Snapshot of the cannabinoid receptor 1-arrestin complex unravels the biased signaling mechanism.

Cannabis activates the cannabinoid receptor 1 (CB1), which elicits analgesic and emotion regulation benefits, along with adverse effects, via Gi and ß-arrestin signaling pathways. However, the lack of understanding of the mechanism of ß-arrestin-1 (ßarr1) coupling and signaling bias has hindered drug development targeting CB1. Here, we present the high-resolution cryo-electron microscopy structure of CB1-ßarr1 complex bound to the synthetic cannabinoid MDMB-Fubinaca (FUB), revealing notable differences in the transducer pocket and ligand-binding site compared with the Gi protein complex. ßarr1 occupies a wider transducer pocket promoting substantial outward movement of the TM6 and distinctive twin toggle switch rearrangements, whereas FUB adopts a different pose, inserting more deeply than the Gi-coupled state, suggesting the allosteric correlation between the orthosteric binding pocket and the partner protein site. Taken together, our findings unravel the molecular mechanism of signaling bias toward CB1, facilitating the development of CB1 agonists.

Community engagement on-site rapid test for chlamydia and gonorrhea among men who have sex with men: a pioneering study in Guangzhou, China.

BACKGROUND: Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) infections are prevalent among men who have sex with men (MSM) in China. However, compared to syphilis and HIV, the testing rate for chlamydia and gonorrhea remains low. The purpose of this pilot study was to evaluate the feasibility for conducting rapid nucleic acid test for chlamydia and gonorrhea in MSM community-based organizations (CBO). METHOD: We recruited our participants through an MSM CBO where free HV and syphilis testing were routinely provided. We collected data including social-demographic background, sexual history, chlamydia and gonorrhea testing history, and reasons for accepting this on-site rapid testing. Urine and/or anorectal swab samples were collected and tested for chlamydia and gonorrhea on-site and the testing results were delivered in about 1.5 h. Positive cases received on-site free treatment. RESULTS: From August 2020 to October 2020, 634 MSM visited the CBO for syphilis and HIV testing and 158 (158/634, 24.9%) accepted the on-site chlamydia and gonorrhea rapid test, 135 were finally enrolled. The positive rate fo chlamydia was 16.3% (22/135) and 3.0% (4/135) for gonorrhea, respectively. Only 19.3% participants had previously undergone chlamydia and gonorrhea testing and 68.9% (93/135) participants reported that they had heard of gonorrhea, 47.4% (64/135) had heard of chlamydia. The main reason for testing was "free for charge" (66.2%), followed by "convenient, 'shorter waiting time" (45.2%) and "had high-risk sexual behavior recently" (16.3%). CONCLUSIONS: This pilot study showed that the chlamydia and gonorrhea infection rate remains high among MSM, while the testing rate was low. On-site rapid testing is feasible and potentially preferred by MSM.

Prevalence and correlates of Mycoplasma genitalium infection among patients attending a sexually transmitted infection clinic in Guangdong, China: a cross-sectional study.

BACKGROUND: Mycoplasma genitalium (MG) causes urogenital tract infections and is associated with reproductive morbidity. Although MG has been reported across many regions and population groups, it is not yet routinely tested for in China. Our study contributes to current research by reporting the prevalence and correlates of MG infection in patients attending a sexually transmitted infection (STI) clinic in Guangdong from Jan 2017-May 2018. METHODS: Urethral (from 489 men) and endo-cervical (from 189 women) samples, blood samples, and patient histories (via questionnaires) were collected. Doctors clinically diagnosed anogenital warts (GW) during the examination (n = 678). The presence of MG was evaluated using an in-house via polymerase chain reaction protocol. We also tested all participants for herpes simplex virus-2 (HSV-2), Neisseria gonorrhoeae (NG), Chlamydia trachomatis (CT), syphilis and HIV. Univariate and multivariate logistic regression were used to evaluate factors associated with MG. RESULTS: MG was detected in 7.2% (49/678) of the patients (men, 7.4%; women, 6.9%). The MG positivity rate was 14.2% among symptomatic patients, and 5.6% for asymptomatic patients, respectively. Only 36.7% (18/49) Mg positive patients were symptomatic. Among the MG-infected patients, 10.2% were co-infected with CT, 6.1% with NG, 8.2% with HSV-2, 4.1% with syphilis and 22.4% with GW. Presentation with clinical symptoms was significantly associated with MG infection [OR = 2.52 (2.03-3.13)]. In our analysis, MG was not associated with other STIs. CONCLUSIONS: MG is a relatively common infection among individuals attending an STI clinic in Guangdong Province. Routine testing of symptomatic patients may be necessary, and more epidemiological studies are needed to provide evidence for future testing guidelines.

Selection signatures of Fuzhong Buffalo based on whole-genome sequences.

BACKGROUND: Fuzhong buffalo, a native breed of Guangxi Zhuang Autonomous Region, is traditionally used as a draft animal to provide farm power in the rice cultivation. In addition, the Fuzhong buffalo also prepared for the bullfighting festival organized by the locals. The detection of the selective signatures in its genome can help in elucidating the selection mechanisms in its stamina and muscle development of a draft animal. RESULTS: In this study, we analyzed 27 whole genomes of buffalo (including 15 Fuzhong buffalo genomes and 12 published buffalo genomes from Upper Yangtze region). The ZHp, ZFst, π-Ratio, and XP-EHH statistics were used to identify the candidate signatures of positive selection in Fuzhong buffalo. Our results detected a set of candidate genes involving in the pathways and GO terms associated with the response to exercise (e.g., ALDOA, STAT3, AKT2, EIF4E2, CACNA2D2, TCF4, CDH2), immunity (e.g., PTPN22, NKX2-3, PIK3R1, ITK, TMEM173), nervous system (e.g., PTPN21, ROBO1, HOMER1, MAGI2, SLC1A3, NRG3, SNAP47, CTNNA2, ADGRL3). In addition, we also identified several genes related to production and growth traits (e.g., PHLPP1, PRKN, MACF1, UCN3, RALGAPA1, PHKB, PKD1L). Our results depicted several pathways, GO terms, and candidate genes to be associated with response to exercise, immunity, nervous system, and growth traits. CONCLUSIONS: The selective sweep analysis of the Fuzhong buffalo demonstrated positive selection pressure on potential target genes involved in behavior, immunity, and growth traits, etc. Our findings provided a valuable resource for future research on buffalo breeding and an insight into the mechanisms of artificial selection.

Comorbidities and complications influence the diagnosis and management of geriatric supraglottitis.

INTRODUCTION: This study aimed to assess the differences in the clinical characteristics, management, and outcomes of supraglottitis between geriatric and nongeriatric adults over a 30-month period. METHODS: All adult patients admitted to the emergency department with suspected supraglottitis and who underwent laryngoscopy for confirmation were included. We collected the clinical characteristics, management, and outcomes of these patients and compared geriatric (≥60 years old) and nongeriatric (12-59 years old) groups in terms of these data. RESULTS: Eighty-one geriatric patients and 205 nongeriatric patients were reviewed during the study period. The accuracies of the clinical suspicions of supraglottitis were lower in the geriatric group (geriatric vs nongeriatric, 29.4% vs 47.3%, P = .008). The geriatric group constituted 19.8% of all supraglottitis patients. Comorbidities were discovered in 74.1% of the geriatric group and 25.4% of the nongeriatric group (P = .000). The complication rate in the geriatric patients was almost twice that of the nongeriatric patients (20.8% vs 10.8%). Additionally, the geriatric patients exhibited tendencies toward longer periods of intubation, hospitalization, and stay in the intensive care unit. CONCLUSIONS: The clinical characteristics and management were similar between the geriatric and nongeriatric supraglottitis patients. Nevertheless, the comorbidities altered the clinical presentations of the geriatric patients and resulted in lower diagnostic accuracy. Additionally, the elevated complication rates of the geriatric patient might have negatively affected their outcomes.

Systemic lupus erythematosus presenting with cardiac symptoms.

BACKGROUND: The objective of this study was to describe the characteristics of patients presenting to the emergency department with cardiac symptoms subsequently diagnosed to have systemic lupus erythematosus (SLE). METHODS: The authors performed a review of newly diagnosed SLE patients at 2 hospitals in Tainan city between January 2010 and December 2013. Patients initially presenting with cardiac symptoms were included. Demographic data, presenting symptomatology, laboratory data, and imaging studies were obtained and analyzed. RESULTS: Eight cases, including 5 female and 3 male patients, were identified during the 4-year study period. The mean age was 37 (range, 15-54) years. Pericardial effusion (63%) and mitral regurgitation (63%) were the most common cardiac abnormalities, followed by impairment of left ventricular systolic function (25%) and tricuspid regurgitation (13%). Most patients showed signs of increased generalized inflammation and immunological activity with elevated levels of C-reactive protein (100%) and anti-dsDNA (88%) and decreased complement levels (63%). The median duration from admission to the diagnosis of SLE was 6.3 (range, 1-13) days, and all patients showed multiple-organ involvement in addition to the cardiovascular system. CONCLUSIONS: Patients presenting to the emergency department with cardiac symptoms without a history of cardiopulmonary disease or traditional cardiovascular disease risk factors should be assessed for an underlying cause of cardiac decompensation. If the patients exhibit extracardiac manifestations or their illnesses involve multiple-organ systems, screening tests for autoimmune diseases such as SLE are mandatory.

Structural insights into human brain-gut peptide cholecystokinin receptors.

The intestinal hormone and neuromodulator cholecystokinin (CCK) receptors CCK1R and CCK2R act as a signaling hub in brain-gut axis, mediating digestion, emotion, and memory regulation. CCK receptors exhibit distinct preferences for ligands in different posttranslational modification (PTM) states. CCK1R couples to Gs and Gq, whereas CCK2R primarily couples to Gq. Here we report the cryo-electron microscopy (cryo-EM) structures of CCK1R-Gs signaling complexes liganded either by sulfated cholecystokinin octapeptide (CCK-8) or a CCK1R-selective small-molecule SR146131, and CCK2R-Gq complexes stabilized by either sulfated CCK-8 or a CCK2R-selective ligand gastrin-17. Our structures reveal a location-conserved yet charge-distinct pocket discriminating the effects of ligand PTM states on receptor subtype preference, the unique pocket topology underlying selectivity of SR146131 and gastrin-17, the conformational changes in receptor activation, and key residues contributing to G protein subtype specificity, providing multiple structural templates for drug design targeting the brain-gut axis.

Does CT evidence of a flat inferior vena cava indicate hypovolemia in blunt trauma patients with solid organ injuries?

BACKGROUND: Nonoperative management for selective patients with solid organ injuries from blunt trauma has gained wide acceptance. However, for trauma surgeons, it is often difficult to estimate a patient's circulatory volume. Some authors have proposed that the presence of a collapsed inferior vena cava (IVC) on computed tomography (CT) scan correlates with inadequate circulatory volume. Our aim was to verify whether CT evidence of a flat IVC (FI) is an indicator of hypovolemia in blunt trauma patients with solid organ injuries. METHODS: We conducted a retrospective chart review of all blunt trauma patients with solid organ injuries admitted to our Medical Center from July 2003 to September 2006. Of the 226 patients reviewed, 29 had CT evidence of FI. We compared Injury Severity Scores, hemodynamic parameters, fluid and blood transfusion requirements, mortality rate, and hospital course between patients with (FI group) and without FI (non-FI [NFI] group). RESULTS: The FI group had higher rates of intensive care unit admission and mortality, in addition to longer intensive care unit stays, when compared with the NFI group. In addition, the patients in the FI group needed larger amounts of fluid and blood transfusions and presented lower hemoglobin levels during the first week of admission; furthermore, the majority deteriorated to a state of shock in the emergency department. CONCLUSIONS: CT evidence of FI is a good indicator of hypovolemia and an accurate predictor for prognosis in trauma patients with blunt solid organ injuries.

Clinical Image: Leriche Syndrome.

Lower extremity weakness is a neurological symptom that can be caused by several factors, including cerebrovascular accident, spinal cord disease, peripheral nerve disease, neuromuscular junction disease, muscle disease, or other metabolic conditions, such as hypoglycemia and hypokalemia. However, vascular occlusive disease may exhibit neurological symptoms. Here, we present a case of aortoiliac artery total occlusion, Leriche syndrome.

Scaling characteristics in ozone concentration time series (OCTS).

One-year series of hourly average ozone observations, which were obtained from urban and national park air monitoring stations at Taipei (Taiwan), were analyzed by means of descriptive statistics and fractal methods to examine the scaling structures of ozone concentrations. It was found that all ozone measurements exhibited the characteristic right-skewed frequency distribution, cyclic pattern, and long-term memory. A mono-fractal analysis was performed by transferring the ozone concentration time series (OCTS) into a useful compact form, namely, the box-dimension (D(B))-threshold (T(h)) and critical scale (C(S))-threshold (T(h)) plots. Scale invariance was found in these time series and the box dimension was shown to be a decreasing function of the threshold ozone level, implying the existence of multifractal characteristics. To test this hypothesis, the OCTS were transferred into the multifractal spectra, namely, the tau(q)-q plots. The analysis confirmed the existence of multifractal characteristics in the investigated OCTS. A simple two-scale Cantor set with unequal scales and weights was then used to fit the calculated tau(q)-q plots. This model fitted remarkably well the entire spectrum of scaling exponents for the examined OCTS. Because the existence of chaos behavior in OCTS has been reported in the literature, the possibility of a chaotic multifractal approach for OCTS characterization was discussed.

Successful cloning of an adult breeding boar from the novel Chinese Guike No. 1 swine specialized strain.

Somatic cloning, also known as somatic cell nuclear transfer (SCNT), is a promising technology which has been expected to rapidly extend the population of elaborately selected breeding boars with superior production performance. Chinese Guike No. 1 pig breed is a novel swine specialized strain incorporated with the pedigree background of Duroc and Chinese Luchuan pig breeds, thus inherits an excellent production performance. The present study was conducted to establish somatic cloning procedures of adult breeding boars from the Chinese Guike No. 1 specialized strain. Ear skin fibroblasts were first isolated from a three-year-old Chinese Guike No. 1 breeding boar, and following that, used as donor cell to produce nuclear transfer embryos. Such cloned embryos showed full in vitro development and with the blastocyst formation rate of 18.4 % (37/201, three independent replicates). Finally, after transferring of 1187 nuclear transfer derived embryos to four surrogate recipients, six live piglets with normal health and development were produced. The overall cloning efficiency was 0.5 % and the clonal provenance of such SCNT derived piglets was confirmed by DNA microsatellite analysis. All of the cloned piglets were clinically healthy and had a normal weight at 1 month of age. Collectively, the first successful cloning of an adult Chinese Guike No. 1 breeding boar may lay the foundation for future improving the pig production industry.

Acute poisoning with neonicotinoid insecticides: a case report and literature review.

Neonicotinoids are a new class of insecticides widely applied for crop protection. These insecticides act as agonists at nicotinic acetylcholine receptors, which cause insect paralysis and death. The high specificity for receptors in insects was considered to possess highly selective toxicity to insects and relative sparing of mammals. However, an increasing number of cases of acute neonicotinoid poisoning have been reported in recent years. We reported a man who developed respiratory failure and shock after ingestion of neonicotinoid insecticide. A detailed literature review found that respiratory, cardiovascular and certain neurological presentations are warning signs of severe neonicotinoid intoxication. The amounts of ingested neonicotinoid insecticide and the plasma neonicotinoid concentration are not useful guides for the management of intoxicated patients. Supportive treatment and decontamination are the practical methods for the management of all neonicotinoid-poisoned patients.