bluuebunny/crossref_metadata_2025 huggingface dataset:
Sextus chest radiograph severity score correlates to clinical outcomes in patients with COVID-19
Authors: Sun Justin , Yu Daohai , Yoo Kevin , Choi Robert , Lu Xiaoning , Standiford Taylor , Cohen Gary , Marchetti Nathaniel , Agosto Omar , Kumaran Maruti , Maresky Hillel
Published: November 2021

The value of chest radiography (CXR) in detection and as an outcome predictor in the management of patients with coronavirus disease-2019 (COVID-19) has not yet been fully understood.

To validate a standardized CXR scoring system and assess its prognostic value in hospitalized patients found to have COVID-19 by imaging criteria and to compare it to computed tomography (CT).

In this cross-sectional chart review study, patients aged 18-years or older who underwent chest CT at a single institution with an imaging-based diagnosis of COVID-19 between March 15, 2020 to April 15, 2020 were included. Each patient's CXR and coronal CT were analyzed for opacities in a 6-zonal assessment method and aggregated into a “Sextus score.” Inter-reader variability and correlation between CXR and coronal CT images were investigated to validate this scoring system. Univariable and multiple logistic regression techniques were used to investigate relationships between CXR scores and clinical parameters in relation to patient outcomes.

One hundred twenty-four patients (median [interquartile range] age 58.5 [47.5–69.0] years, 72 [58%] men, 58 [47%] Blacks, and 35 [28%] Hispanics) were included. The CXR Sextus score (range: 0–6) was reliable (inter-rater kappa = 0.76; 95% confidence interval [CI]: 0.69–0.83) and correlated strongly with the CT Sextus score (Spearman correlation coefficient = 0.75, P < .0001). Incremental increases of CXR Sextus scores of 2 points were found to be an independent predictor of intubation (adjusted odds ratio [95% CI]: 4.49 [1.98, 10.20], P = .0003) and prolonged hospitalization (≥10 days) (adjusted odds ratio [95% CI]: 4.06 [1.98, 8.32], P = .0001).

The CXR Sextus score was found to be reproducible and CXR-CT severity scores were closely correlated. Increasing Sextus scores were associated with increased risks for intubation and prolonged hospitalization for patients with COVID-19 in a predominantly Black population. The CXR Sextus score may provide insight into identifying and monitoring high-risk patients with COVID-19.
Pneumocystis pneumonia secondary to intensive immunosuppression treatment for anti-GBM disease complicated with IgA nephropathy
Authors: Zhang Manyu , Yang Dingwei , Wang Weixiu , Zhao Fuhao , Zhang Xiaoxiao , Li Xue
Published: November 2021

Rationale:

The estimated incidence of anti-glomerular basement membrane (anti-GBM) disease complicated with immunoglobulin A (IgA) nephropathy is minimal, there have only been 15 cases (including this case) reported in the literature, and only 5 (33.33%) of them showed significant improvement in renal function after treatment. Pneumocystis pneumonia is a severe opportunistic pulmonary infection of pneumocystis jiroveci in immunocompromised patients. Here, we report a case of pneumocystis pneumonia secondary to intensive immunosuppression treatment for anti-GBM disease complicated with IgA nephropathy, with no similar reports or studies published before to our knowledge.

Patient concerns:

The patient was admitted to our hospital with a 1-week diagnosis of crescent glomerulonephritis who had been suffered from hematuria and foamy urine for more than 1 month. Before admission, the patient received pulse dose intravenous methylprednisolone and immunosuppression with rituximab, but the renal function and titer of pathogenic antibody did not improve significantly.

Diagnosis:

Crescentic glomerulonephritis, anti-glomerular basal membrane disease complicated with IgA nephropathy (Type I+II) was pathologically confirmed by renal biopsy. Secondary pneumocystis pneumonia was diagnosed by acute progressive respiratory failure, chest computed tomography and metagenomic next-generation sequencing of transbronchoscopic bronchoalveolar lavage fluid.

Interventions:

The key to successful treatment was to make the pathogenic antibody turn negative quickly by combining pulse dose intravenous methylprednisolone, immunosuppression with rituximab, and plasma exchange therapy. Early identification of pneumocystis pneumonia, accurate etiological identification, and active anti-infective treatment were also crucial.

Outcomes:

The patient was discharged after 16 days of anti-infection with secondary infection controlled and dialysis catheter removed. Up to now, the patient has been followed for a period of 28 weeks, results showed renal function had been repaired even hematuria and proteinuria were basically alleviated.

Lessons:

Our case provided experience in the treatment of anti-GBM disease complicated with IgA nephropathy, further proposed the potential therapeutic effects of rituximab, also illustrated low dose hormone combined with tacrolimus can be used as sequential therapy after plasma exchange and intensive immunosuppression. Our research also suggested that resulting in severe immune suppression, a high risk of secondary pneumocystis opportunistic infection should be aware of. metagenomic next-generation sequencing might increase the detection rate of the pathogen.
Relationship between the proficiency level and anxiety-reducing effect in a one-time heart rate variability biofeedback
Authors: Saito Ryuji , Sawamura Daisuke , Yoshida Kazuki , Sakai Shinya
Published: November 2021

Introduction:

Previous studies have reported that the proficiency level of heart rate variability biofeedback (HRVBF) contributes significantly to the anxiety-reducing effects in continuous HRVBF interventions. Meanwhile, anxiety-reducing effects have been confirmed in one-time HRVBF interventions as well as continuous HRVBF; however, no study has analyzed the relationship between the proficiency level of a one-time HRVBF and its anxiety-reducing effects. To pursuit the effectiveness of a one-time HRVBF intervention, it is necessary to clarify whether the proficiency level is an important predictor of anxiety-reducing effects from a dose-response relationship between these 2 variables. The purpose of this study was to examine the dose-response relationship between the proficiency level and anxiety-reducing effects of a one-time HRVBF.

Methods:

This study was a single-blinded, randomized, controlled trial with stratification based on trait anxiety of the State-Trait Anxiety Inventory-JYZ. In total, 45 healthy young males aged 20 to 30 years were allocated to the HRVBF or control group with simple breathing at rest. The intervention was performed for 15 minute in each group. The state anxiety score of the State-Trait Anxiety Inventory-JYZ was measured to evaluate the anxiety-reducing effect before and after training.

Results:

The results showed no significant linear relationship between the proficiency level and anxiety-reducing effect, and variations in the proficiency level were observed post-intervention in the HRVBF group. A significant anxiety-reducing effect was only observed in the HRVBF group (P = .001, effect size r = 0.62).

Conclusions:

These results suggest that there is no close relationship between the proficiency level and anxiety-reducing effect in one-time HRVBF and that HRVBF is effective in reducing anxiety regardless of individual differences in the proficiency level. Therefore, a one-time HRVBF may be a useful breathing technique for reducing state anxiety without specific education and breathing techniques.

Trial registration:

University Hospital Medical Information Network Clinical Trial Registry (UMIN000041760).
APOL1 renal risk variants are associated with obesity and body composition in African ancestry adults
Authors: Nadkarni Girish N. , Fei Kezhen , Galarneau Genevieve , Gao Yan , Wilson James G. , Cooper Richard , Madden Ebony B. , Denny Joshua C. , Richardson Lynne D. , Pollak Martin , Loos Ruth J. F. , Horowitz Carol R.
Published: November 2021

While increased obesity prevalence among persons of African ancestry (AAs) compared to persons of European ancestry (EAs) is linked to social, environmental and behavioral factors, there are no gene variants that are common and significantly associated with obesity in AA populations. We sought to explore the association between ancestry specific renal risk variants in the apolipoprotein L1 (APOL1) gene with obesity related traits in AAs.

We conducted a genotype–phenotype association study from 3 electronic medical record linked cohorts (BioMe Biobank, BioVU, nuGENE); randomized controlled trials (genetic testing to understand and address renal disease disparities) and prospective cohort study (Jackson Heart Study). We analyzed association of APOL1 renal risk variants with cross-sectional measures of obesity (average body mass index (BMI), and proportion of overweight and obesity) and with measures of body composition (in Jackson Heart Study).

We had data on 11,930 self-reported AA adults. Across cohorts, mean age was from 42 to 49 years and percentage female from 58% to 75.3%. Individuals who have 2 APOL1 risk alleles (14% of AAs) have 30% higher obesity odds compared to others (recessive model adjusted odds ratio 1.30; 95% confidence interval 1.16–1.41; P = 2.75 × 10−6). An additive model better fit the association, in which each allele (47% of AAs) increases obesity odds by 1.13-fold (adjusted odds ratio 1.13; 95% confidence interval 1.07–1.19; P = 3.07 × 10−6) and increases BMI by 0.36 kg/m2 (∼1 kg, for 1.7 m height; P = 2 × 10−4). APOL1 alleles are not associated with refined body composition traits overall but are significantly associated with fat free mass index in women [0.30 kg/m2 increment per allele; P = .03].

Thus, renal risk variants in the APOL1 gene, found in nearly half of AAs, are associated with BMI and obesity in an additive manner. These variants could, either on their own or interacting with environmental factors, explain a proportion of ethnic disparities in obesity.
Proximal gastrectomy with double-tract reconstruction versus total gastrectomy for proximal early gastric cancer
Authors: Xiang Renshen , Song Wei , Ren Jun , Lu Wei , Zhang Heng , Fu Tao
Published: November 2021

Background:

The incidence of proximal gastric cancer in the gastric fundus, cardia, and other parts is increasing rapidly. The purpose of this study was to systematically compare the short-term and long-term clinical effects of proximal gastrectomy with double tract reconstruction (PG-DTR) to total gastrectomy (TG) for proximal early gastric cancer (EGC).

Methods:

A systematic review and meta-analysis was conducted through searching the literature in PubMed, Web of Science, Cochrane Library, EMBASE, CNKI, WAN FANG, and VIP databases. All clinical controlled trials and randomized controlled trials (RCTs) of PG-DTR and PG were included. Simultaneously, the relevant data were extracted, and the software RevMan version 5.1 was used for the meta-analysis.

Results:

Eight studies with a total of 753 patients were eligible for the meta-analysis. There were no significant differences in the operation time, intraoperative blood loss, postoperative hospital stay, early complications (anastomotic fistula and anastomotic bleeding), late complications (reflux symptoms and anastomotic stenosis), and 5-year survival rate between PG-DTR and TG. However, the levels of partial nutritional indicators (vitamin B12 supplements and vitamin B12 deficiency) were significantly higher in the PG-DTR group than in the TG group.

Conclusion:

This study showed ample evidence to suggest that PG-DTR improved the postoperative nutritional status without compromising patient safety while providing the same surgical characteristics and postoperative morbidity as TG.
Severe types of fetopathy are associated with changes in the serological proteome of diabetic mothers
Authors: Kopylov Arthur T. , Papysheva Olga , Gribova Iveta , Kaysheva Anna L. , Kotaysch Galina , Kharitonova Lubov , Mayatskaya Tatiana , Nurbekov Malik K. , Schipkova Ekaterina , Terekhina Olga , Morozov Sergey G.
Published: November 2021

Pregestational or gestational diabetes are the main risk factors for diabetic fetopathy. There are no generalized signs of fetopathy before the late gestational age due to insufficient sensitivity of currently employed instrumental methods. In this cross-sectional observational study, we investigated several types of severe diabetic fetopathy (cardiomyopathy, central nervous system defects, and hepatomegaly) established in type 2 diabetic mothers during 30 to 35 gestational weeks and confirmed upon delivery. We examined peripheral blood plasma and determined a small proportion of proteins strongly associated with a specific type of fetopathy or anatomical malfunction. Most of the examined markers participate in critical processes at different stages of embryogenesis and regulate various phases of morphogenesis. Alterations in CDCL5 had a significant impact on mRNA splicing and DNA repair. Patients with central nervous system defects were characterized by the greatest depletion (ca. 7% of the basal level) of DFP3, a neurotrophic factor needed for the proper specialization of oligodendrocytes. Dysregulation of noncanonical wingless-related integration site signaling pathway (Wnt) signaling guided by pigment epithelium-derived factor (PEDF) and disheveled-associated activator of morphogenesis 2 (DAAM2) was also profound. In addition, deficiency in retinoic acid and thyroxine transport was exhibited by the dramatic increase of transthyretin (TTHY). The molecular interplay between the identified serological markers leads to pathologies in fetal development on the background of a diabetic condition. These warning serological markers can be quantitatively examined, and their profile may reflect different severe types of diabetic fetopathy, producing a beneficial effect on the current standard care for pregnant women and infants.
Effects of flexible reamer on the femoral tunnel characteristics in anterior cruciate ligament reconstruction
Authors: Seo Young-Jin , Song Si Young , Im Woo-Young , Kim Yoon Sang , Jang Seong-wook
Published: November 2021

To compare the femoral tunnel characteristics using a rigid versus flexible reamer during anterior cruciate ligament reconstruction. It was hypothesized that the employment of a flexible reamer along with femoral tunnel would exhibit longer tunnel length and more acute femoral graft tunnel angle compared to the case of a rigid reamer.

The study population included 28 patients who underwent anatomical single-bundle anterior cruciate ligament reconstruction using transportal technique and were able to take postoperative computed tomography (CT) evaluation. Of these, the femoral tunnel of 14 cases was drilled with a flexible reamer (group I) and in another 14 cases drill was performed with a conventional rigid reamer (group II). The femoral tunnel in group I was made at 90° of knee flexion. In group II, the femoral tunnel was created at 120° of knee flexion. The parameters of the femoral tunnels were compared in terms of the femoral tunnel length and femoral graft tunnel angle. Special software was used to create and manipulate (3-D) 3-dimensional knee models.

The difference in the mean femoral tunnel locations expressed in percentage distance between the 2 groups was not significantly different. The mean femoral tunnel length of group I was significantly longer than that of group II, (P = .03, 36.7 ± 2.9 vs 32.9 ± 9.0 mm). The angle formed by the femoral tunnel and the graft in group I was significantly smaller than in group II (P = .01, 109.8° ± 9.4° vs 118.1° ± 7.2°).

Our data suggest that the flexible reamer can provide sufficient tunnel length for the suspensory fixation with a fixed loop. Whereas, the femoral graft-tunnel angle through flexible reaming at 90° of knee flexion was more acute compared to rigid reaming at 120° of knee flexion.

Study Design: level of evidence III
How Are Attention-deficit Hyperactivity and Internet Gaming Disorders Related in Children and Youth?
Authors: Muzwagi Ashraf B. , Motiwala Fatima B. , Manikkara Geetha , Rizvi Abid , Varela Mark A. , Rush A. John , Zafar Muhammad K. , Jain Shailesh B.
Published: November 2021

Objectives:

This review addresses important practical questions facing clinicians regarding internet gaming disorder (IGD) and attention-deficit/hyperactivity disorder (ADHD) in children and youth (C-Y). The authors investigated data concerning the risk that C-Y who have ADHD will develop IGD, whether effective treatment of ADHD positively influences the course of IGD in C-Y who have both, and other findings that might be of benefit to clinicians who treat C-Y with these conditions.

Methods:

We conducted a literature review using 4 databases: PubMed, Scopus, PsychInfo, and Embase.

Results:

C-Y with ADHD are at greater risk for developing IGD than those without ADHD. A close association exists between the severity of ADHD symptoms and the severity of IGD. It is unknown what proportion of C-Y with ADHD will develop IGD during their developmental trajectory; however, C-Y with IGD are at risk for developing ADHD, and ADHD can also increase the vulnerability of C-Y to IGD. Adolescents with ADHD and IGD have greater deficits in social skills than those with ADHD but no IGD. Lower parental occupational and socioeconomic status and poor family relationships are associated with more severe IGD symptoms. Atomoxetine and methylphenidate are equally effective in alleviating IGD symptoms comorbid with ADHD.

Conclusions:

C-Y with ADHD are at increased risk for developing IGD compared with C-Y without ADHD, but it has not been determined at what developmental stage IGD is likely to emerge. Since IGD and ADHD are strongly associated, it is imperative to consider ADHD as a significant risk factor for IGD and vice versa, which can help psychiatrists be alert for early signs of IGD and manage them accordingly.
A Case of Intranasal Ketamine Misuse: Considerations for Clinical Practice
Authors: Rivas-Grajales Ana M. , Mathew Sanjay J. , Rodgers Joshua J.
Published: November 2021

Despite the growing off-label use of ketamine for depression and other psychiatric indications, its long-term safety profile and abuse potential remain unclear. We present a case of a patient who presented with paranoia and personality changes attributed to ketamine misuse, which illustrates the need for more robust screening and systematic monitoring with this medication. Continued evaluation of the abuse potential of ketamine in long-term treatment as well as restricted access and in-office administration are important, to develop a better understanding of the risk-benefit profile of this drug.
Commentary: Treatment-resistant Depression: Considerations Related to ECT and Ketamine
Authors: Garakani Amir
Published: November 2021

Treatment-resistant depression (TRD) may be responsive to interventions beyond antidepressants including brain stimulation such as electroconvulsive therapy (ECT) or to ketamine or esketamine, the latter of which is approved for TRD in an intranasal form. The 3 cases presented in this issue deal with an array of clinical considerations in treating patients with TRD, including the use of ECT in a patient with a history of liver transplantation, the use of heated yoga in a patient nonresponsive to ECT, and intranasal ketamine abuse in a patient with comorbid migraines. Gunther and colleagues described the case of a 73-year-old man who presented with a major depressive episode with psychotic features not responsive to medications 26 years after liver transplantation. Despite his past transplant and antirejection medications, the patient was cleared for ECT and received 9 bitemporal treatments with good response. Sakurai and colleagues reported the case of a 28-year-old woman with chronic TRD and multiple previous ECT treatments who had only a partial response to several antidepressants and maintenance ECT. She was evaluated and treated with a course of twice-weekly 90-minute heated yoga and experienced a remission of her depression. Finally, Rivas-Grajales and colleagues described a 52-year-old woman with recurrent TRD and chronic migraines who was receiving 2 antidepressants and migraine medication, who presented emergently with agitation and paranoia in the context of receiving intranasal ketamine from multiple providers, suggesting a pattern of misuse. Her symptoms abated despite her refusal of prescribed antipsychotics. These 3 cases highlight different challenges and complexities in treating patients with TRD. While ECT remains safe and effective, even in cases of organ transplantation, there is potential for the development of nonpharmacologic adjunctive treatments, such as heated yoga (which is under randomized study). And while eskatamine is an approved treatment for TRD, screening and ongoing monitoring is important to prevent misuse or abuse.
Noninvasive neuromodulation and rehabilitation to promote functional restoration in persons with spinal cord injury
Authors: Iddings Jennifer A. , Zarkou Anastasia , Field-Fote Edelle C.
Published: November 2021

Purpose of review

This review will focus on the use of clinically accessible neuromodulatory approaches for functional restoration in persons with spinal cord injury (SCI).

Recent findings

Functional restoration is a primary rehabilitation priority for individuals with SCI. High-tech neuromodulatory modalities have been used in laboratory settings to improve hand and walking function as well as to reduce spasticity and pain in persons with SCI. However, the cost, limited accessibility, and required expertise are prohibitive for clinical applicability of these high-tech modalities. Recent literature indicates that noninvasive and clinically accessible approaches targeting supraspinal, spinal, and peripheral neural structures can modulate neural excitability. Although a limited number of studies have examined the use of these approaches for functional restoration and amelioration of secondary complications in SCI, early evidence investigating their efficacy when combined with training is encouraging.

Larger sample studies addressing both biomarker identification and dosing are crucial next steps in the field of neurorehabilitation research before novel noninvasive stimulation approaches can be incorporated into standard clinical practice.
Integration of vascular progenitors into functional blood vessels represents a novel mechanism of vascular growth
Authors: Metikala Sanjeeva , Warkala Michael , Chetty Satish Casie , Chestnut Brendan , Plender Elizabeth , Nester Olivia , Astrof Sophie , Sumanas Saulius
Published: November 2021

During embryogenesis, the initial vascular network is thought to form by the process of vasculogenesis, or the specification of vascular progenitors de novo. After the initial blood circulation has been established, the majority of later-forming vessels are thought to arise by angiogenesis from the already established vasculature. Here we show that new vascular progenitors in zebrafish embryos contribute to functional vasculature even after blood circulation has been established. Based on the expression analysis of early vascular progenitor markers etv2 and tal1, we characterized a novel site of late vasculogenesis (termed secondary vascular field, SVF), located bilaterally along the yolk extension. Using time-lapse imaging of etv2 reporter lines, we show that SVF cells migrate and incorporate into functional blood vessels and contribute to the formation of the posterior cardinal vein and subintestinal vasculature, suggesting a novel mode of vascular growth. We further demonstrate that SVF cells participate in vascular recovery after chemical ablation of vascular endothelial cells. Inducible inhibition of etv2 function prevented SVF cell differentiation and resulted in the defective formation of subintestinal vasculature. In addition, we performed single-cell RNA-seq analysis to identify the transcriptional profile of SVF cells, which demonstrated similarities and differences between the transcriptomes of SVF cells and early vascular progenitors. Our results characterize a novel mechanism of how new vascular progenitors incorporate into established vasculature and revise our understanding of basic mechanisms that regulate vascular development.
Toeholder: a Software for Automated Design andIn SilicoValidation of Toehold Riboswitches
Authors: Cisneros Angel F. , Rouleau François D. , Bautista Carla , Lemieux Pascale , Dumont-Leblond Nathan
Published: November 2021

Synthetic biology aims to engineer biological circuits, which often involve gene expression. A particularly promising group of regulatory elements are riboswitches because of their versatility with respect to their targets, but early synthetic designs were not as attractive because of a reduced dynamic range with respect to protein regulators. Only recently, the creation of toehold switches helped overcome this obstacle by also providing an unprecedented degree of orthogonality. However, a lack of automated design and optimization tools prevents the widespread and effective use of toehold switches in high throughput experiments. To address this, we developed Toeholder, a comprehensive open-source software for toehold design andin silicocomparison. Toeholder takes into consideration sequence constraints from experimentally tested switches, as well as data derived from molecular dynamics simulations of a toehold switch. We describe the software and itsin silicovalidation results, as well as its potential applications and impacts on the management and design of toehold switches.
Total virome characterizations of game animals in China reveals a spectrum of emerging viral pathogens
Authors: He Wan-Ting , Hou Xin , Zhao Jin , Sun Jiumeng , He Haijian , Si Wei , Wang Jing , Jiang Zhiwen , Yan Ziqing , Xing Gang , Lu Meng , Suchard Marc A. , Ji Xiang , Gong Wenjie , He Biao , Li Jun , Lemey Philippe , Guo Deyin , Tu Changchun , Holmes Edward C. , Shi Mang , Su Shuo
Published: November 2021

Game animals are wildlife species often traded and consumed as exotic food, and are potential reservoirs for SARS-CoV and SARS-CoV-2. We performed a meta-transcriptomic analysis of 1725 game animals, representing 16 species and five mammalian orders, sampled across China. From this we identified 71 mammalian viruses, with 45 described for the first time. Eighteen viruses were considered as potentially high risk to humans and domestic animals. Civets (Paguma larvata) carried the highest number of potentially high risk viruses. We identified the transmission of Bat coronavirus HKU8 from a bat to a civet, as well as cross-species jumps of coronaviruses from bats to hedgehogs and from birds to porcupines. We similarly identified avian Influenza A virus H9N2 in civets and Asian badgers, with the latter displaying respiratory symptoms, as well as cases of likely human-to-wildlife virus transmission. These data highlight the importance of game animals as potential drivers of disease emergence.

Highlights

1725 game animals from five mammalian orders were surveyed for viruses

71 mammalian viruses were discovered, 18 with a potential risk to humans

Civets harbored the highest number of potential ‘high risk’ viruses

A species jump of an alphacoronavirus from bats to a civet was identified

H9N2 influenza virus was detected in a civet and an Asian badger

Humans viruses were also identified in game animals
Secretory cells are the primary source of pIgR in small airways
Authors: Blackburn Jessica B. , Schaff Jacob A. , Gutor Sergey , Du Rui-Hong , Nichols David , Sherrill Taylor , Gutierrez Austin J. , Xin Matthew K. , Wickersham Nancy , Zhang Yong , Holtzman Michael J. , Ware Lorraine B , Banovich Nicholas E. , Kropski Jonathan A. , Blackwell Timothy S. , Richmond Bradley W.
Published: November 2021

Background

Loss of secretory immunoglobulin A (SIgA) is common in COPD small airways and likely contributes to disease progression. We hypothesized loss of SIgA results from reduced expression of pIgR, a chaperone protein needed for SIgA transcytosis, in the COPD small airway epithelium.

Methods

pIgR-expressing cells were defined and quantified at single-cell resolution in human airways using RNA in-situ hybridization, immunostaining, and single-cell RNA sequencing. Complementary studies in mice utilized immunostaining, primary murine tracheal epithelial cell (MTEC) culture, and transgenic mice with secretory or ciliated cell-specific knockout of pIgR. SIgA degradation by human neutrophil elastase or secreted bacterial proteases from non-typeable Haemophilus influenzae (NTHi) was evaluated in vitro.

Results

We found that secretory cells are the predominant cell type responsible for pIgR expression in human and murine airways. Loss of SIgA in small airways was not associated with a reduction in secretory cells but rather a reduction in pIgR protein expression despite intact PIGR mRNA expression. Neutrophil elastase and NTHi-secreted proteases are both capable of degrading SIgA in vitro and may also contribute to a deficient SIgA immunobarrier in COPD.

Interpretation

Loss of the SIgA immunobarrier in small airways of patients severe COPD is complex and likely results from both pIgR-dependent defects in IgA transcytosis and SIgA degradation.

Key Messages

What is the key question? Localized SIgA deficiency in small airways is an established driver of COPD pathogenesis, but the mechanism of loss remains unclear. We hypothesized loss of SIgA is due to reduced numbers of pIgR-expressing cells in SIgA-deficient small airways.

What is the bottom line? pIgR is primarily expressed by secretory cells in human and murine airways. Although numbers of secretory cells are similar between SIgA-deficient and SIgA-replete airways in COPD, there is reduced expression of pIgR protein, but not mRNA, in SIgA-deficient airways. Additionally, host and bacterial proteases degrade SIgA in vitro, suggesting loss of SIgA may relate to both impaired transcytosis and increased degradation.

Why read on? This study highlights the complexity of SIgA immunobarrier maintenance and suggests that strategies aimed at restoring the SIgA immunobarrier will need to account for both impaired transcytosis and degradation by host and/or bacterial proteases.
8 Å structure of the cytoplasmic ring of the Xenopus laevis nuclear pore complex solved by cryo-EM and AI
Authors: Tai Linhua , Zhu Yun , Ren He , Huang Xiaojun , Zhang Chuanmao , Sun Fei
Published: November 2021

As one of the largest protein complexes in eukaryotes, the nuclear pore complex (NPC) forms a conduit regulating nucleocytoplasmic transport. Here, we determined 8 Å resolution cryo-electron microscopic (cryo-EM) structure of the cytoplasmic ring (CR) from the Xenopus laevis NPC. With the aid of AlphaFold2, we managed to build a most comprehensive and accurate pseudoatomic model of the CR to date, including the Y complexes and flanking components of Nup358, Nup214 complexes, Nup205 and Nup93. Comparing with previously reported CR model, the Y complex structure in our model exhibits much tighter interactions in the hub region mediated by α-solenoid domain in Nup160 C-terminus. Five copies of Nup358 are identified in each CR subunit to provide rich interactions with other Nups in stem regions of Y complexes. Two copies of Nup214 complexes lay in a parallel pattern and attach to the short arm region of Y complexes towards the central channel of NPC. Besides, the structural details of two copies of Nup205 on the side of the short arm region and one copy of Nup93 on the stem region of Y complexes in each CR subunit are also revealed. These in-depth novel structural features represent a great advance in understanding the assembly of NPCs.
An essential role for a discrete parasubthalamic nucleus subpopulation in appetite suppression
Authors: Kim Jessica H. , Kromm Grace H. , Barnhill Olivia K. , Han Kenneth , Heuer Lauren B. , Loomis Sierra , Newman Matthew C. , Sperber Jacob , Legan Theresa B. , Gulamali Faris F. , Jensen Katharine E. , Funderburk Samuel C. , Krashes Michael J. , Carter Matthew E.
Published: November 2021

Food intake behavior is regulated by a network of appetite-inducing and appetite-suppressing neuronal populations throughout the brain. The parasubthalamic nucleus (PSTN), a relatively unexplored population of neurons in the posterior hypothalamus, has been hypothesized to regulate appetite due to its connectivity with other anorexigenic neuronal populations and because these neurons express Fos, a marker of neuronal activation, following a meal. However, the individual cell types that make up the PSTN are not well characterized, nor are their functional roles in food intake behavior. Here we identify and distinguish between two discrete PSTN subpopulations, those that express tachykinin-1 (PSTNTac1 neurons) and those that express corticotropin-releasing hormone (PSTNCRH neurons), and use a panel of genetically encoded tools in mice to show that PSTNTac1 neurons play an essential role in appetite suppression. Both subpopulations increase activity following a meal and in response to administration of the anorexigenic hormones amylin, cholecystokinin (CCK), and peptide YY (PYY). Interestingly, chemogenetic inhibition of PSTNTac1, but not PSTNCRH neurons, reduces the appetite-suppressing effects of these hormones. Consistently, optogenetic and chemogenetic stimulation of PSTNTac1 neurons, but not PSTNCRH neurons, is sufficient to reduce food intake in hungry mice. PSTNTac1 and PSTNCRH neurons project to distinct downstream brain regions, and stimulation of PSTNTac1 projections to individual anorexigenic populations reduces food consumption. Taken together, these results reveal the functional properties and projection patterns of distinct PSTN cell types and demonstrate an essential, anorexigenic role for PSTNTac1 neurons in the hormonal and central regulation of appetite.
Persistent CAD activity in memory CD8+ T cells supports rRNA synthesis and ribosomal biogenesis required at rechallenge
Authors: Claiborne Michael D. , Sengupta Srona , Zhao Liang , Arwood Matthew L. , Sun Im-Meng , Wen Jiayu , Thompson Elizabeth A. , Mitchell-Flack Marisa , Laiho Marikki , Powell Jonathan D.
Published: November 2021

Memory CD8+ T cells are characterized by their ability to persist long after the initial antigen encounter and their ability to generate a rapid recall response. Recent studies have identified a role for metabolic reprogramming and mitochondrial function in promoting the longevity of memory T cells. However, detailed mechanisms involved in promoting the rapid recall response are incompletely understood. Here we identify a novel role for the initial and continued activation of the trifunctional rate-limiting enzyme of the de novo pyrimidine synthesis pathway CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase) as critical in promoting the rapid recall response of previously-activated CD8+ T cells. CAD is rapidly phosphorylated upon T cell activation in an mTORC1-dependent manner yet remains phosphorylated long after initial activation. Previously-activated CD8+ T cells display continued de novo pyrimidine synthesis in the absence of mitogenic signals and interfering with this pathway diminishes the speed and magnitude of cytokine production upon rechallenge. Inhibition of CAD does not affect cytokine transcript levels, but diminishes available pre-rRNA, the polycistronic rRNA precursor whose synthesis is the rate-limiting step in ribosomal biogenesis. CAD inhibition additionally decreases levels of detectable ribosomal proteins in previously-activated CD8+ T cells. Overexpression of CAD improves both the cytokine response and proliferation of memory T cells. Overall, our studies reveal a novel and critical role for CAD-induced pyrimidine synthesis and ribosomal biogenesis in promoting the rapid recall response characteristic of memory T cells.

One Sentence Summary

Pyrimidine synthesis fuels ribosomal biogenesis to facilitate rapid recall responses in CD8+ T cells
Divergent phenotypic plasticity of a convergent Mendelian trait in Drosophila
Authors: Francelle Pascaline , David Jean R. , Yassin Amir
Published: November 2021

In Drosophila, comparisons of the thermal plasticity of pigmentation across serially homologous abdominal segments have been conducted in two species, namely Drosophila melanogaster and D. kikkawai. Pigmentation variation has different genetic architecture in the two species, being oligogenic in the former and monogenic in the later. Here, we analyze the thermal plasticity of abdominal pigmentation in a third species, D. erecta, which is phylogenetically close to D. melanogaster but like D. kikkawai has a monogenic basis for pigmentation variation. However, the underlying locus differs between D. erecta and D. kikkawai, being the X-linked melanin-synthesis gene tan in the former and the autosomal transcription factor pdm3 in the later. We found that in spite of a low overall plasticity in monogenic species compared to D. melanogaster, the two monogenic species showed divergent plasticity patterns in respect to the response to temperature and to the degree of dominance in heterozygotes. Those results provide new insights on the dependence of the degree of plasticity on the genetic architecture as well as on the extent of phenotypic convergence.
Sonic hedgehog is basolaterally sorted from the TGN and transcytosed to the apical domain involving Dispatched-1 at Rab11-ARE
Authors: Sandoval Lisette , Labarca Mariana , Retamal Claudio , Sanchez Paula , Larraín Juan , González Alfonso
Published: November 2021

Hedgehog (Hh) secretion from apical and/or basolateral domains occurs in different epithelial cells impacting development and tissue homeostasis. Palmitoylation and cholestyrolation attach Hh proteins to membranes and Dispatched-1 (Disp-1) promotes their release. How these lipidated proteins are handled by the complex secretory and endocytic pathways of polarized epithelial cells remains unknown. We show that MDCK cells address newly synthesized sonic hedgehog (Shh) from the TGN to the basolateral cell surface and then to the apical domain through a transcytosis pathway that includes Rab11-apical recycling endosomes (Rab11-ARE). Both palmitoylation and cholestyrolation contribute to this sorting behavior, otherwise Shh lacking these lipid modifications is unpolarized. Disp-1 mediates first basolateral secretion from the TGN and then transcytosis from the Rab11-ARE. At steady state, Shh predominates apically and can be basolaterally transcytosed. This complex Shh trafficking provides several steps for regulation and variation in different epithelia, subordinating the apical to the basolateral secretion.
Timing of gene expression and recruitment in independent origins of CAM in the Agavoideae (Asparagaceae)
Authors: Heyduk Karolina , McAssey Edward V. , Leebens-Mack Jim
Published: November 2021

CAM photosynthesis has evolved repeatedly across the plant tree of life, yet our understanding of the genetic convergence across independent origins remains hampered by the lack of comparative studies. CAM is furthermore thought to be closely linked to the circadian clock in order to achieve temporal separation of carboxylation and sugar production. Here, we explore gene expression profiles in eight species from the Agavoideae (Asparagaceae) encompassing three independent origins of CAM. Using comparative physiology and transcriptomics, we examined the variable modes of CAM in this subfamily and the changes in gene expression across time of day and between well-watered and drought-stressed treatments. We further assessed gene expression and molecular evolution of genes encoding phosphoenolpyruvate carboxylase (PPC), an enzyme required for primary carbon fixation in CAM. Most time-of-day expression profiles are largely conserved across all eight species and suggest that large perturbations to the central clock are not required for CAM evolution. In contrast, transcriptional response to drought is highly lineage specific. Yucca and Beschorneria have CAM-like expression of PPC2, a copy of PPC that has never been shown to be recruited for CAM in angiosperms, and evidence of positive selection in PPC genes implicates mutations that may have facilitated the recruitment for CAM function early in the evolutionary history of the Agavoideae. Together the physiological and transcriptomic comparison of closely related C3 and CAM species reveals similar gene expression profiles, with the notable exception of differential recruitment of carboxylase enzymes for CAM function.
The hexokinase “HKDC1” interaction with the mitochondria is essential for hepatocellular carcinoma progression
Authors: Khan Md. Wasim , Terry Alexander R. , Priyadarshini Medha , Guzman Grace , Cordoba-Chacon Jose , Ben-Sahra Issam , Wicksteed Barton , Layden Brian T.
Published: November 2021

Hepatocellular carcinoma (HCC) is a leading cause of death from cancer malignancies. Recently, hexokinase domain containing 1 (HKDC1), was shown to have significant overexpression in HCC compared to healthy tissue. Using in vitro and in vivo tools, we examined the role of HKDC1 in HCC progression. Importantly, HKDC1 ablation stops HCC progression by promoting metabolic reprogramming by shifting glucose flux away from the TCA cycle. Next, HKDC1 ablation leads to mitochondrial dysfunction resulting in less cellular energy which cannot be compensated by enhanced glucose uptake. And finally, we show that the interaction of HKDC1 with the mitochondria is essential for its role in HCC progression, and without this mitochondrial interaction mitochondrial dysfunction occurs. In sum, HKDC1 is highly expressed in HCC cells compared to normal hepatocytes, therefore targeting HKDC1, specifically its interaction with the mitochondria, reveals a highly selective approach to target cancer cells in HCC.
Going through phages: A Computational approach to Revealing the role of prophage in Staphylococcus aureus
Authors: Sweet Tyrome , Sindi Suzanne , Sistrom Mark
Published: November 2021

Prophages have important roles in virulence, antibiotic resistance and genome evolution in Staphylococcus aureus. Rapid growth in the number of sequenced S. aureus genomes allows for an investigation of prophage sequences in S. aureus at an unprecedented scale. We developed a computational pipeline to detect and analyze prophage sequences in nearly 10,011 S. aureus genomes, discovering thousands of putative prophage sequences with genes encoding virulence factors and antibiotic resistance.

Importance

Bacteriophages (phages) play key roles in bacterial evolution, governing abundance, adaptation and diversity of bacterial communities. Temperate phage can facilitate bacterial adaptation via transduction of novel genes. This study takes advantage of the unprecedented quantity of genomic sequencing in public repositories to analyze viral genes in 10,000 Staphylococcus aureus genomes. We found 196,727 prophage sequences, with an estimated total of 129,935 genes. We determined the function of these genes, identifying a large quantity of novel genes that benefit the host such as beta-lactamase, enterotoxins and cytotoxins. These results will inform studies of bacterial evolution and adaptation, by identifying the mechanism of horizontal transfer of genes that confer adaptive traits to bacteria, especially in the context of antibiotic resistance.
EBV LMP1-activated mTORC1 and mTORC2 Coordinately Promote Nasopharyngeal Cancer Stem Cell Formation
Authors: Zhu Nannan , Wang Qian , Wu Zhidong , Wang Yan , Zeng Mu-Sheng , Yuan Yan
Published: November 2021

Epstein-Barr Virus (EBV) is associated with several malignant diseases, including Burkitt’s lymphoma, nasopharyngeal carcinoma (NPC), certain types of lymphomas, and a portion of gastric cancers. Virus-encoded oncoprotein LMP1 induces the epithelial-to-mesenchymal transition (EMT), leading to cancer stem cell formation. In the current study, we investigated how LMP1 contributes to cancer stem cell development in NPC. We found that LMP1 plays an essential role in acquiring CSC characteristics, including tumor initiation, metastasis, and therapeutic resistance by activating the PI3K/mTOR/Akt signaling pathway. We dissected the functions of distinct signaling (mTORC1 and mTORC2) in the acquisition of different CSC characteristics. Side population (SP) formation, which represents the chemotherapy resistance feature of CSC, requires mTORC1 signaling. Tumor initiation capability is mainly attributed to mTORC2, which confers on NPC the capabilities of proliferation and survival by activating mTORC2 downstream genes c-Myc. Both mTORC1 and mTORC2 enhance cell migration and invasion of NPC cells, suggesting that mTORC1/2 co-regulate metastasis of NPC. The revelation of the roles of the mTOR signaling pathways in distinct tumorigenic features provides a guideline for designing efficient therapies by choosing specific mTOR inhibitors targeting mTORC1, mTORC2, or both to achieve durable remission of NPC in patients.

Significance

LMP1 endows NPC to gain cancer stem cell characteristics through activating mTORC1 and mTORC2 pathways. The different mTOR pathways are responsible for distinct tumorigenic features. Rapamycin-insensitive mTORC1 is essential for CSC drug resistance. NPC tumor initiation capacity is mainly attributed to mTORC2 signaling. mTORC1 and mTORC2 co-regulate NPC cell migration and invasion. The revelation of the roles of mTOR signaling in NPC CSC establishment has implications for novel therapeutic strategies to treat relapsed and metastatic NPC and achieve durable remission.
Serum methylation of GALNT9, UPF3A, WARS, and LDB2 as non-invasive biomarkers for the early detection of colorectal cancer and premalignant adenomas
Authors: Gallardo-Gómez María , Rodríguez-Girondo Mar , Planell Núria , Moran Sebastian , Bujanda Luis , Etxart Ane , Castells Antoni , Balaguer Francesc , Jover Rodrigo , Esteller Manel , Cubiella Joaquín , Gómez-Cabrero David , Chiara Loretta De
Published: November 2021

Background

Early detection through screening programs has proven to be the most effective strategy to reduce the incidence and mortality of colorectal cancer. The most widely implemented non-invasive screening test is the fecal immunochemical test, which presents an inadequate sensitivity for the detection of precancerous advanced adenomas. This fact, together with the modest participation rates in screening programs, highlights the need for a blood test that could improve both the adherence to screening and the selection to colonoscopy.

Methods

In this study, we conducted a serum-based discovery and validation of circulating cell-free DNA (cfDNA) methylation biomarkers for colorectal cancer screening in a multicentre cohort of 433 serum samples including healthy controls, benign pathologies, advanced adenomas, and colorectal cancer. First, we performed an epigenome-wide methylation analysis with the MethylationEPIC array in 280 cfDNA samples using a pooling approach, followed by a robust prioritization of candidate biomarkers for the joint detection of advanced adenomas and colorectal cancer (advanced neoplasia). Then, candidate biomarkers were validated by pyrosequencing in independent individual 153 cfDNA samples.

Results

We report GALNT9, UPF3A, WARS, and LDB2 as new non-invasive methylation biomarkers for the early detection of colorectal advanced neoplasia. A model composed of GALNT9, UPF3A, WARS, and LDB2 reported a sensitivity of 62.1% and a specificity of 97.4% for the detection of advanced neoplasia. On the other hand, the combination of GALNT9 and UPF3A by logistic regression discriminated advanced neoplasia with 78.8% sensitivity and 100% specificity, outperforming the commonly used fecal immunochemical test and the methylated SEPT9 blood test.

Conclusions

Serum methylation levels of GALNT9, UPF3A, WARS, and LDB2 represent highly specific and sensitive novel blood-based biomarkers for the detection of colorectal cancer and premalignant advanced adenomas of both distal and proximal locations. The reported results show the feasibility of DNA sample pooling strategies for biomarker discovery. Overall, this study highlights the utility of cfDNA methylation for the early detection of colorectal neoplasia, with the potential to be implemented as a non-invasive test for colorectal cancer screening.