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Over the last 2 decades, omalizumab is the only anti-IgE antibody that has been approved for asthma and chronic spontaneous urticaria (CSU). Ligelizumab, a higher-affinity anti-IgE mAb and the only rival viable candidate in late-stage clinical trials, showed anti-CSU efficacy superior to that of omalizumab in phase IIb but not in phase III. This report features the antigenic-functional characteristics of UB-221, an anti-IgE mAb of a newer class that is distinct from omalizumab and ligelizumab. UB-221, in free form, bound abundantly to CD23-occupied IgE and, in oligomeric mAb-IgE complex forms, freely engaged CD23, while ligelizumab reacted limitedly and omalizumab stayed inert toward CD23; these observations are consistent with UB-221 outperforming ligelizumab and omalizumab in CD23-mediated downregulation of IgE production. UB-221 bound IgE with a strong affinity to prevent FcԑRI-mediated basophil activation and degranulation, exhibiting superior IgE-neutralizing activity to that of omalizumab. UB-221 and ligelizumab bound cellular IgE and effectively neutralized IgE in sera of patients with atopic dermatitis with equal strength, while omalizumab lagged behind. A single UB-221 dose administered to cynomolgus macaques and human IgE (ε, κ)-knockin mice could induce rapid, pronounced serum-IgE reduction. A single UB-221 dose administered to patients with CSU in a first-in-human trial exhibited durable disease symptom relief in parallel with a rapid reduction in serum free-IgE level.

Rationale: Stimulation of the NLRP3 inflammasome by metabolic byproducts is known to result in inflammatory responses and metabolic diseases. However, how the host controls aberrant NLRP3 inflammasome activation remains unclear. PPARγ, a known regulator of energy metabolism, plays an anti-inflammatory role through the inhibition of NF-κB activation and additionally attenuates NLRP3-dependent IL-1β and IL-18 production. Therefore, we hypothesized that PPARγ serves as an endogenous modulator that attenuates NLRP3 inflammasome activation in macrophages. Methods: Mouse peritoneal macrophages with exposure to a PPARγ agonist at different stages and the NLRP3 inflammasome-reconstituted system in HEK293T cells were used to investigate the additional anti-inflammatory effect of PPARγ on NLRP3 inflammasome regulation. Circulating mononuclear cells of obese patients with weight-loss surgery were used to identify the in vivo correlation between PPARγ and the NLRP3 inflammasome. Results: Exposure to the PPARγ agonist, rosiglitazone, during the second signal of NLRP3 inflammasome activation attenuated caspase-1 and IL-1β maturation. Moreover, PPARγ interfered with NLRP3 inflammasome formation by decreasing NLRP3-ASC and NLRP3-NLRP3 interactions as well as NLRP3-dependent ASC oligomerization, which is mediated through interaction between the PPARγ DNA-binding domain and the nucleotide-binding and leucine-rich repeat domains of NLRP3. Furthermore, PPARγ was required to limit metabolic damage-associated molecular pattern-induced NLRP3 inflammasome activation in mouse macrophages. Finally, the mature caspase-1/PPARγ ratio was reduced in circulating mononuclear cells of obese patients after weight-loss surgery, which we define as an “NLRP3 accelerating index”. Conclusions: These results revealed an additional anti-inflammatory role for PPARγ in suppressing NLRP3 inflammasome activation through interaction with NLRP3. Thus, our study highlights that PPARγ agonism may be a therapeutic option for targeting NLRP3-related metabolic diseases.

Rationale: Subjects unable to sustain β-cell compensation develop type 2 diabetes. Early growth response-1 protein (EGR-1), implicated in the regulation of cell differentiation, proliferation, and apoptosis, is induced by diverse metabolic challenges, such as glucose or other nutrients. Therefore, we hypothesized that deficiency of EGR-1 might influence β-cell compensation in response to metabolic overload. Methods: Mice deficient in EGR-1 (Egr1-/-) were used to investigate the in vivo roles of EGR-1 in regulation of glucose homeostasis and beta-cell compensatory responses. Results: In response to a high-fat diet, Egr1-/- mice failed to secrete sufficient insulin to clear glucose, which was associated with lower insulin content and attenuated hypertrophic response of islets. High-fat feeding caused a dramatic impairment in glucose-stimulated insulin secretion and downregulated the expression of genes encoding glucose sensing proteins. The cells co-expressing both insulin and glucagon were dramatically upregulated in islets of high-fat-fed Egr1-/- mice. EGR-1-deficient islets failed to maintain the transcriptional network for β-cell compensatory response. In human pancreatic tissues, EGR1 expression correlated with the expression of β-cell compensatory genes in the non-diabetic group, but not in the diabetic group. Conclusion: These results suggest that EGR-1 couples the transcriptional network to compensation for the loss of β-cell function and identity. Thus, our study highlights the early stress coupler EGR-1 as a critical factor in the development of pancreatic islet failure.

Taiwan Blue Magpie (Urocissa caerulea) is endemic to Taiwan and listed as threatened species protected by law. In this study, we first determined and described the complete mitochondrial genome of Taiwan Blue Magpie. The circle genome is 16,928 bp in length, and contains 13 protein coding, 22 tRNA, two rRNA genes, and one non-coding control region (CR). The overall base composition of the mitochondrial DNA is 30.99% for A, 24.69% for T, 30.07% for C, and 14.25% for G. The percentage of G + C content is 44.32%. This work provides fundamental molecular data which will be useful for evolution and phylogeny studies on Corvidae in the future.

Background Our goal was to describe the characteristics and posttreatment outcomes of pediatric patients with central nervous system (CNS) tuberculosis (TB) and to identify factors associated with poor outcome. Methods We included children aged 0 to 18 years with CNS TB reported to the California TB registry between 1993 and 2011. Demographics, clinical characteristics, severity of disease at presentation (Modified Medical Research Council stage I, II, or III [III is most severe]), treatment, and outcomes during the year after treatment completion were abstracted systematically from the medical and public health records. Patient outcomes were categorized as good or poor on the basis of disability in hearing, vision, language, ambulation, and development and other neurologic deficits. Results Among 151 pediatric CNS TB cases reported between 1993 and 2011 in California for which records were available, 92 (61%) cases included sufficient information to determine outcome. Overall, 55 (60%) children had a poor outcome. After we adjusted for age (0 to 4 years), children with stage III severity (vs I or II; prevalence rate ratio [PRR], 1.4 [95% confidence interval (CI), 1.1–1.9]), a protein concentration of >100 mg/dL on initial lumbar puncture (PRR, 1.2 [95% CI, 1.03–1.4]), or infarct on neuroimaging (PRR, 1.2 [95% CI, 1.04–1.3]) were at increased risk for a poor outcome. In multivariate analysis, an age of 0 to 4 years (vs >4 years; PRR, 1.4 [95% CI, 1.2–1.7]) and a stage II or III Modified Medical Research Council score (vs stage I; PRR, 1.2 [95% CI, 1.03–1.5]) remained significantly associated with poor outcome. Conclusions Pediatric patients with CNS TB in California are left with high rates of disabling clinical sequelae after treatment. The identification of modifiable factors is critical for improving outcomes.

The Somali wild ass (Equus africanus somaliensis) is the world’s most endangered equid and listed as a critically endangered (CR) species by the IUCN red list of threatened animals. In this study, we first determined and described the complete mitochondrial genome of Somali wild ass. The circle genome is 16,663 bp in length, and contains 13 protein coding, 22 tRNA, two rRNA genes and one non-coding control region (D-loop). The overall base composition of the mitochondrial DNA is 32.4% for A, 25.7% for T, 28.8% for C, and 13.2% for G. The percentage of G + C content is 42%. This work provides fundamental molecular data, which will be useful for species identification, forensic genetics and further researches on genetic diversity and conservation of this vulnerable equid.

Taiwan Blue Magpie (Urocissa caerulea) is endemic to Taiwan and listed as threatened species protected by law. In this study, we first determined and described the complete mitochondrial ge...

Background Repeated chest X-rays serve as an essential screening tool to identify and describe new or stable (i.e., unchanged) lung abnormalities suggestive of pulmonary tuberculosis (TB) disease. The time for which a patient’s chest X-ray has not demonstrated appreciable change prior to treatment, or pretreatment chest X-ray stability duration, has been considered clinically useful in distinguishing inactive from active disease at four or 6 months. This relationship, however, has not been previously quantified. Methods This study relied on retrospective medical record review to assess the relationship of documented pretreatment chest X-ray stability duration thresholds relative to four and 6 months with a future clinical or culture-confirmed (Class 3) diagnosis of pulmonary TB disease. Multivariable logistic regression quantified this association among 146 patients who were evaluated and started on treatment for pulmonary TB disease in the San Diego County tuberculosis clinic between May 2012 and March 2017. Results After adjusting for age and Class B1 TB, Pulmonary status, a CXR stability duration of 4 months or more was not significantly associated with a Class 3 pulmonary TB diagnosis (adjusted odds ratio [AOR], 0.830; 95% confidence interval [CI], 0.198–3.48). Results were similar for the 6-month cut-point after adjusting for age and Class B1 Pulmonary status (AOR, 0.970; 95% CI, 0.304–3.10). Compared with less than 4 months, CXR stability durations of four to 6 months (AOR, 0.778; 95% CI, 0.156–3.89) and greater than 6 months (AOR, 0.875; 95% CI, 0.187–4.10) were also not significantly associated with a Class 3 TB diagnosis after adjusting for covariates. Conclusion Repeated chest X-rays remain a valuable tool for clinicians identifying and describing new or unchanged lung abnormalities suggestive of pulmonary TB disease. This study found no statistically significant association between pretreatment chest X-ray stability duration and subsequent TB disease diagnosis, with a wide range of estimates compatible with the data, suggesting the stability duration cut points relative to four and 6 months may not be as informative as previously understood. Disclosures All authors: No reported disclosures.

Background. Data from international settings suggest that isolates of Mycobacterium tuberculosis with rpoB mutations testing phenotypically susceptible to rifampin (RIF) may have clinical significance. We analyzed treatment outcomes of California patients with discordant molecular-phenotypic RIF results. Methods. We included tuberculosis (TB) patients, during 2003–2013, whose specimens tested RIF susceptible phenotypically but had a rpoB mutation determined by pyrosequencing. Demographic data were abstracted from the California TB registry. Phenotypic drug-susceptibility testing, medical history, treatment, and outcomes were abstracted from medical records. Results. Of 3330 isolates tested, 413 specimens had a rpoB mutation (12.4%). Of these, 16 (3.9%) had molecular-phenotypic discordant RIF results. Seven mutations were identified: 511Pro, 516Phe, 526Asn, 526Ser (AGC and TCC), 526Cys, and 533Pro. Fourteen (88%) had isoniazid (INH) resistance, 6 of whom were also phenotypically resistant to ethambutol (EMB) and/or pyrazinamide (PZA). Five patients (25%), 1 with 511Pro and 4 with 526Asn, relapsed or failed treatment. The initial regimen for 3 patients was RIF, PZA, and EMB; 1 patient received RIF, PZA, EMB, and a fluoroquinolone (FQN); and 1 patient received RIF, EMB, FQN, and some second-line medications. Upon retreatment with an expanded regimen, 3 (75%) patients completed treatment, 1 patient moved before treatment completion, and 1 patient continues on treatment. The remaining 11 patients had a successful outcome with 9 having received a FQN and/or a rifamycin. Conclusions. Rifampin molecular-phenotypic discordance was rare, and most isolates had INH resistance. Patients who did not receive an expanded regimen had poor outcomes. These mutations may have clinical importance, and expanded treatment regimens should be considered.

Pancreatic β-cells are particularly susceptible to fatty-acid-induced endoplasmic reticulum (ER) stress and apoptosis. To understand how β-cells sense fatty acid stimuli and translate into a long-term adaptive response, we investigated whether palmitic acid (PA) regulates early growth response-1 (Egr-1), an immediate-early transcription factor, which is induced by many environmental stimuli and implicated in cell proliferation, differentiation, and apoptosis. We found that Egr-1 was rapidly and transiently induced by PA in MIN6 insulinoma cells, which was accompanied by calcium influx and ERK1/2 phosphorylation. Calcium chelation and MEK1/2 inhibition blocked PA-induced Egr-1 upregulation, suggesting that PA induces Egr-1 expression through a calcium influx-MEK1/2-ERK1/2 cascade. Knockdown of Egr-1 increased PA-induced caspase-3 activation and ER stress markers and decreased PA-induced Akt phosphorylation and insulin secretion and signaling. Akt replenishment and insulin supplementation rescued PA-induced apoptosis in Egr-1 knockdown cells. These results suggest that the absence of Egr-1 loses its ability to couple the short-term insulin/Akt pathway to long-term survival adaptation. Finally, Egr-1-deficient mouse islets are more susceptible to ex vivo stimuli of apoptosis. In human pancreatic tissues, EGR1 expression correlated with expression of ER stress markers and anti-apoptotic gene. In conclusion, Egr-1 is induced by PA and further attempts to rescue β-cells from ER stress and apoptosis through improving insulin/Akt signaling. Our study underscores Egr-1 as a critical early sensor in pancreatic β-cells to translate fatty acid stimuli into a cellular adaptation mechanism.PA stimulates Egr-1 expression via a calcium influx-MEK1/2-ERK1/2-Elk-1 cascade. Egr-1 attenuates PA-induced ER stress and apoptosis. Egr-1 maintains Akt survival pathway to protect β-cells from PA-induced apoptosis. Egr-1-deficient islets are prone to ex vivo stimuli of apoptosis. Human EGR1 expression correlates with genes for ER stress and anti-apoptosis.

Heart activities are governed by the sympathetic and parasympathetic nervous system. Changes in these neural signals influence the development of arrhythmias, including ventricular tachyarrhythmias that often progress to sudden cardiac death (SDC). A simultaneous study of the cardioneural signals with the electrical heart activity can elucidate the mechanism of abnormal heart activity. In this work, we identify the locations to detect cardioneural signals. We first perform a 108 channel measurement to explore the cardioneural signals. We then focus on selected locations for longer period measurement. We monitor the changes in the heart rate following each sympathetic or vagal nerve activity. The neural signals are extracted from ECG by applying independent component analysis. The work provides a promising approach for studying the association of cardioneural signals with electrical heart activity.

Tumor angiogenesis is postulated to be regulated by the balance between pro- and anti-angiogenic factors. We demonstrate that the critical step in establishing the angiogenic capability of human cells is the repression of the critical anti-angiogenic factor, thrombospondin-1 (Tsp-1). This repression is essential for tumor formation by mammary epithelial cells and kidney cells engineered to express SV40 early region proteins, hTERT, and H-RasV12. We have uncovered the signaling pathway leading from Ras to Tsp-1 repression. Ras induces the sequential activation of PI3 kinase, Rho, and ROCK, leading to activation of Myc through phosphorylation; phosphorylation of Myc via this mechanism enables it to repress Tsp-1 expression. We thus describe a novel mechanism by which the cooperative activity of the oncogenes, ras and myc, leads directly to angiogenesis and tumor formation.