bluuebunny/crossref_metadata_2025 huggingface dataset:
True hermaphroditism with dysgerminoma
Authors: Chen Chun-Qiao , Liu Zheng , Lu Yu-Song , Pan Min , Huang Hui
Published: May 2020

Introduction:

True hermaphroditism is a rare and usually sporadic disorder. It is defined by the presence of both ovarian and testicular tissues together as ovotestis.

Patient concerns:

In this study, we reported a rare true hermaphroditism case with dysgerminoma. A 49-year-old woman developed masses in both inguinal regions for 30 years. Recently 3 months, the patient found that the size of mass in her left inguinal region was significantly increased.

Diagnosis:

After surgical resection, the results of immunohistochemical examination in left mass revealed a dysgerminoma with positive expression of placental alkaline phosphatase and octamer-binding transcription factor 3/4, and right mass was a cryptorchidism. Chromosomal analysis revealed the karyotype 46, XY. Combined immunohistochemical and karyotype analysis, a diagnosis of true hermaphroditism with dysgerminoma was made.

Interventions:

Radiotherapy combined with chemotherapy after tumor resection was used to improve her prognosis. Hormone replacement therapy with conjugated estrogen and medroxyprogesterone acetate were used to maintain her female characteristics.

Outcomes:

The patient underwent hormonal replacement and has been well for 6 months.

Conclusion:

The positive expression of placental alkaline phosphatase and octamer-binding transcription factor 3/4 could be 2 diagnosis markers of dysgerminoma. Surgery combined with radiotherapy and chemotherapy could improve the prognosis of dysgerminoma. Moreover, hormone replacement therapy with conjugated estrogen and medroxyprogesterone acetate was very helpful to maintain the female characteristic of patients with true hermaphroditism.
Plasma protein patterns are strongly correlated with pressure pain thresholds in women with chronic widespread pain and in healthy controls—an exploratory case-control study
Authors: Gerdle Björn , Wåhlén Karin , Ghafouri Bijar
Published: May 2020

Chronic widespread pain (CWP) is a complex pain condition characterized by generalized musculoskeletal pain and often associated with other symptoms. An important clinical feature is widespread increased pain sensitivity such as lowered pain thresholds for mechanical stimuli (pressure pain thresholds [PPT]). There is a growing interest in investigating the activated neurobiological mechanisms in CWP, which includes fibromyalgia. In CWP, strong significant correlations have been found between muscle protein patterns and PPT. This explorative proteomic study investigates the multivariate correlation pattern between plasma proteins and PPT in CWP and in healthy controls (CON). In addition, this study analyses whether the important proteins for PPT differ between the 2 groups.

Using 2-dimensional gel electrophoresis, we analyzed the plasma proteome of the CWP (n = 15) and the CON (n = 23) and proteins were identified using mass spectrometry. For both the CWP and the CON, the associations between the identified proteins and PPT were analyzed using orthogonal partial least square in 2 steps.

Significant associations between certain plasma proteins and PPT existed both in CWP (R
2 = 0.95; P = .006) and in CON (R
2 = 0.89; P < .001). For both groups of subjects, we found several proteins involved in PPT that reflect different biological processes. The plasma proteins as well as the biological processes involved in PPT differed markedly between the 2 groups of subjects.

This study suggests that plasma protein patterns are associated with pain thresholds in CWP. Using the plasma proteome profile of CWP to study potential biomarker candidates could provide a snapshot of ongoing systemic mechanisms in CWP.
Nasopharyngeal carcinoma perfusion MRI
Authors: Xiao Bohan , Wang Peiguo , Zhao Yingru , Liu Ying , Ye Zhaoxiang
Published: May 2020

To investigate the feasibility of 3D arterial spin labeling (ASL) as an alternative to dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) for the qualitative and quantitative evaluation of nasopharyngeal carcinoma (NPC) perfusion.

Fifty-two newly diagnosed NPC patients underwent 3D ASL and DCE-MRI scans on a 3.0-T MRI system. The visual qualitative evaluation of the NPC perfusion level was scored from 0 to 3 (0 = no contrast to normal peripheral soft tissue, 3 = pronounced contrast to normal peripheral soft tissue). The visual evaluation of the NPC outline was scored from 0 to 2 (0 = very vague outline, 2 = clear outline). Comparisons of the ASL-derived blood flow (BF) with the DCE-MRI-derived positive enhancement integral, maximum slope of increase, maximum slope of decrease, and time to peak (TTP) were conducted between NPC and non-NPC areas with independent samples t-tests. The diagnostic performance of these parameters was assessed by receiver operating characteristic curve analysis. The correlations between ASL BF and DCE parameters were assessed by Spearman correlation analysis.

There was no difference in the visual scores of the NPC perfusion level between the 2 perfusion methods (P= .963). ASL had a lower visual score for describing the outline of NPC than DCE-MRI (P < .001). The ASL and DCE parameters of the NPC areas were significantly different from those of the non-NPC areas (P < .001). The ASL BF showed the largest area under the receiver operating characteristic curve (AUC) of 0.936 for identifying NPC. When all NPC and non-NPC areas were taken into account, significant correlations were observed between the ASL BF and the DCE parameters positive enhancement integral (r = 0.503, P < .001), maximum slope of increase (r = 0.616, P < .001), maximum slope of decrease (r = 0.380, P < .001), and TTP (r = -0.601, P < .001).

3D ASL could reveal the hyperperfusion of NPC in a qualitative and quantitative manner without using contrast agent. Additionally, the ASL BF correlated significantly with the semiquantitative DCE-MRI parameters.
Factors associated with fat stranding on computed tomography in acute appendicitis
Authors: Lin Hui-An , Lin Sheng-Feng
Published: May 2020

To determine which factor is associated with presence of fat stranding sign for acute appendicitis on computed tomography (CT).

This study reviewed the CT imaging of adults with proven acute appendicitis at a single center from January 1, 2015 to December 31, 2019. Logistic regression models were used to investigate the association between clinical characteristics and fat stranding sign. Receiver operating characteristic (ROC) curve analysis was used to determine the cutoff value that helped predict the presence of fat stranding on CT.

In total, 413 patients were included. Age of ≥40 years (OR: 3.10; 95% CI, 2.02–4.74; P < .0001), body mass index of ≥23 kg/m2 (OR: 2.86; 1.89–4.34; P < .0001), white blood cell count of ≥10,000/μl (OR: 1.77; 1.05–2.99; P = .0316), and C-reactive protein level of ≥2.4 mg/dl (OR: 3.17; 1.97–5.08; P < .0001) were significant factors predicting fat stranding on CT. The ROC analysis with above 4 factors showed an area under the curve of 0.76 (0.71–0.80).

Body habitus, advanced age, and elevated inflammatory marker levels were independent in predicting fat stranding for patients with acute appendicitis.
Effect of intravitreal ceftazidime injection on endogenous klebsiella pneumoniae endophthalmitis, a single center case series
Authors: Sim Ha Eun , Kang Min-Ji , Kim Jae-Suk , Park Jae Yong , Hwang Je-Hyung
Published: May 2020

To report long-term outcomes of intravitreal ceftazidime injection in patients with endogenous Klebsiella pneumoniae endophthalmitis (EKPE).

This was a retrospective observational case study, including 7 eyes from 6 patients with EKPE. The medical records from January 2010 to December 2018 were reviewed.

Diagnosis of EKPE was made based on the finding of endophthalmitis with concurrent systemic infection and positive blood culture result. All patients received tap and intravitreal ceftazidime injection base on the results of antibiotics sensitivity test. Visual acuity ranged from no light perception to 20/60 at initial visit, and the final visual acuity was 20/20. Two eyes underwent evisceration after intravitreal injection.

Intravitreal ceftazidime injection showed favorable results in patients with EKPE.
Efficacy and safety of local infiltration analgesia for pain management in total knee and hip arthroplasty
Authors: Peng Xiao-Qiang , Fei Zheng-Guo , Sun Chun-Guang , Zhou Qi-Jia
Published: May 2020

Background:

Local infiltration analgesia (LIA) has become popular in postoperative pain relief after total hip arthroplasty (THA) or total knee arthroplasty (TKA). The aim of this meta-analysis was to compare the efficacy and safety of LIA with intrathecal morphine and epidural analgesia after THA and TKA.

Methods:

A systematic article search was performed from PubMed, Embase, and Web of Science databases, up to February 21, 2019. The main outcomes included visual analog scale for assessment of pain, morphine equivalent consumption, length of hospital stay, and adverse events. The data were calculated using weight mean difference (WMD) or risk ratio (RR) with 95% confidence intervals (95% CIs).

Results:

Eleven studies with a total of 707 patients met the inclusion criteria and were included in this meta-analysis. LIA provided better pain control than other 2 techniques at 24-hour (WMD = 10.61, 95% CI: 3.36–17.87; P = .004), 48-hour (WMD = 16.0, 95% CI: 8.87–23.13; P < .001), and 72-hour (WMD = 11.31, 95% CI: 3.78–18.83; P < .001). Moreover, LIA had similar morphine consumption and duration of hospital stay with intrathecal morphine and epidural analgesia. There was significantly lower incidence of adverse events with LIA than with the other 2 techniques.

Conclusion:

LIA provided better postoperative pain control and less adverse events than intrathecal morphine and epidural analgesia after THA and TKA.
How to Reduce Cardiovascular Risk in Nonalcoholic Fatty Liver Disease
Authors: Ismaiel Abdulrahman , Dumitrascu Dan L.
Published: May 2020

Background:

Nonalcoholic fatty liver disease (NAFLD) is a rapidly growing multisystem disease with extrahepatic manifestations, including effects on the cardiovascular (CV) system. The leading cause of death in NAFLD is of cardiac etiology being ischemic heart disease.

Areas of Uncertainty:

NAFLD is associated with several CV complications including cardiac structural and functional alterations. However, there are no current approved pharmacotherapies for treating NAFLD, leading to increased CV risk with an increasing morbidity and mortality.

Data Sources:

We summarize the currently available therapeutic strategies in managing NAFLD and their cardioprotective effects according to recently published data, guidelines, and practice guidance recommendations.

Therapeutic Advances:

Several therapeutic modalities evaluated in NAFLD include nonpharmacological strategies, pharmacotherapies and surgical management. Nonpharmacological strategies are recommended in early stages of NAFLD and include weight loss, physical activity, and dietary changes. Personalized management strategies with nonpharmacological lifestyle modifications are associated with reduced CV risk, improved liver enzyme levels, in addition to liver fat content, injury, and fibrosis. Several pharmacotherapies including lipid-lowering agents and antidiabetic drugs such as insulin sensitizers and incretin mimetics, in addition to antioxidants, ursodeoxycholic acid, semi-synthetic bile acid analogue, acetylsalicylic acid, and renin–angiotensin system inhibitors have been evaluated in the current literature. Despite promising results of several drugs in NAFLD with cardioprotective effects, we currently remain with no approved medical drugs for treating NAFLD. Although bariatric surgery was demonstrated to be associated with CV risk reduction and improvements in hepatic steatosis, inflammation, and fibrosis, it remains of limited use because of its invasiveness.

Conclusions:

Management of NAFLD necessitates a multidisciplinary team with a patient-centered and individualized medicine approach. Early lifestyle modifications are essential in NAFLD to reduce CV risk. Experimental studies are required to confirm hepatic and cardioprotective effects associated with several drugs. Bariatric surgery remains of limited use.
Impact of Time to Receipt of Prosthesis on Total Healthcare Costs 12 Months Postamputation
Authors: Miller Taavy A. , Paul Rajib , Forthofer Melinda , Wurdeman Shane R.
Published: May 2020

Objective

The objective was to assess the impact of a prosthesis and the timing of prosthesis receipt on total direct healthcare costs in the 12-mo postamputation period.

Design

Data on patients with lower limb amputation (n = 510) were obtained from a commercial claims database for retrospective cohort analysis. Generalized linear multivariate modeling was used to determine differences in cost between groups according to timing of prosthesis receipt compared with a control group with no prosthesis.

Results

Receipt of a prosthesis between 0 and 3 mos post lower limb amputation yielded a reduced total cost by approximately 0.23 in log scale within 12 mos after amputation when compared with the no-prosthesis group. Despite the included costs of a prosthesis, individuals who received a prosthesis either at 4–6 mos postamputation or 7–9 mos postamputation incurred costs similar to the no-prosthesis group.

Conclusion

Earlier receipt of a prosthesis is associated with reduced spending in the 12 mos postamputation of approximately $25,000 compared with not receiving a prosthesis. The results of this study suggest that not providing or delaying the provision of a prosthesis increases costs by about 25%.
COVID-19 Guide for the Rehabilitation Clinician
Authors: Lopez Marielisa , Bell Kathleen , Annaswamy Thiru , Juengst Shannon , Ifejika Nneka
Published: May 2020

Severe acute respiratory syndrome coronavirus 2—also known as COVID-19—is primarily known for respiratory illness. Although it is clear that patients with moderate to severe cases of COVID-19 will require pulmonary rehabilitation, physiatrists will need to consider effective management plans for COVID-19 survivors with extrapulmonary involvement. This report will summarize key nonpulmonary considerations to guide rehabilitation clinicians who may be involved in the care of COVID-19 survivors with the best available early evidence.
Neck Imaging Reporting and Data System: What Does Radiologist Want to Know?
Authors: Abdel Razek Ahmed Abdel Khalek , Abdelaziz Tougan Taha
Published: May 2020

The aim of this work was to review Neck Imaging Reporting and Data System (NI-RADS) that was designed for reporting and surveillance of head and neck cancer after therapy and their subsequent management. The categories of NI-RADS can be designated as belonging in 1 of the 4 categories: negative; low suspicion; high suspicion; and definite recurrence. Lexicon of NI-RADS-1 shows nonmass-like distortion of soft tissues, NI-RADS-2 lesions divided into mucosal (2A) versus deep (2B) abnormalities, NI-RADS-3 primary site can either be a submucosal or deep lesion, and NI-RADS-4 is a biopsy-proven residual or recurrent disease. The NI-RADS Lexicon of radiology reporting categories linked to management protocols and surveillance for these patients. Neck Imaging Reporting and Data System is to provide guidance for next-imaging decisions either a follow-up period, biopsy, or surgery.
How Do Standardized Patients Form Their Complex Identities? The Impact of Interactions With Medical Students
Authors: Starr Samantha A. , Plack Margaret M. , Lewis Karen L. , Blatt Benjamin
Published: May 2020

Introduction

Little is known about the nature of standardized patient (SP) identity and its formation. Understanding identity and formation can have important implications for recruiting, working with, and retaining SPs. Social relational theory explains how identity is formed in a social context in relationship with others. In keeping with social relational theory, this study explored SP identity formation through the SP experience with one of the most important elements of their social context—medical students.

Methods

Using qualitative methods, we conducted four 1-hour semistructured focus group interviews with SPs (N = 18). Interviews were audio recorded and transcribed verbatim. We used a constant comparative approach and consensus development to analyze the data and identify codes, categories, and ultimately themes. We used multiple methods to ensure credibility and trustworthiness of the study, as well as transparency of methods and thick rich descriptions to enable readers to judge transferability of the findings and conclusions.

Results

We identified 4 major themes. Through their interactions, SPs experienced: (1) identity transformation toward a new professional identity; (2) self-actualization toward their maximum potential; (3) judgmental reactions to medical student behaviors; and (4) simulation-reality interaction between their simulated and real selves.

Conclusions

Through their interactions with medical students, SPs experienced a transformation into a complex identity composed of multiple roles. Within this identity, they found purpose, fulfillment, and self-actualization through fostering students', as well as their own, personal, and professional growth and through developing a higher sense of social responsibility. Within this identity, they also encountered the challenges of navigating between judging and supporting medical students, and toggling between their real and simulated selves. Guided by the SPs' perspectives, and in conjunction with professional organizational standards, we provide recommendations for training, recruitment, and retention of SPs.
Spirometry not pain level predicts outcomes in geriatric patients with isolated rib fractures
Authors: Schuster Kevin M. , Sanghvi Mansi , O'Connor Rick , Becher Robert , Maung Adrain A. , Davis Kimberly A.
Published: May 2020

BACKGROUND

Geriatric patients with rib fractures are at risk for developing complications and are often admitted to a higher level of care (intensive care units [ICUs]) based on existing guidelines. Forced vital capacity (FVC) has been shown to correlate with outcomes in patients with rib fractures. Complete spirometry may quantify pulmonary capacity, predict outcome, and potentially assist with admission triage decisions.

METHODS

We prospectively enrolled 86 patients, 60 years or older with three or more isolated rib fractures presenting after injury. After informed consent, patients were assessed with respect to pain (visual analog scale), grip strength, FVC, forced expiratory volume 1 second (FEV1), and negative inspiratory force on hospital days 1, 2, and 3. Outcomes included discharge disposition, length of stay (LOS), pneumonia, intubation, and unplanned ICU admission.

RESULTS

Mean age was 77.4 (SD, 10.2) and 43 (50.0%) were female. Forty-five patients (55.6%) were discharged home, median LOS was 4 days (interquartile range, 3–7). Pneumonias (2), unplanned ICU admissions (3), and intubation (1) were infrequent. Spirometry measures including FVC, FEV1, and grip strength predicted discharge to home and FEV1, and pain level on day 1 moderately correlated with the LOS. Within each subject, FVC, FEV1, and negative inspiratory force did not change for 3 days despite pain at rest and pain after spirometry improving from day 1 to 3 (p = 0.002, p < 0.001 respectively). Change in pain also did not predict outcomes and pain level was not associated with respiratory volumes on any of the 3 days. After adjustment for confounders, FEV1 remained a significant predictor of discharge home (odds ratio, 1.03; 95% confidence interval, 1.01–1.06) and LOS (p = 0.001).

CONCLUSION

Spirometry measurements early in the hospital stay predict ultimate discharge home, and this may allow immediate or early discharge. The impact of pain control on pulmonary function requires further study.

LEVEL OF EVIDENCE

Diagnostic test, level IV.
Therapeutic anticoagulation in patients with traumatic brain injuries and pulmonary emboli
Authors: Chipman Amanda M. , Radowsky Jason , Vesselinov Roumen , Chow David , Schwartzbauer Gary , Tesoriero Ronald , Stein Deborah
Published: May 2020

BACKGROUND

Patients with traumatic intracranial hemorrhage (ICH) and concomitant pulmonary embolus (PE) have competing care needs and demand a careful balance of anticoagulation (AC) versus potential worsening of their ICH. The goal of this study is to determine the safety of therapeutic AC for PE in patients with ICH.

METHODS

This is a retrospective single-center study of patients older than 16 years with concomitant ICH and PE occurring between June 2013 and December 2017. Early AC was defined as within 7 days of injury or less; late was defined as after 7 days. Primary outcomes included death, interventions for worsening ICH following AC, and pulmonary complications. Multivariate logistic regression was used to evaluate for clinical and demographic factors associated with worsening traumatic brain injury (TBI), and recursive partitioning was used to differentiate risk in groups.

RESULTS

Fifty patients met criteria. Four did not receive any AC and were excluded. Nineteen (41.3%) received AC early (median, 4.1; interquartile range, 3.1–6) and 27 (58.7%) received AC late (median, 14; interquartile range, 9.7–19.5). There were four deaths in the early group, and none in the late cohort (21.1% vs. 0%, p = 0.01). Two deaths were due to PE and the others were from multi-system organ failure or unrecoverable underlying TBI. Three patients in the early group, and two in the late, had increased ICH on computed tomography (17.6% vs. 7.4%, p = 0.3). None required intervention.

CONCLUSION

This retrospective study failed to find instances of clinically significant progression of TBI in 46 patients with computed tomography–proven ICH after undergoing AC for PE. Therapeutic AC is not associated with worse outcomes in patients with TBI, even if initiated early. However, two patients died from PE despite AC, underlining the severity of the disease. Intracranial hemorrhage should not preclude AC treatment for PE, even early after injury.

LEVEL OF EVIDENCE

Care management, Level IV.
The Association Between Vena Cava Implantation Technique and Acute Kidney Injury After Liver Transplantation
Authors: Hannon Vivienne , Kothari Rishi P. , Zhang Li , Bokoch Michael P. , Hill Rachel , Roll Garrett R. , Mello Anna , Feiner John R. , Liu Kathleen D. , Niemann Claus U. , Adelmann Dieter
Published: May 2020

Background.

Acute kidney injury (AKI) after liver transplantation is associated with increased morbidity and mortality. It remains controversial whether the choice of vena cava reconstruction technique impacts AKI.

Methods.

This is a single-center retrospective cohort of 897 liver transplants performed between June 2009 and September 2018 using either the vena cava preserving piggyback technique or caval replacement technique without veno-venous bypass or shunts. The association between vena cava reconstruction technique and stage of postoperative AKI was assessed using multivariable ordinal logistic regression. Causal mediation analysis was used to evaluate warm ischemia time as a potential mediator of this association.

Results.

The incidence of AKI (AKI stage ≥2) within 48 h after transplant was lower in the piggyback group (40.3%) compared to the caval replacement group (51.8%, P < 0.001). Piggyback technique was associated with a reduced risk of developing a higher stage of postoperative AKI (odds ratio, 0.49; 95% confidence interval, 0.37-0.65, P < 0.001). Warm ischemia time was shorter in the piggyback group and identified as potential mediator of this effect. There was no difference in renal function (estimated glomerular filtration rate and the number of patients alive without dialysis) 1 y after transplant.

Conclusions.

Piggyback technique, compared with caval replacement, was associated with a reduced incidence of AKI after liver transplantation. There was no difference in long-term renal outcomes between the 2 groups.
Anti-biofilm and anti-virulence effects of zerumbone against Acinetobacter baumannii
Authors: Kim Hye-Rim , Shin Da-Seul , Jang Hye-In , Eom Yong-Bin
Published: May 2020

Acinetobacter baumannii

is a multidrug-resistant opportunistic pathogen that affects patients with a compromised immune system and is becoming increasingly important as a hospital-derived infection. This pathogen is difficult to treat owing to its intrinsic multidrug resistance and ability to form antimicrobial-tolerant biofilms. In the present study, we aimed to assess the potential use of zerumbone as a novel anti-biofilm and/or anti-virulence agent against

A. baumannii

. The results showed that zerumbone at sub-inhibitory doses decreased biofilm formation and disrupted established

A. baumannii

biofilms. The zerumbone-induced decrease in biofilm formation was dose-dependent based on the results of microtitre plate biofilm assays and confocal laser scanning microscopy. In addition, our data validated the anti-virulence efficacy of zerumbone, wherein it significantly interfered with the motility of

A. baumannii

. To support these phenotypic results, transcriptional analysis revealed that zerumbone downregulated the expression of biofilm- and virulence-associated genes (adeA, adeB, adeC and bap) in

A. baumannii

. Overall, our findings suggested that zerumbone might be a promising bioactive agent for the treatment of biofilm- and virulence-related infections caused by multidrug-resistant

A. baumannii

.
A unique small molecule pair controls the plant circadian clock
Authors: Uehara Takahiro N , Takao Saori , Matsuo Hiromi , Saito Ami N. , Ota Eisuke , Ono Azusa , Itami Kenichiro , Kinoshita Toshinori , Yamaguchi Junichiro , Nakamichi Norihito
Published: May 2020

Circadian clocks are the biological time keeping systems that coordinate genetic, metabolic, and physiological behaviors with the external day-night cycle. Previous studies have suggested possible molecular mechanisms for the circadian clock inArabidopsis thaliana(Arabidopsis), but there might be additional mechanisms that have been hidden due to genetic redundancy.

A clock reporter line of Arabidopsis was screened against the 10,000 chemicals in the Maybridge Hitfinder10K chemical library, and a structure-activity relationship study of hit compounds was conducted. Clock mutants were treated with two of the small molecules to gain insight into their mode of action.

The screening identified 5-(3,4-dichlorophenyl)-1-phenyl-1,7-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4,6(5H)-dione (TU-892) as a period lengthening molecule. From a structure-activity relationship study, we found that a molecule possessing 2,4-dichlorophenyl instead of a 3,4-dichlorophenyl group (TU-923) had period shortening activity. The period shortening activity ofTU-923was reversed to a lengthening activity in double mutants lackingPSEUDO-RESPONSE REGULATOR 9(PRR9) andPRR7(prr9-10 prr7-11).

Our study provides a unique small molecule pair that regulates the pace of the clock in opposite ways, likely by targeting unknown factors. Small differences at the atomic level can reverse the period tuning activities.PRR9andPRR7are essential for the activity ofTU-923in period shortening.
Defense versus growth in a hostile world – Lessons from phage and bacteria
Authors: Eriksen Rasmus Skytte , Krishna Sandeep
Published: May 2020

Bacterial communities are often highly diverse with several closely related species (or strains) coexisting together. These bacteria compete for resources and the competitive exclusion principle predicts that all but the fastest-growing bacteria will go extinct. When exposed to phage, it is predicted that bacterial strains with restriction-modification (RM) systems can circumvent the competitive exclusion principle and reach diversity on the order of the phage burst size. We show that with a trade-off between bacterial growth rates and the strength of their RM systems, the diversity of such an ecosystem can further increase several fold beyond the burst size limit. Moreover, we find that the ratio of the growth rate of a bacterial strain to the imperfection of its RM system is an excellent predictor of (i) whether the strain will go extinct or not, and (ii) the biomass of the strain if it survives. In contrast, the growth rate alone is not a determinant of either of these properties. Our work provides a quantitative example of a model ecosystem where the fitness of a species is determined not by growth rate, but by a trade-off between growth and defence against predators.
Discovery of novel haplotypes for complex traits in landraces
Authors: Mayer Manfred , Hölker Armin C. , González-Segovia Eric , Presterl Thomas , Ouzunova Milena , Melchinger Albrecht E. , Schön Chris-Carolin
Published: May 2020

Genetic variation is of crucial importance for selection and genetic improvement of crops. Landraces are valuable sources of diversity for germplasm improvement, but for quantitative traits efficient strategies for their targeted utilization are lacking. Here, we propose a genome-based strategy for making native diversity accessible for traits with limited genetic variation in elite germplasm. We generated ~ 1,000 doubled-haploid (DH) lines from three European maize landraces, pre-selected based on molecular and phenotypic information. Using GWAS, we mapped haplotype-trait associations for early development traits at high resolution in eleven environments. Molecular haplotype inventories of landrace derived DH libraries and a broad panel of 65 breeding lines based on 501,124 SNPs revealed novel variation for target traits in the landraces. DH lines carrying these novel haplotypes outperformed breeding lines not carrying the respective haplotypes. Most haplotypes associated with target traits showed stable effects across populations and environments and only limited correlated effects with undesired traits making them ideal for introgression into elite germplasm. Our strategy was successful in linking molecular variation to meaningful phenotypes and identifying novel variation for quantitative traits in plant genetic resources.
LETR1 is a lymphatic endothelial-specific lncRNA that governs cell proliferation and migration through KLF4 and SEMA3C
Authors: Ducoli Luca , Agrawal Saumya , Sibler Eliane , Kouno Tsukasa , Tacconi Carlotta , Hon Chung-Chao , Berger Simone D. , Müllhaupt Daniela , He Yuliang , D’Addio Marco , Dieterich Lothar C. , Carninci Piero , de Hoon Michiel J. L. , Shin Jay W. , Detmar Michael
Published: May 2020

Recent studies have revealed the importance of long noncoding RNAs (lncRNAs) as tissue-specific regulators of gene expression. There is ample evidence that distinct types of vasculature undergo tight transcriptional control to preserve their structure, identity, and functions. We determined, for the first time, the global lineage-specific lncRNAome of human dermal blood and lymphatic endothelial cells (BECs and LECs), combining RNA-Seq and CAGE-Seq. A subsequent genome-wide antisense oligonucleotide-knockdown screen of a robust set of BEC- and LEC-specific lncRNAs identified LETR1 as a critical gatekeeper of the global LEC transcriptome. Deep RNA-DNA, RNA-protein, and phenotype rescue analyses revealed that LETR1 acts as a nucleartrans-acting lncRNA modulating, via key epigenetic factors, the expression of essential target genes, including KLF4 and SEMA3C, governing the growth and migratory ability of LECs. Together, our study provides new evidence supporting the intriguing concept that every cell type expresses precise lncRNA signatures to control lineage-specific regulatory programs.
IMiDs induce FAM83F degradation via an interaction with CK1α to attenuate Wnt signalling
Authors: Dunbar Karen , Macartney Thomas J. , Sapkota Gopal P.
Published: May 2020

Immunomodulatory imide drugs (IMiDs) bind CRBN, a substrate receptor of the Cul4A E3 ligase complex, enabling neo-substrate recruitment and degradation via the ubiquitin-proteasome system. Here, we report FAM83F as such a neo-substrate. We recently showed that the eight FAM83 proteins (A-H) interact with members of the serine/threonine protein kinase CK1 family, to regulate their subcellular distribution and distinct biological roles. CK1α is a well-established IMiD neo-substrate and we demonstrate here that IMiD-induced FAM83F degradation requires its association with CK1α. Despite all FAM83 proteins interacting with CK1α, no other FAM83 protein is degraded by IMiDs. FAM83F is localised to the plasma membrane, and consistent with this, IMiD treatment results in depletion of both FAM83F and CK1α levels from the plasma membrane. We have recently identified FAM83F as a mediator of the canonical Wnt signalling pathway. The IMiD-induced degradation of FAM83F attenuated Wnt signalling in colorectal cancer cells and removed CK1α from the plasma membrane, mirroring the phenotypes observed with genetic ablation of FAM83F. Intriguingly, in many cancer cell lines, IMiD-induced degradation of CK1α is only modest and incomplete. In line with this observation, the expression of FAM83G, which also binds to CK1α, appears to attenuate the IMiD-induced degradation of CK1α, suggesting a protective role for FAM83G on CK1α. Our findings reveal that the efficiency of target protein degradation by IMiDs, and perhaps other degraders such as PROTACs, relies on the nature of the inherent multiprotein complex in which the target protein exists. Our findings unearth opportunities for developing degraders to target specific protein complexes.
Fast in vivo23Na imaging and T2*mapping using accelerated 2D-FID magnetic resonance spectroscopic imaging at 3 T: Proof of concept and reliability study
Authors: Alhulail Ahmad A. , Xia Pingyu , Shen Xin , Nichols Miranda , Volety Srijyotsna , Farley Nicholas , Thomas M. Albert , Nagel Armin M , Dydak Ulrike , Emir Uzay E.
Published: May 2020

Purpose

To implement an accelerated MR-acquisition method allowing to map sodium T2*relaxation and absolute concentration within skeletal muscles at 3T.

Methods

A fast-2D density-weighted concentric-ring-trajectory23Na-MRSI technique was used to acquire 64 time-points of FID with a spectral bandwidth of 312.5 Hz from a 2.5 x 2.5 mm2in-plane resolution within about 15 minutes. The fast relaxing23Na signal was localized with a single-shot, inversion-recovery based, non-echo (SIRENE) OVS method. The sequence was verified using simulation and phantom studies before implementing it in human calf muscles. Within two same-day sessions, 2D-SIRENE-MRSI (UTE = 0.55 ms) and 3D-MRI (UTE = 0.3 ms) data were acquired. The T2*values were fitted voxel-by-voxel using a bi-exponential model for the 2D-MRSI data. Within-subject coefficients of variation were estimated for both acquisition methods.

Results

The MRSI-FID data allowed for fast and slow T2*mapping of the calf muscles in vivo with minimal sensitivity reduction. The spatial-distributions of23Na concentration for both in vivo MRSI and 3D-MRI acquisitions were significantly correlated (r = 0.7,P<0.001). The test-retest results rendered high reliability for both MRSI (CV = 5%) and 3D MRI (CV = 6%). The meanin calf muscles was 0.7 ± 0.1 (contribution fraction = 37%), whilewas 13.2 ± 0.2 ms (63%). The mean absolute muscle23Na concentration calculated from the T2*-corrected data was 28.6 ± 3.3 mM.

Conclusion

The proposed MRSI technique is a reliable technique to map sodium’s absolute concentration and T2*within a clinically acceptable scan time at 3T.
Neutrophils Mediate Kidney Inflammation Following Acute Skin Exposure to UVB Light
Authors: Skopelja-Gardner Sladjana , Tai Joyce , Sun Xizhang , Tanaka Lena , Kuchenbecker James A. , Snyder Jessica M. , Kubes Paul , Mustelin Tomas , Elkon Keith B.
Published: May 2020

Photosensitivity to ultraviolet (UV) light affects up to ~80% of lupus patients and can exacerbate local skin disease as well as systemic disease, including lupus nephritis. While neutrophils have been implicated in local tissue injury in lupus in response to immune complex deposition, whether and how they play a role in photosensitivity induced systemic disease is unknown. Here, we show that following skin exposure to UV light, neutrophils migrate not only to the skin, but also to the kidney, in an IL-17A-dependent manner. Kidney infiltrating neutrophils produced reactive oxygen species and their presence was associated with upregulation of endothelial adhesion molecules and inflammatory cytokines as well as the induction of kidney injury markers, including transient proteinuria. Neutrophils were responsible for inflammation and renal injury as demonstrated by experiments that inhibited neutrophil mobilization. Exploiting a mouse model containing photoactivatable immune cells, we observed that a subset of neutrophils found in the kidney had transited through UV light-exposed skin suggesting reverse transmigration. These findings demonstrate that neutrophils mediate transient kidney injury following skin exposure to UV light and, coupled with observations identifying similar neutrophil phenotypes in human lupus, could provide a mechanistic link to explain sun-induced systemic lupus flares.
UPhyloplot2: Visualizing Phylogenetic Trees from Single-Cell RNA-seq Data
Authors: Kurtenbach Stefan , Rodriguez Daniel A. , Durante Michael A. , Harbour J. William
Published: May 2020

Recent advances in single cell sequencing technologies allow for greater resolution in assessing tumor clonality using chromosome copy number variations (CNVs), which can be inferred from single cell RNA-seq (scRNA-seq) data using applications such as inferCNV. Inferences regarding tumor clonality are frequently visualized using phylogenetic plots, which previously required time-consuming and tedious manual analysis. Here, we present UPhyloplot2, a python script that generates phylogenetic plots directly from inferCNV output files. The tool is publicly available athttps://github.com/harbourlab/UPhyloplot2/.
14-3-3 shuttles Activity-dependent neuroprotective protein to the cytoplasm to promote appropriate neuronal morphogenesis, cortical connectivity and calcium signaling
Authors: Bennison Sarah A. , Blazejewski Sara M. , Liu Xiaonan , Toyo-oka Kazuhito
Published: May 2020

Neurite formation is the earliest stage of neuronal morphogenesis, where primitive dendrites and the primitive axon emerge from a spherical neuron and begin to elongate. Defective neuritogenesis is a contributing pathogenic mechanism behind a variety of neurodevelopmental disorders. Activity-dependent neuroprotective protein (Adnp) is essential to embryonic and postnatal brain development, and mutations inADNPare among the most frequent underlying autism spectrum disorder (ASD). We found that knockdown of Adnpin vitroandin vivoin mouse layer 2/3 pyramidal neurons leads to increased neurite initiation and defective neurite elongation, suggesting that Adnp has distinct roles in each.In vivoanalysis revealed that deficits begin at P0 and are sustained throughout development, the most notable of which include increased neurite stabilization, disrupted angle of the apical dendrite, increased basal dendrite number, and increased axon length. Because small changes in neuronal morphology can have large-scale effects on neuronal function and connectivity, we performedex vivocalcium imaging to assess spontaneous function of layer 2/3 pyramidal neurons deficient in Adnp. This revealed that Adnp deficient neurons had a greater spontaneous calcium influx and a higher proportion of cells firing action potentials. Next, we utilized GRAPHIC, a novel synaptic tracing technology, to assess interhemispheric cortical connectivity. We found increased interhemispheric excitatory connectivity between Adnp deficient layer 2/3 pyramidal neurons. Because Adnp is a multifunctional protein with both transcription factor and cytoskeletal activity, we performed localization analysis of Adnp as neurons underwent neurite formation to probe the mechanism of our morphological defects. We found that Adnp is shuttled from the nucleus to the cytoplasm upon differentiation and this shuttling can be blocked via application of a global 14-3-3 inhibitor, difopein. Furthermore, we found that Adnp binds nuclear-cytoplasmic shuttle 14-3-3ε. We conclude that Adnp is shuttled from the nucleus to the cytoplasm by 14-3-3ε, where it regulates neuronal morphology, maturation, cortical connectivity, and calcium signaling.
Genetic, lifestyle and environmental risk factors for chronic pain revealed through GWAS
Authors: Lundberg Mischa , Campos Adrian I. , Farrell Scott F. , Wang Geng , Sterling Michele , Renteria Miguel E. , Ngo Trung Thanh , Cuellar-Partida Gabriel
Published: May 2020

Chronic pain (CP) is a leading cause of disability worldwide with complex aetiologies that remain elusive. Here we addressed this issue by performing a GWAS on a large UK Biobank sample (N=188,352 cases & N=69,627 controls) which identified two independent loci associated with CP nearADAMTS6andLEMD2. Gene-based tests revealed additional CP-associated genes (DCAKD, NMT1, MLN, IP6K3). Across 1328 complex traits, 548 (41%) were genetically correlated with CP, of which 175 (13%) showed genetic causal relationships using the latent causal variable approach and Mendelian randomization. In particular, major depressive disorder, anxiety, smoking, body fat & BMI were found to increase the risk of CP, whereas diet, walking for pleasure & higher educational attainment were associated with a reduced risk (i.e., protective effect). This data-driven hypothesis-free approach has uncovered several specific risk factors that warrant further examination in longitudinal trials to help deliver effective early screening & management strategies for CP.
Different pattern of pre-existing SARS-COV-2 specific T cell immunity in SARS-recovered and uninfected individuals
Authors: Bert Nina Le , Tan Anthony T , Kunasegaran Kamini , Tham Christine Y L , Hafezi Morteza , Chia Adeline , Chng Melissa , Lin Meiyin , Tan Nicole , Linster Martin , Chia Wan Ni , Chen Mark I-Cheng , Wang Lin-Fa , Ooi Eng Eong , Kalimuddin Shirin , Tambyah Paul Anantharajal , Low Jenny Guek-Hong , Tan Yee-Joo , Bertoletti Antonio
Published: May 2020

Memory T cells induced by previous infections can influence the course of new viral infections. Little is known about the pattern of SARS-CoV-2 specific pre-existing memory T cells in human. Here, we first studied T cell responses to structural (nucleocapsid protein, NP) and non-structural (NSP-7 and NSP13 of ORF1) regions of SARS-CoV-2 in convalescent from COVID-19 (n=24). In all of them we demonstrated the presence of CD4 and CD8 T cells recognizing multiple regions of the NP protein. We then show that SARS-recovered patients (n=23), 17 years after the 2003 outbreak, still possess long-lasting memory T cells reactive to SARS-NP, which displayed robust cross-reactivity to SARS-CoV-2 NP. Surprisingly, we observed a differential pattern of SARS-CoV-2 specific T cell immunodominance in individuals with no history of SARS, COVID-19 or contact with SARS/COVID-19 patients (n=18). Half of them (9/18) possess T cells targeting the ORF-1 coded proteins NSP7 and 13, which were rarely detected in COVID-19- and SARS-recovered patients. Epitope characterization of NSP7-specific T cells showed recognition of protein fragments with low homology to “common cold” human coronaviruses but conserved among animal betacoranaviruses.

Thus, infection with betacoronaviruses induces strong and long-lasting T cell immunity to the structural protein NP. Understanding how pre-existing ORF-1-specific T cells present in the general population impact susceptibility and pathogenesis of SARS-CoV-2 infection is of paramount importance for the management of the current COVID-19 pandemic.
Structure and reconstitution of a MCU-EMRE mitochondrial Ca2+uniporter complex
Authors: Wang Chongyuan , Baradaran Rozbeh , Long Stephen Barstow
Published: May 2020

The proteins MCU and EMRE form the minimal functional unit of the mitochondrial calcium uniporter complex in metazoans, a highly selective and tightly controlled Ca2+channel of the inner mitochondrial membrane that regulates cellular metabolism. Here we present functional reconstitution of an MCU-EMRE complex from the red flour beetle,Tribolium castaneum, and a cryo-EM structure of the complex at 3.5 Å resolution. Robust Ca2+uptake is observed into proteoliposomes containing the purified complex and is dependent on EMRE. The structure reveals a tetrameric channel with a single ion pore. EMRE is located at the periphery of the transmembrane domain and associates primarily with the first transmembrane helix of MCU. Coiled coil and juxtamembrane domains within the matrix portion of the complex adopt markedly different conformations than in a structure of a human MCU-EMRE complex, suggesting that the structures represent different conformations of these functionally similar metazoan channels.
Assessment of sample pooling for clinical SARS-CoV-2 testing
Authors: Griesemer Sara B , Van Slyke Greta , St. George Kirsten
Published: May 2020

Accommodating large increases in sample workloads has presented one of the biggest challenges to clinical laboratories during the COVID-19 pandemic. Despite the implementation of new automated detection systems, and previous efficiencies such as barcoding, electronic data transfer and extensive robotics, throughput capacities have struggled to meet the demand. Sample pooling has been suggested as an additional strategy to further address this need. The greatest concern with this approach in a clinical setting is the potential for reduced sensitivity, particularly the risk of false negative results when weak positive samples are pooled. To investigate this possibility, detection rates in pooled samples were evaluated, with extensive assessment of pools containing weak positive specimens. Additionally, the frequency of occurrence of weak positive samples across ten weeks of the pandemic were reviewed. Weak positive specimens were detected in all five-sample pools but failed to be detected in four of the 24 nine-sample pools tested. Weak positive samples comprised an average 16.5% of the positive specimens tested during the pandemic thus far, slightly increasing in frequency during later weeks. Other aspects of the testing process should be considered, however, such as accessioning and reporting, which are not streamlined and may be complicated by pooling procedures. Therefore, the impact on the entire laboratory process needs to be carefully assessed prior to implementing such a strategy.