bluuebunny/crossref_metadata_2025 huggingface dataset:
Sodium arsenite induces spatial learning and memory impairment associated with oxidative stress and activates the Nrf2/PPARγ pathway against oxidative injury in mice hippocampus
Authors: Xiong Liang , Huang Jinyu , Gao Ying , Gao Yanfang , Wu Chunmei , He Shengfa , Zou Lijun , Yang Dongmei , Han Yuhao , Yuan Qiong , Zheng Zuobing , Hu Gonghua
Published: January 2021

Arsenic (As) is a ubiquitous environmental and industrial toxin with known correlates of oxidative stress and cognitive deficits in the brain. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcriptional factor that represents a central cellular antioxidant defense mechanism and transcribes many antioxidant genes. Peroxisome proliferator-activated receptor-gamma (PPARγ) is a well-known nuclear receptor to regulate lipid metabolism in many tissues, and it has been also associated with the control of oxidative stress, neuronal death, neurogenesis and differentiation. The role of Nrf2 and PPARγ in As-induced neurotoxicity is still debated. The present study was designed to investigate the neurobehavioral toxic effect of sub-chronic and middle-dose sodium arsenite exposure in mice hippocampus, as well as the response of Nrf2/PPARγ expression and influence on protein expression levels of their downstream antioxidant genes. Our results showed that mice treated with intraperitoneal injection of sodium arsenite (50 mg/kg body wt.) twice a week for 7 weeks resulted in increased generation of reactive oxygen species and impairment of spatial cognitive function. The present study also found a positive association between Nrf2/PPARγ expression in hippocampus of mice, and activation of antioxidant defenses by the evidently upregulated expression of their downstream genes, including superoxide dismutase, heme oxygenase-1 and glutathione peroxidase-3. Therefore, our findings were helpful for further understanding the role of Nrf2/PPARγ feedback loop in As-induced neurobehavioral toxicity.
Nurse Practitioner Preceptor Plan: A Focus on Preceptor Rewards and Preferences
Authors: Gaynor Beatrice , Barnes Hilary
Published: January 2021

Recruiting and retaining preceptors is a major challenge for nurse practitioner (NP) programs. The purpose of this project was to identify preceptor rewards that may foster NP preceptor recruitment and retention at one university. Seventy preceptors were surveyed regarding their reward preferences using rewards identified in the literature and among regional NP programs. The most preferred rewards included continuing education credits, professional growth opportunities, maintaining professional relationships with the university, and financial remuneration. To provide NP students with positive and effective clinical experiences, it is essential that NP program leaders understand preceptors’ preferences and commit to preceptor support.
Baseball performance via the lens of anthropometric testing, fitness metrics, and statistics: a longitudinal cross-sectional study
Authors: Papadakis Zacharias , Padgett Robert N. , Stamatis Andreas , Karasch Richard A.
Published: January 2021

Background:

Anthropometric testing (AT) and fitness metrics (FM) are contributing factors for success in sports. Limited evidence exists regarding longitudinal baseball AT or FM roles on baseball performance statistics (PS). AT, FM, and PS associations were examined for 5 yr to create a performance model.

Methods:

Eighty collegiate Division I players participated in this study. Height, mass, and body fat percentage (BF%) were selected as AT variables of interest. Grip strength (GS), one repetition maximum squat (1RMSQ), and vertical-jump height were selected for FM. Batting average percentage (AVG), slugging percentage (SLG), on-base percentage (OBP) baseball statistics were selected as offensive PS. Earned run average (ERA), batting average against percentage (B/AVG), and strike-out per innings pitched for 9 innings (SO/IP)*9 were selected for defensive PS.

Results:

Offensive (r=−0.15, P<0.005; rs=−0.17, P<0.001) and defensive (r=−0.253, P<0.001; rs=−0.314, P<0.001) statistics correlated with BF%. Offensive (r=0.26, P<0.001; rs=0.43, P<0.001) and defensive (r=0.39, P<0.001) statistics correlated with GS. Offensive (r=0.26, P<0.001; rs=0.43, P<0.001) and defensive (r=0.27, P<0.001) statistics correlated with 1RMSQ. Offensive statistics AVG (R2=0.48) and SLG (R2=0.46) were explained by 1RMSQ. For defensive statistics, 1RMSQ was the best fit for (SO/IP)*9 (R2=0.43) and B/AVG (R2=0.52), and GS was the best fit for ERA (R2=0.39). Squat and time interaction for B/AVG was significant (P=0.04).

Conclusions:

Baseball PS are associated with 1RMSQ and GS. Time moderates the effect of squat training on B/AVG. Pitchers need to include squats to lower their B/AVG. Coaches may focus on improving such FM variables and consider the time effect on selected FM that may affect PS.

Level of Evidence:

Level IV
Is it a must to tenotomize the biceps intraarticular origin during tenodesis? A prospective case series study of biceps tenodesis without tenotomy
Authors: Kandeel Amr Abdel-Mordy
Published: January 2021

Background:

This study was conducted to investigate three questions; Does biceps tenodesis without tenotomy reduce short-term tenodesis failure and revision rate? Does preserved biceps origin increase the prevalence of postoperative bicipital pain and tenderness? Does this technical modification limit postoperative range of motion?

Methods:

Between October 2014 and December 2018, a case series of 24 patients with different isolated biceps tendon lesions were prospectively managed by arthroscopic intraarticular suture-anchor biceps tenodesis without tenotomizing the biceps intraarticular origin. Patients were evaluated for demographics and for preoperative and 2-year postoperative range of motion, University of California Los Angeles (UCLA) scoring system, return to work, persistent bicipital pain or tenderness, and Popeye sign (tenodesis failure).

Results:

Mean age of the group was 46.7 yr. Statistical analysis revealed highly significant postoperative improvement in UCLA score parameters (P<0.001) and in active range of motion (P<0.001). However, when compared with its sound counterpart, the operated shoulder had 12.5-degree range deficits of external rotation at 0-degree abduction. Five (20.8%) patients reported persistent or recurrent bicipital pain or tenderness; four (80%) of those five patients responded well to local steroid injection. A Popeye sign was not reported subjectively or objectively, and there was no reported tenodesis revision.

Conclusions:

Providing potential biological, biomechanical, and technical advantages and rendering low rates of short-term tenodesis failure and revision, this technique of modified (without-tenotomy) arthroscopic biceps tenodesis can achieve satisfactory outcomes. However, this technique could have the disadvantages of external rotational range deficits, relatively high prevalence of postoperative bicipital pain and tenderness, and technical irreproducibility in extensive biceps lesions that involve the tendon segment proposed for tenodesis.

Level of Evidence:

Level IV.
Novel diagnostic approaches for Fanconi anemia (FA) by single-cell sequencing and capillary nano-immunoassay
Authors: Chang Lixian , Gao Xingjie , Ji Guangzhen , Cheng Xuelian , Zou Yao , Cheng Tao , Yuan Weiping , Zhu Xiaofan
Published: January 2021

Next-generation sequencing technology has been widely utilized for the diagnosis of Fanconi anemia (FA). However, mixed cell sequencing and chimerism of FA patients may lead to unconfirmed genetic subtypes. Herein, we introduced two novel diagnostic methods, including single-cell sequencing and capillary nano-immunoassay. One FA case with FANCM c.4931G>A p.R1644Q and FANCD1 c.6325G>A p.V2109I was studied. The DNA of 28 cells was amplified and eight types of cells were observed after Sanger sequencing. There were two homozygous mutations (FANCM/FANCD1). Furthermore, the capillary nano-immunoassay was conducted to analyze the expression profile of FA-associated proteins. Abnormal FANCM and FANCD1 expressions simultaneously existed. This case was thus diagnosed as FA-D1/FA-M dual subtype. Compared with mixed cell sequencing, single-cell sequencing data shows more accuracy for the FA subtype evaluation, while the capillary nano-immunoassay is a good method to detect the expression profile of abnormal or modified FA protein.
A Validated Photonumeric Scale for the Evaluation of Neck Skin Laxity
Authors: Guida Stefania , Spadafora Marco , Longhitano Sabrina , Pellacani Giovanni , Farnetani Francesca
Published: January 2021

BACKGROUND

Neck aging is usually evaluated together with the lower face. To date, a skin laxity scale for the neck as an independent anatomical district is lacking.

OBJECTIVE

To create and validate a proposed photonumeric neck skin laxity (NSL) scale.

MATERIALS AND METHODS

Frontal neck photographic images of 110 subjects were collected. Each standardized neck image was evaluated twice by 3 independent doctors, 1 week apart. A 4-point photonumeric NSL scale was developed (0 = absence of skin laxity and 4 = severe skin laxity) and validated in terms of intraobserver and interobserver correlation and internal consistency.

RESULTS

The intraobserver reliability analysis of the 2 assessments performed by each observer revealed excellent correlation and consistency of the severity grading, independently of the time of evaluation (from 0.96 to 0.99, p < .01). Furthermore, the interobserver reliability analysis revealed an excellent agreement between the evaluators and an internal consistency independent of the evaluator (0.97, p < .01).

CONCLUSION

The newly developed NSL scale is a reliable and reproducible scoring system for the aesthetic evaluation of skin laxity of the neck.
CLOUDING OF INTRAOCULAR SILICONE OIL IN THE ABSENCE OF EMULSIFICATION
Authors: Zheng Ying , de Vries Jan Willem , Herrmann Andreas , Bartz-Schmidt Karl-Ulrich , Dammeier Sascha , Spitzer Martin S.
Published: January 2021

Purpose:

To describe intraocular clouding of silicone oil in the absence of emulsification.

Methods:

Retrospective observational case series of patients who received silicone oil injections and developed silicone oil discoloration without emulsification after pars plana vitrectomy. Clinical examinations and physicochemical analyses were performed to find out the common cause for the opaque oil.

Results:

Thirteen patients developed silicone oil discoloration after pars plana vitrectomy. It could be traced down that all patients had received silicone oil from one respective production batch. The silicone oil was removed as soon as possible after the changes were detected (range, 8–16 weeks). Gas chromatography flame ionization detector, size exclusion chromatography, and high-performance liquid chromatography analysis showed the absence of low-molecular-weight compounds in the opaque lot. Thermogravimetric analysis revealed the opaque lot was more temperature stable. During the follow-ups, no obvious retinal toxicity could be observed and best-recorded visual acuity improved considerably in 12 patients and was only limited by the underlying retinal pathologic conditions.

Conclusion:

This is the first report on opacification of intraocular silicone oil without emulsification. This discoloration of silicone oil may disturb vision and prevent proper fundus examination; however, it seems to be a nontoxic phenomenon without serious long-term consequences.
LONG-TERM FOLLOW-UP OF ASYMMETRIC BILATERAL DIFFUSE UVEAL MELANOCYTIC PROLIFERATION IN A PATIENT WITH METASTASIZED UROTHELIAL CARCINOMA
Authors: Lentzsch Anna M. , Siggel Robert , Schnorr Christel , Holtick Udo , Liakopoulos Sandra
Published: January 2021

Purpose:

To report a case of bilateral diffuse uveal melanocytic proliferation over 30 months follow-up.

Methods:

Multimodal imaging including ultra-wide-field color fundus photography, blue light fundus autofluorescence, swept-source optical coherence tomography, fluorescein angiography, and indocyanine green angiography.

Results:

A 49-year-old woman presented with decreased vision 2 months after bladder cancer surgery. Exudative retinal detachment and leopard spot pattern chorioretinopathy were observed in the right eye. Chemotherapy and cystectomy were initiated. Progressive bilateral vision loss occurred with melanocytic proliferation, choroidal thickening, subretinal fibrosis, fluid extravasation, rapid development of mature cataract, multiple iris cysts, and rubeosis, despite plasmapheresis and IV immunoglobulins. After cataract surgery, massive fibrin reaction resulted in a ciliolenticular block. One year later, positron emission tomography–computed tomography revealed absence of metastases. At Month 23, choroidal thickness increased in line with tumor progression. Palliative systemic therapy was initiated. Secondary macular neovascularization was treated with intravitreal antivascular endothelial growth factor injections. Visual acuity was light perception in the right eye and 20/200 in the left eye at last follow-up.

Conclusion:

Bilateral diffuse uveal melanocytic proliferation results in progressive melanocyte proliferation and exudation, leading to severe visual loss. In our case, visual acuity was preserved at a low level in one eye under continuous systemic treatment. Systemic corticosteroids are recommended for cataract surgery in the setting of bilateral diffuse uveal melanocytic proliferation to prevent massive fibrin reaction. Intravitreal antivascular endothelial growth factor injections may be indicated if secondary macular neovascularization develops.
Vision Loss Secondary to Facial and Periorbital Steroid Injection: A Systematic Review
Authors: Park Sally S. E. , Barmettler Anne
Published: January 2021

Purpose:

The risk of ophthalmic and retinal artery occlusions following facial and periorbital steroid injection has not been explored. This systematic review examines the prevalence, risk factors, and treatment outcomes of steroid-induced vision losses.

Methods:

A literature search in Evidence Based Medicine Reviews, MEDLINE, Embase, Pubmed, ClinicalTrials, and WHO ICTRP was performed for vision loss following facial and periorbital corticosteroid injections through July 2020.

Results:

Of 35 case reports, series, and reviews, 49 patients (56 eyes) with steroid-induced vision loss were analyzed. Injection sites predominantly involved the nose (45%) and periocular regions (10%). The most common type of steroid is triamcinolone (54%). Most cases were unilateral, except 7 cases of bilateral vision losses, 4 of which resulted from unilateral steroid injection. Symptoms were reported during or immediately after injections in 49% of cases. Most occlusions occurred in the ophthalmic (53%) or central retinal artery (33%). Vision most commonly presented as no light perception (37%), and 90% were 20/200 or worse. Final visual outcomes varied from 20/200 or worse (56%), 20/40 or better (30%), to in between (13%).

Conclusion:

Most vision losses resulted from steroid injections in the nasal and periorbital area. Triamcinolone was the most common offending agent, likely due to large particle size, low solubility, and extensive particle aggregation. Dexamethasone has the opposite pharmacologic properties and has never been reported in association with vascular occlusion related vision loss. Careful steroid selection, injection techniques, and treatment strategies should be considered to prevent and treat artery occlusion.
Assessing the dyslipidemias: to fast or not to fast?
Authors: Farukhi Zareen , Mora Samia
Published: January 2021

Purpose of review

Nonfasting lipid testing has been introduced into several guidelines over the past decade or so however, the uptake into clinical practice has not been universal. This review highlights some of the prevalent reasons for provider reluctance to use nonfasting testing and the evidence to support nonfasting testing for routine screening in most patients.

Recent findings

Several studies have found nonfasting lipids to be as, or more, strongly associated with cardiovascular disease (CVD) risk prediction. In particular, nonfasting tests improve system efficiency, are safe for patients with diabetes, the elderly, children, and in the vast majority of patients, do not need to be followed up with fasting studies due to severe hypertriglyceridemia.

Nonfasting lipids are a convenient first test for screening that offers equivalent, if not improved CVD risk prediction. Common misconceptions about nonfasting tests are not supported by the evidence.
Targeted pharmacotherapy of irritable bowel syndrome
Authors: Arokiadoss Abishek , Weber H. Christian
Published: January 2021

Purpose of review

Irritable bowel syndrome (IBS) is a highly prevalent functional gastrointestinal (GI) disorder with negative impact on quality of life and it represents a substantial economic burden on healthcare cost. The medical management of IBS is symptom directed. This review provides an update related to clinical trial data for novel treatment modalities in IBS targeting the gut epithelium secretagogue receptors and channels.

Recent findings

The new Rome IV criteria define functional gastrointestinal disorders (FGID) as disorders of the gut–brain interaction. Pharmacological treatment modalities for IBS target gastrointestinal receptors and ion channels, peripheral opioid receptor, gut serotonin receptors, and the gut microbiome. New targeted pharmacotherapies have shown efficacy and safety in the treatment of patients with IBS.

Diagnostic criteria for FGID, including IBS, have been revised in Rome IV and are defined as gut-brain disorders. Newly approved pharmacotherapy options with proven efficacy and acceptable side-effect profiles are available for the symptom-based management of IBS.
Changes in Patient Reported Pain Measures With the Citrate-free Adalimumab Formulation in Pediatric Inflammatory Bowel Disease Patients
Authors: Patel Ashish S. , Luu Phuong
Published: January 2021

Inflammatory bowel diseases (IBD) are characterized by chronic inflammation in the gastrointestinal tract. The perception of pain in children is very complex and involves psychological, physiological, behavioral, and developmental factors. For children with chronic diseases, the medical procedures and treatments are often painful, unexpected, and heightened by situational stress and anxiety leading to an overall unpleasant experience. Pain and injection-site reaction are major predictors of nonadherence to antitumor necrosis factor treatment.

The most commonly reported adalimumab adverse event was injection-site reaction. This study compares reported pain in pediatric IBD patients between the 2 formulations using a visual analog scale (VAS). Our hypothesis is that the citrate-free formulation would have significantly less injection-site pain than the original formulation.

We evaluated injection-site pain in 6- to 17-year olds with IBD between the original formulation and citrate-free using the Faces Pain Scale-Revised for pain from 0 (no pain) to 10 (worse pain possible).

Ninety-five percent of patients reported that their pain score was greater than 3 with original formulation, while only 5% of them reported their pain score was greater than 3 with citrate free. The McNemar’s test showed significant difference in the pain score between the 2 types of injection (P < 0.0001).
Gut Microbial Changes and their Contribution to Post-Burn Pathology
Authors: Luck Marisa E. , Herrnreiter Caroline J. , Choudhry Mashkoor A.
Published: January 2021

Burn injuries are a common form of traumatic injury that leads to significant morbidity and mortality worldwide. Burn injuries are characterized by inflammatory processes and alterations in numerous organ systems and functions. Recently, it has become apparent that the gastrointestinal bacterial microbiome is a key component of regulating the immune response and recovery from burn and can also contribute to significant detrimental sequelae after injury, such as sepsis and multiple organ failure. Microbial dysbiosis has been linked to multiple disease states; however, its role in exacerbating acute traumatic injuries, such as burn, is poorly understood. In this article, we review studies that document changes in the intestinal microbiome after burn injury, assess the implications in post-burn pathogenesis, and the potential for further discovery and research.
Clinicopathological Analysis of Uterine Allografts Including Proposed Scoring of Ischemia Reperfusion Injury and T-cell–mediated Rejection—Dallas UtErus Transplant Study: A Pilot Study
Authors: Agarwal Atin , Johannesson Liza , Findeis Sarah K. , Punar Metin , Askar Medhat , Ma Tsung-Wei , Pinto Karen , Demetris Anthony J. , Testa Giuliano
Published: January 2021

Background.

Uterus transplantation (UTx) enables pregnancy in infertile women. This study describes the histopathological changes of ischemia reperfusion injury and mostly acute T-cell–mediated rejection (TCMR) in UTx and proposes modification toward a working formulation grading system with associated treatments.

Methods.

Protocol and indication biopsies from 11 living and 2 deceased donor UTx recipients were analyzed. Serving as a control were 49 age-matched nontransplanted uteri. All posttransplant histopathological specimens were evaluated in a blinded fashion by 3 pathologists. Response to treatment was assessed by follow-up biopsies. Serial serum donor-specific antibody (DSA) responses were also recorded.

Results.

Changes attributed to ischemia reperfusion resolved within 2 wk of UTx in most of the patients. For TCMR grading, perivascular inflammation, focal capillary disruption, and interstitial hemorrhage were added to interface inflammation, intercellular edema, stromal inflammation, and epithelial apoptotic bodies. Of the 173 protocol biopsies, 98 were classified as negative for TCMR; 34 as indeterminate-borderline; 35 as mild; 3 as moderate; and 3 as severe, 1 of which occurred in a DSA-positive recipient and also showed microvascular injury. Corticosteroids successfully treated all moderate-to-severe TCMR episodes. Mild TCMR was treated by increasing existing baseline immunosuppression. Indeterminate-borderline episodes were not treated. Neither ischemia-reperfusion injury nor TCMR with DSA adversely affected embryo transfer.

Conclusions.

Relying on a modified histopathological grading system, we developed a treatment strategy resulting in resolution of TCMR and successful pregnancies.
Retrospective SARS-CoV-2 Real-Time PCR Testing of Stored Bronchoalveolar Lavage Samples from February 2020
Authors: Challener Douglas , Shah Aditya , Binnicker Matthew , Badley Andrew , O’Horo John
Published: January 2021

Bronchoalveolar lavage samples (n=34) collected in February, 2020 prior to the wide availability of molecular testing for SARS-CoV-2 were retrospectively assayed for presence of viral RNA. None of these patients qualified for SARS-CoV-2 testing based on Centers for Disease Control criteria at the time. None of the samples tested positive for SARS-CoV-2, suggesting that the virus was not yet widespread in Minnesota at the time these samples were obtained.
Head-to-head comparison of direct-input RT-PCR and RT-LAMP against RT-qPCR on extracted RNA for rapid SARS-CoV-2 diagnostics
Authors: Kellner Max J. , Matl Martin , Ross James J. , Schnabl Jakob , Handler Dominik , Heinen Robert , Schaeffer Justine , Hufnagl Peter , Indra Alexander , Dekens Marcus P.S. , Fritsche-Polanz Robert , Födinger Manuela , Zuber Johannes ,   Vienna Covid-19 Detection Initiative (VCDI), Allerberger Franz , Pauli Andrea , Brennecke Julius
Published: January 2021

Viral pandemics, such as Covid-19, pose serious threats to human societies. To control the spread of highly contagious viruses such as SARS-CoV-2, effective test-trace-isolate strategies require population-wide, systematic testing. Currently, RT-qPCR on extracted RNA is the only broadly accepted test for SARS-CoV-2 diagnostics, which bears the risk of supply chain bottlenecks, often exaggerated by dependencies on proprietary reagents. Here, we directly compare the performance of gold standard diagnostic RT-qPCR on extracted RNA to direct input RT-PCR, RT-LAMP and bead-LAMP on 384 primary patient samples collected from individuals with suspected Covid-19 infection. With a simple five minute crude sample inactivation step and one hour of total reaction time, we achieve assay sensitivities of 98% (direct RT-PCR), 93% (bead-LAMP) and 82% (RT-LAMP) for clinically relevant samples (diagnostic RT-qPCR Ct <35) and a specificity of >98%. For direct RT-PCR, our data further demonstrate a perfect agreement between real-time and end-point measurements, which allow a simple binary classification similar to the powerful visual readout of colorimetric LAMP assays. Our study provides highly sensitive and specific, easy to implement, rapid and cost-effective alternatives to diagnostic RT-qPCR tests.
The Association of COVID-19 Incidence with Sport and Face Mask Use in United States High School Athletes
Authors: Watson Andrew M. , Haraldsdottir Kristin , Biese Kevin , Goodavish Leslie , Stevens Bethany , McGuine Timothy
Published: January 2021

Purpose

To evaluate the influence of sport characteristics and face mask use on COVID-19 incidence among high school athletes.

Methods

Surveys were distributed to high school athletic directors throughout the United States regarding sport re-initiation, COVID-19 cases, and risk reduction procedures in fall 2020.

Separate mixed effects Poisson regression models were developed to evaluate the associations between reported COVID-19 incidence and 1) sport characteristics (contact/non-contact, individual/team, indoor/outdoor) and 2) face mask use while playing (yes/no).

Results

991 schools had restarted fall sports, representing 152,484 athletes on 5,854 teams. 2,565 cases of COVID-19 were reported, representing a case rate of 1,682 cases per 100,000 athletes and an incidence rate of 24.6 cases per 100,000 player-days. COVID-19 incidence was lower among outdoor versus indoor sports (incidence rate ratio [IRR]=0.54, 95% CI=0.49-0.60, p<0.001) and non-contact versus contact sports (IRR=0.78 [0.70-0.87], p<0.001), but not team versus individual sports (IRR=0.96 [0.84-1.1], p=0.49). Face mask use was associated with a decreased incidence in girls’ volleyball (IRR=0.53 [0.37-0.73], p<0.001), boys’ basketball (IRR=0.53 [0.33-0.83], p=0.008) and girls’ basketball (IRR=0.36 [0.19-0.63], p<0.001), and approached statistical significance in football (IRR=0.79 [0.59-1.04], p=0.10) and cheer/dance (IRR=0.75 [0.53-1.03], p=0.081).

Conclusions

In this nationwide survey of US high school athletic directors representing 152,484 athletes, lower COVID-19 incidence was independently associated with participation in outdoor versus indoor and non-contact versus contact sports, but not team versus individual sports. Face mask use was associated with decreased COVID-19 incidence among indoor sports, and may be protective among outdoor sports with prolonged close contact between participants.
Clinical Associations of Functional Dyspepsia with Gastric Dysrhythmia on Electrogastrography: A Comprehensive Systematic Review and Meta-Analysis
Authors: Varghese C , Carson DA , Bhat S , Hayes TCL , Gharibans AA , Andrews CN , O’Grady G
Published: January 2021

Background

Functional dyspepsia (FD) is a common gastroduodenal disorder, yet its pathophysiology remains poorly understood. Bioelectrical gastric slow wave abnormalities are thought to contribute to its multifactorial pathophysiology. Electrogastrography (EGG) has been used to record gastric electrical activity, however the clinical associations require further evaluation.

Aims

This study aimed to systematically assess the clinical associations of EGG in FD.

Methods

MEDLINE, EMBASE, and CENTRAL databases were systematically searched for articles using EGG in adults with FD. Primary outcomes were percentage normal vs abnormal rhythm (bradygastria, normogastria, tachygastria). Secondary outcomes were dominant power, dominant frequency, percentage coupling and the meal responses.

Results

1751 FD patients and 555 controls from 47 studies were included. FD patients spent less time in normogastria while fasted (SMD −0.74; 95%CI −1.22 - −0.25) and postprandially (−0.86; 95%CI −1.35 - −0.37) compared to controls. FD patients also spent more fasted time in bradygastria (0.63; 95%CI 0.33 – 0.93) and tachygastria (0.45; 95%CI 0.12 – 0.78%). The power ratio (−0.17; 95%CI −0.83 - 0.48), and dominant frequency meal-response ratio (0.06; 95%CI −0.08 - 0.21) were not significantly different to controls. Correlations between EGG metrics and the presence and timing of FD symptoms were inconsistent. EGG methodologies were diverse and variably applied.

Conclusion

Abnormal gastric slow wave rhythms are a consistent abnormality present in FD, as defined by EGG, and therefore likely play a role in pathophysiology. The aberrant electrophysiology identified in FD warrants further investigation, including into underlying mechanisms, associated spatial patterns, and symptom correlations.
N-glycan chitobiose core biosynthesis by Agl24 strengthens the hypothesis of an archaeal origin of the eukaryal N-glycosylation
Authors: Meyer Benjamin H. , Wagstaff Ben A. , Adam Panagiotis S. , Albers Sonja-Verena , Dorfmueller Helge C.
Published: January 2021

Protein N-glycosylation is the most common posttranslational modifications found in all three domains of life. The crenarchaeal N-glycosylation begins with the synthesis of a lipid-linked chitobiose core structure, identical to that in eukaryotes. Here, we report the identification of a thermostable archaeal beta-1,4-N-acetylglucosaminyltransferase, named archaeal glycosylation enzyme 24 (Agl24), responsible for the synthesis of the N-glycan chitobiose core. Biochemical characterization confirmed the function as an inverting β-D-GlcNAc-(1→4)-α-D-GlcNAc-diphosphodolichol glycosyltransferase. Substitution of a conserved histidine residue, found also in the eukaryotic and bacterial homologs, demonstrated its functional importance for Agl24. Furthermore, bioinformatics and structural modeling revealed strong similarities between Agl24 and both the eukaryotic Alg14/13 and a distant relation to the bacterial MurG, which catalyze the identical or a similar process, respectively. Our data, complemented by phylogenetic analysis of Alg13 and Alg14, revealed similar sequences in Asgardarchaeota, further supporting the hypothesis that the Alg13/14 homologs in eukaryotes have been acquired during eukaryogenesis.

Highlights

First identification and characterization of a thermostable β-D-GlcNAc-(1→4)-α-D-GlcNAc-diphosphodolichol glycosyltransferase (GT family 28) in Archaea.

A highly conserved histidine, within a GGH motif in Agl24, Alg14, and MurG, is essential for function of Agl24.

Agl24-like homologs are broadly distributed among Archaea.

The eukaryotic Alg13 and Alg14 are closely related to the Asgard homologs, suggesting their acquisition during eukaryogenesis.
Conserved and non-conserved triggers of 24-nt reproductive phasiRNAs in eudicots
Authors: Pokhrel Suresh , Huang Kun , Meyers Blake C.
Published: January 2021

Plant small RNAs (sRNAs) play important roles in plant growth and development by modulating expression of genes and transposons. In many flowering plant species, male reproductive organs, the anthers, produce abundant phased small interfering RNAs (phasiRNAs). Two classes of reproductive phasiRNAs are generally known, mostly from monocots: pre-meiotic 21-nt phasiRNAs triggered by miR2118, and meiotic 24-nt phasiRNAs triggered by miR2275. Here, we describe conserved and non-conserved triggers of 24-nt phasiRNAs in several eudicots. We found that the abundant 24-nt phasiRNAs in the basal eudicot columbine are produced by the canonical trigger, miR2275, as well as by other non-conserved triggers, miR482/2118 and aco_cand81. These triggering miRNAs are localized in microspore mother cells (MMC) and tapetal cells of meiotic and post-meiotic stage anthers. Furthermore, we identified a new trigger (miR11308) of 24-nt phasiRNAs and an expanded number of 24-PHASloci in wild strawberry. We validated the presence of miR2275-derived 24-nt phasiRNAs pathway in rose. Finally, we evaluated all the eudicots that have been validated for the presence of 24-nt phasiRNAs as models to study biogenesis and function of 24-nt phasiRNAs and conclude that columbine would be an excellent model because of its extensive number of 24-PHASloci and its diversity of trigger miRNAs.
Adaptive laboratory evolution triggers pathogen-dependent broad-spectrum antimicrobial potency inStreptomyces
Authors: Harwani Dharmesh , Begani Jyotsna , Barupal Sweta , Lakhani Jyoti
Published: January 2021

In the present study, adaptive laboratory evolution was used to stimulate antibiotic production in a weak antibiotic-producingStreptomycesstrain JB140. The seven different competition experiments utilized three serial passages (three cycles of adaptation-selection of 15 days each) of a weak antibiotic-producingStreptomycesstrain (wild-type) against one (biculture) or two (triculture) or three (quadriculture) target pathogens. This resulted in the evolution of a weak antibiotic-producing strain into the seven unique mutant phenotypes that acquired the ability to constitutively exhibit increased antimicrobial activity against bacterial pathogens. The mutant not only effectively inhibited the growth of the tested pathogens but also observed to produce antimicrobial against multidrug-resistant (MDR)E. coli.Intriguingly, the highest antimicrobial activity was registered with theStreptomycesmutants that were adaptively evolved against the three pathogens (quadriculture competition). In contrast to the adaptively evolved mutants, a weak antimicrobial activity was detected in the un-evolved, wild-typeStreptomyces. To get molecular evidence of evolution, RAPD profiles of the wild-typeStreptomycesand its evolved mutants were compared that revealed significant polymorphism among them. These results demonstrated that competition-based adaptive laboratory evolution method can constitute a platform for evolutionary engineering to select improved phenotypes (mutants) with increased production of antibiotics against targeted pathogens.
Coiled coils 9-to-5: Rationalde novodesign of α-helical barrels with tunable oligomeric states
Authors: Dawson William M. , Martin Freddie J.O. , Rhys Guto G. , Shelley Kathryn L. , Brady R. Leo , Woolfson Derek N.
Published: January 2021

The rational design of linear peptides that assemble controllably and predictably in water is challenging. Sequences must encode unique target structures and avoid alternative states. However, the stabilizing and discriminating non-covalent forces available are weak in water. Nonetheless, for α-helical coiled-coil assemblies considerable progress has been made in rationalde novodesign. In these, sequence repeats of nominally hydrophobic (h) and polar (p) residues,hpphppp, direct the assembly of amphipathic helices into dimeric to tetrameric bundles. Expanding this pattern tohpphhphcan produce larger α-helical barrels. Here, we show that pentamers to nonamers are achieved simply by varying the residue at one of thesehsites. In L/I-K-E-I-A-x-Z repeats, decreasing the size of Z from threonine to serine to alanine to glycine gives progressively larger oligomers. X-ray crystal structures of the resulting α-helical barrels rationalize this: side chains at Z point directly into the helical interfaces, and smaller residues allow closer helix contacts and larger assemblies.
Enrichment of Zα domains at cytoplasmic stress granules is due to their innate ability to bind nucleic acids
Authors: Gabriel Luisa , Srinivasan Bharath , Kuś Krzysztof , Mata João F. , Amorim Maria João , Jansen Lars E.T. , Athanasiadis Alekos
Published: January 2021

Zα domains are a subfamily of winged Helix-Turn-Helix (wHTH) domains found exclusively in proteins involved in the nucleic acids sensory pathway of vertebrate innate immune system and host evasion by viral pathogens. Interestingly, they are the only known protein domains that recognise the left-handed helical conformation of both dsDNA and dsRNA, known as Z-DNA and Z-RNA. Previously, it has been demonstrated that ADAR1 and ZBP1, two proteins possessing the Zα domains, localize to cytosolic stress granules. It was further speculated that such localization is principally mediated by Zα domains. To characterize and better understand such distinct and specific localization, we characterised thein vivointeractions and localization pattern for the amino terminal region of human DAI harbouring two Zα domains (ZαβDAI). Using immunoprecipitation and mass spectrometry, we identified several interacting partners that were components of the complex formed by Zα domains and RNAs. Differential interacting partners to wild-type Zα, relative to mutant proteins, demonstrated that most of the physiologically relevant interactions are mediated by the nucleic acid binding ability of the Zαβ. Further, we also show enrichment of selected complex components in cytoplasmic stress granules under conditions of stress. This ability is mostly lost in the mutants of ZαβDAI(ZαβDAI4×mut) that lack nucleic-acid binding ability. Thus, we posit that the mechanism for the translocation of Zα domain-containing proteins to stress granules is mainly mediated by the nucleic acid binding ability of their Zα domains. Finally, we demonstrate that FUS and PSF/p54nrb, two RNA binding proteins with established roles in stress granules, interact with Zα, which provides strong evidence for a role of these proteins in the innate immune system.
Systemic inflammation recruits fast-acting anti-inflammatory innate myeloid progenitors from BM into lymphatics
Authors: Serrano-Lopez Juana , Hegde Shailaja , Kumar Sachin , Serrano Josefina , Fang Jing , Wellendorf Ashley M. , Roche Paul A. , Rangel Yamileth , Carrington Léolène J. , Geiger Hartmut , Grimes H. Leighton , Luther Sanjiv , Maillard Ivan , Sanchez-Garcia Joaquin , Starczynowski Daniel T. , Cancelas Jose A.
Published: January 2021

Innate immune cellular effectors are actively consumed during systemic inflammation but the systemic traffic and the mechanisms that support their replenishment remain unknown. Here we demonstrate that acute systemic inflammation induces the emergent activation of a previously unrecognized system of rapid migration of granulocyte-macrophage progenitors and committed macrophage-dendritic progenitors, but not other progenitors or stem cells, from bone marrow (BM) to lymphatic capillaries. The progenitor traffic to the systemic lymphatic circulation is mediated by Ccl19/Ccr7 and is NFκB independent, Traf6/IκB-kinase/SNAP23 activation which is responsible for the secretion of pre-stored Ccl19 by a subpopulation of CD205+/CD172a+conventional dendritic cells type 2 (cDC2) and upregulation of BM myeloid progenitor Ccr7 signaling. The consequence of this progenitor traffic is anti-inflammatory with promotion of early survival and initiation of replenishment of lymph node cDC.
Differential requirement of NPHP1 for compartmentalized protein localization during photoreceptor outer segment development and maintenance
Authors: Datta Poppy , Cribbs J. Thomas , Seo Seongjin
Published: January 2021

Nephrocystin (NPHP1) is a ciliary transition zone protein and its ablation causes nephronophthisis (NPHP) with partially penetrant retinal dystrophy. However, the precise requirements of NPHP1 in photoreceptors are not well understood. Here, we characterize retinal degeneration in a mouse model of NPHP1 and show that NPHP1 is required to prevent infiltration of inner segment plasma membrane proteins into the outer segment during the photoreceptor maturation. We demonstrate thatNphp1gene-trap mutant mice, which were previously described as null, are in fact hypomorphs due to the production of a small quantity of functional mRNAs derived from nonsense-associated altered splicing and skipping of two exons including the one harboring the gene-trap. In homozygous mutant animals, inner segment plasma membrane proteins such as syntaxin-3 (STX3), synaptosomal-associated protein 25 (SNAP25), and interphotoreceptor matrix proteoglycan 2 (IMPG2) accumulate in the outer segment when outer segments are actively elongating. This phenotype, however, is spontaneously ameliorated after the outer segment elongation is completed. Retinal degeneration also occurs temporarily during the photoreceptor maturation but stops afterward. We further show thatNphp1genetically interacts withCep290, another NPHP gene, and that a reduction ofCep290gene dose results in retinal degeneration that continues until adulthood inNphp1mutant mice. These findings demonstrate that NPHP1 is required for the confinement of inner segment plasma membrane proteins during the outer segment development, but its requirement diminishes as photoreceptors mature. Our study also suggests that additional mutations in other NPHP genes may influence the penetrance of retinopathy in human NPHP1 patients.
Pharmacokinetics of long-term low-dose oral rapamycin in four healthy middle-aged companion dogs
Authors: Evans Jeremy B. , Morrison Ashley J , Javors Martin A. , Lopez-Cruzan Marisa , Promislow Daniel E.L. , Kaeberlein Matt , Creevy Kate E.
Published: January 2021

Objective

To determine the blood concentration and pharmacokinetic parameters of rapamycin in companion dogs following long-term, low-dose oral administration of rapamycin.

Animals

Four healthy, middle-aged, medium-to-large breed privately owned dogs participated.

Procedures

All dogs had been receiving oral rapamycin at a dose of 0.025 mg/kg on Monday, Wednesday, and Friday mornings for at least one month. An initial blood sample was collected prior to morning rapamycin administration, and samples were collected at 1, 2, 6, and 24 hours after rapamycin was given. Blood samples were transferred to blood spot collection cards, air-dried and stored at −80°C. Rapamycin concentrations were determined via HPLC/MS. All blood collections occurred on Wednesdays, so that the previous dose of rapamycin had taken place 48 hours prior to blood collection.

Results

For all dogs, rapamycin Tmaxwas 2 hours. Median Cmaxwas 1.47 ng/ml (0.912 – 2.13), and the median AUC0-lastwas 15.7 ng*hr/mL (1.30 – 36.3). Due to sample size and timing, the only estimates related to elimination rate reported are for mean residence time with a median of 4.70 hrs (0.90 – 7.30).

Conclusions and Clinical Relevance

A 0.025 mg/kg oral dose of rapamycin, administered three times a week, resulted in concentrations of rapamycin in the blood capable of being measured in ng/ml.
The Predicted Metabolic Function of the Gut Microbiota ofDrosophila melanogaster
Authors: Ankrah Nana Y.D. , Barker Brandon E. , Song Joan , Wu Cindy , McMullen John G. , Douglas Angela E.
Published: January 2021

An important goal for many nutrition-based microbiome studies is to identify the metabolic function of microbes in complex microbial communities and its impact on host physiology. This research can be confounded by poorly-understood effects of community composition and host diet on the metabolic traits of individual taxa. Here, we investigated these multi-way interactions by constructing and analyzing metabolic models comprising every combination of five bacterial members of theDrosophilagut microbiome (from single taxa to the five-member community ofAcetobacterandLactobacillusspecies) under three nutrient regimes. We show that the metabolic function ofDrosophilagut bacteria is dynamic, influenced by community composition and responsive to dietary modulation. Furthermore, we show that ecological interactions such as competition and mutualism identified from the growth patterns of gut bacteria are underlain by a diversity of metabolic interactions, and show that the bacteria tend to compete for amino acids and B vitamins more frequently than for carbon sources. Our results reveal that in addition to fermentation products such as acetate, intermediates of the tricarboxylic acid (TCA) cycle including 2-oxoglutarate and succinate are produced at high flux and cross-fed between bacterial taxa suggesting important roles for TCA cycle intermediates in modulatingDrosophilagut microbe interactions and the potential to influence host traits. These metabolic models provide specific predictions of the patterns of ecological and metabolic interactions among gut bacteria under different nutrient regimes, with potentially important consequences for overall community metabolic function and nutritional interactions with the host.

IMPORTANCE

Drosophilais an important model for microbiome research partly because of the low complexity of its mostly culturable gut microbiota. Our current understanding of howDrosophilainteracts with its gut microbes and how these interactions influence host traits derives almost entirely from empirical studies that focus on individual microbial taxa or classes of metabolites. These studies have failed to capture fully the complexity of metabolic interactions that occur between host and microbe. To overcome this limitation, we reconstructed and analyzed 31 metabolic models for every combination of the five principal bacterial taxa in the gut microbiome ofDrosophila. This revealed that metabolic interactions between betweenDrosophilagut bacterial taxa are highly dynamic and influenced by co-occurring bacteria and nutrient availability. Our results generate testable hypothesis about among-microbe ecological interactions in theDrosophilagut and the diversity of metabolites available to influence host traits.
ATGs ubiquitination is required for circumsporozoite protein to subvert host innate immunity against malaria liver stage
Authors: Zheng Hong , Lu Xiao , Li Kai , Zhu Feng , Zhao Chenhao , Liu Taiping , Ding Yan , Fu Yong , Zhang Kun , Zhou Taoli , Dai Jigang , Wu Yuzhang , Xu Wenyue
Published: January 2021

Although exoerythrocytic forms (EEFs) of liver stage malaria parasite in parasitophorous vacuole (PV) encountered with robust host innate immunity, EEFs can still survive and successfully complete infection of hepatocytes, and the underlying mechanism is largely unknown. Here, we showed that sporozoite circumsporozoite protein (CSP) translocated from the parasitophorous vacuole into the hepatocyte cytoplasm significantly inhibited the killing of exo-erythrocytic forms (EEFs) by interferon-gamma (IFN-γ). Attenuation of IFN-γ-mediated killing of EEFs by CSP was dependent on its ability to reduce the levels of autophagy-related genes (ATGs) in hepatocytes. The ATGs downregulation occurred through its enhanced ubiquitination mediated by E3 ligase NEDD4, an enzyme that was upregulated by CSP when it translocated from the cytoplasm into the nucleus of hepatocytes via its nuclear localization signal (NLS) domain. Thus, we have revealed an unrecognized role of CSP in subverting host innate immunity and shed new light for a prophylaxis strategy against liver-stage infection.
The spatial extent of a single lipid’s influence on bilayer mechanics
Authors: Sapp Kayla C. , Sodt Alexander J. , Beaven Andrew H.
Published: January 2021

To what spatial extent does a single lipid affect the mechanical properties of the membrane that surrounds it? The lipid composition of a membrane determines its mechanical properties. The shapes available to the membrane depend on its compositional material properties, and therefore, the lipid environment. Because each individual lipid species’ chemistry is different, it is important to know its range of influence on membrane mechanical properties. This is defined herein as the lipid’s mechanical extent. Here, a lipid’s mechanical extent is determined by quantifying lipid redistribution and the average curvature that lipid species experience on fluctuating membrane surfaces. A surprising finding is that, unlike unsaturated lipids, saturated lipids have a complicated, non-local effect on the surrounding surface, with the interaction strength maximal at a finite length-scale. The methodology provides the means to substantially enrich curvature-energy models of membrane structures, quantifying what was previously only conjecture.