breeding behavior in starlings, which in turn leads to larger geographic ranges. However, cooperatively breeding hornbills occur in benign and stable environments, but sociality does not influence range size. Our study suggests that the paradox of environmental quality and sociality arises largely because cooperative breeding is an umbrella term encompassing social species that form groups for different reasons. We demonstrate that differentiating among the functional causes of social group formation is critical for developing a predictive framework for understanding the evolution of cooperative breeding behavior.