bluuebunny/crossref_metadata_2025 huggingface dataset:
Auts2
deletion involves in DG hypoplasia and social recognition deficit: The developmental and neural circuit mechanisms
Authors: Li Jun , Sun Xiaoxuan , You Yang , Li Qiongwei , Wei Chengwen , Zhao Linnan , Sun Mengwen , Meng Hu , Zhang Tian , Yue Weihua , Wang Lifang , Zhang Dai
Published: March 2022

The involvement of genetic risk and the underlying developmental and neural circuit mechanisms in autism-related social deficit are largely unclear. Here, we report that deletion of
AUTS2
, a high-susceptibility gene of ASDs, caused postnatal dentate gyrus (DG) hypoplasia, which was closely relevant to social recognition deficit. Furthermore, a previously unknown mechanism for neural cell migration in postnatal DG development was identified, in which Auts2-related signaling played a vital role as the transcription repressor. Moreover, the supramammillary nucleus (SuM)–DG-CA3 neural circuit was found to be involved in social recognition and affected in
Auts2
-deleted mice due to DG hypoplasia. Correction of DG-CA3 synaptic transmission by using a pharmacological approach or chemo/optogenetic activation of the SuM-DG circuit restored the social recognition deficit in
Auts2
-deleted mice. Our findings demonstrated the vital role of Auts2 in postnatal DG development, and this role was critical for SuM-DG-CA3 neural circuit-mediated social recognition behavior.
Premature aging in mice with error-prone protein synthesis
Authors: Shcherbakov Dimitri , Nigri Martina , Akbergenov Rashid , Brilkova Margarita , Mantovani Matilde , Petit Patricia Isnard , Grimm Amandine , Karol Agnieszka A. , Teo Youjin , Sanchón Adrián Cortés , Kumar Yadhu , Eckert Anne , Thiam Kader , Seebeck Petra , Wolfer David P. , Böttger Erik C.
Published: March 2022

The main source of error in gene expression is messenger RNA decoding by the ribosome. Translational accuracy has been suggested on a purely correlative basis to positively coincide with maximum possible life span among different rodent species, but causal evidence that translation errors accelerate aging in vivo and limit life span is lacking. We have now addressed this question experimentally by creating heterozygous knock-in mice that express the ribosomal ambiguity mutation RPS9 D95N, resulting in genome-wide error-prone translation. Here, we show that
Rps9
D95N knock-in mice exhibit reduced life span and a premature onset of numerous aging-related phenotypes, such as reduced weight, chest deformation, hunchback posture, poor fur condition, and urinary syndrome, together with lymphopenia, increased levels of reactive oxygen species–inflicted damage, accelerated age-related changes in DNA methylation, and telomere attrition. Our results provide an experimental link between translational accuracy, life span, and aging-related phenotypes in mammals.
Cryo-EM structure and electrophysiological characterization of ALMT from
Glycine max
reveal a previously uncharacterized class of anion channels
Authors: Qin Li , Tang Ling-hui , Xu Jia-shu , Zhang Xian-hui , Zhu Yun , Zhang Chun-rui , Wang Mei-hua , Liu Xue-lei , Li Fei , Sun Fei , Su Min , Zhai Yujia , Chen Yu-hang
Published: March 2022

Aluminum-activated malate transporters (ALMTs) form an anion channel family that plays essential roles in diverse functions in plants.
Arabidopsis
ALMT12, also named QUAC1 (quick anion channel 1), regulates stomatal closure in response to environmental stimuli. However, the molecular basis of ALMT12/QUAC1 activity remains elusive. Here, we describe the cryo-EM structure of ALMT12/QUAC1 from
Glycine max
at 3.5-Å resolution.
Gm
ALMT12/QUAC1 is a symmetrical dimer, forming a single electropositive T-shaped pore across the membrane. The transmembrane and cytoplasmic domains are assembled into a twisted two-layer architecture, with their associated dimeric interfaces nearly perpendicular.
Gm
ALMT12/QUAC1-mediated currents display rapid kinetics of activation/deactivation and a bell-shaped voltage dependency, reminiscent of the rapid (R)–type anion currents. Our structural and functional analyses reveal a domain-twisting mechanism for malate-mediated activation. Together, our study uncovers the molecular basis for a previously uncharacterized class of anion channels and provides insights into the gating and modulation of the ALMT12/QUAC1 anion channel.
Assets, stressors, and symptoms of persistent depression over the first year of the COVID-19 pandemic
Authors: Ettman Catherine K. , Cohen Gregory H. , Abdalla Salma M. , Trinquart Ludovic , Castrucci Brian C. , Bork Rachel H. , Clark Melissa A. , Wilson Ira B. , Vivier Patrick M. , Galea Sandro
Published: March 2022

The coronavirus disease 2019 (COVID-19) pandemic has been accompanied by an increase in depression in U.S. adults. Previous literature suggests that having assets may protect against depression. Using a nationally representative longitudinal panel survey of U.S. adults studied in March and April 2020 and in March and April 2021, we found that (i) 20.3% of U.S. adults reported symptoms of persistent depression in Spring 2020 and Spring 2021, (ii) having more assets was associated with lower symptoms of persistent depression, with financial assets—household income and savings—most strongly associated, and (iii) while having assets appeared to protect persons—in particular those without stressors—from symptoms of persistent depression over the COVID-19 pandemic, having assets did not appear to reduce the effects of job loss, financial difficulties, or relationship stress on symptoms of persistent depression. Efforts to reduce population depression should consider the role played by assets in shaping risk of symptoms of persistent depression.
Modeling injury and repair in kidney organoids reveals that homologous recombination governs tubular intrinsic repair
Authors: Gupta Navin , Matsumoto Takuya , Hiratsuka Ken , Garcia Saiz Edgar , Zhang Chengcheng , Galichon Pierre , Miyoshi Tomoya , Susa Koichiro , Tatsumoto Narihito , Yamashita Michifumi , Morizane Ryuji
Published: March 2022

Kidneys have the capacity for intrinsic repair, preserving kidney architecture with return to a basal state after tubular injury. When injury is overwhelming or repetitive, however, that capacity is exceeded and incomplete repair results in fibrotic tissue replacing normal kidney parenchyma. Loss of nephrons correlates with reduced kidney function, which defines chronic kidney disease (CKD) and confers substantial morbidity and mortality to the worldwide population. Despite the identification of pathways involved in intrinsic repair, limited treatments for CKD exist, partly because of the limited throughput and predictivity of animal studies. Here, we showed that kidney organoids can model the transition from intrinsic to incomplete repair. Single-nuclear RNA sequencing of kidney organoids after cisplatin exposure identified 159 differentially expressed genes and 29 signal pathways in tubular cells undergoing intrinsic repair. Homology-directed repair (HDR) genes including Fanconi anemia complementation group D2 (
FANCD2
) and RAD51 recombinase (
RAD51
) were transiently up-regulated during intrinsic repair but were down-regulated in incomplete repair. Single cellular transcriptomics in mouse models of obstructive and hemodynamic kidney injury and human kidney samples of immune-mediated injury validated HDR gene up-regulation during tubular repair. Kidney biopsy samples with tubular injury and varying degrees of fibrosis confirmed loss of FANCD2 during incomplete repair. Last, we performed targeted drug screening that identified the DNA ligase IV inhibitor, SCR7, as a therapeutic candidate that rescued FANCD2/RAD51-mediated repair to prevent the progression of CKD in the cisplatin-induced organoid injury model. Our findings demonstrate the translational utility of kidney organoids to identify pathologic pathways and potential therapies.
Pathogenic variants in
MDFIC
cause recessive central conducting lymphatic anomaly with lymphedema
Authors: Byrne Alicia B. , Brouillard Pascal , Sutton Drew L. , Kazenwadel Jan , Montazaribarforoushi Saba , Secker Genevieve A. , Oszmiana Anna , Babic Milena , Betterman Kelly L. , Brautigan Peter J. , White Melissa , Piltz Sandra G. , Thomas Paul Q. , Hahn Christopher N. , Rath Matthias , Felbor Ute , Korenke G. Christoph , Smith Christopher L. , Wood Kathleen H. , Sheppard Sarah E. , Adams Denise M. , Kariminejad Ariana , Helaers Raphael , Boon Laurence M. , Revencu Nicole , Moore Lynette , Barnett Christopher , Haan Eric , Arts Peer , Vikkula Miikka , Scott Hamish S. , Harvey Natasha L.
Published: March 2022

Central conducting lymphatic anomaly (CCLA), characterized by the dysfunction of core collecting lymphatic vessels including the thoracic duct and cisterna chyli, and presenting as chylothorax, pleural effusions, chylous ascites, and lymphedema, is a severe disorder often resulting in fetal or perinatal demise. Although pathogenic variants in RAS/mitogen activated protein kinase (MAPK) signaling pathway components have been documented in some patients with CCLA, the genetic etiology of the disorder remains uncharacterized in most cases. Here, we identified biallelic pathogenic variants in
MDFIC
, encoding the MyoD family inhibitor domain containing protein, in seven individuals with CCLA from six independent families. Clinical manifestations of affected fetuses and children included nonimmune hydrops fetalis (NIHF), pleural and pericardial effusions, and lymphedema. Generation of a mouse model of human
MDFIC
truncation variants revealed that homozygous mutant mice died perinatally exhibiting chylothorax. The lymphatic vasculature of homozygous
Mdfic
mutant mice was profoundly mispatterned and exhibited major defects in lymphatic vessel valve development. Mechanistically, we determined that MDFIC controls collective cell migration, an important early event during the formation of lymphatic vessel valves, by regulating integrin β
1
activation and the interaction between lymphatic endothelial cells and their surrounding extracellular matrix. Our work identifies
MDFIC
variants underlying human lymphatic disease and reveals a crucial, previously unrecognized role for MDFIC in the lymphatic vasculature. Ultimately, understanding the genetic and mechanistic basis of CCLA will facilitate the development and implementation of new therapeutic approaches to effectively treat this complex disease.
Draft Genome Sequence of a Kazachstania humilis Strain Isolated from Agave Fermentation
Authors: García-Ortega Luis F. , Colón-González Maritrini , Sedeño Iván , Santiago-Garduño Erick , Avelar-Rivas J. Abraham , Kirchmayr Manuel R. , DeLuna Alexander , Delaye Luis , Morales Lucia , Mancera Eugenio
Published: March 2022

The ascomycetous yeast
Kazachstania humilis
is an active species in backslopped sourdough and in the spontaneous fermentation of several traditional foods and beverages. Here, we report the draft genome sequence of a
K. humilis
strain isolated from agave must from a traditional distillery in Mexico.
Clemastine Inhibits the Biofilm and Hemolytic of Staphylococcus aureus through the GdpP Protein
Authors: Shang Yongpeng , Guo Jie , Zhao Yuxi , Chen Junwen , Meng Qingyin , Qu Di , Zheng Jinxin , Yu Zhijian , Wu Yang , Deng Qiwen
Published: March 2022

The biofilm formation, which protects bacteria from stresses, including antibiotics and host immune responses, can be commonly found in clinical
S. aureus
isolates worldwide. Treatment failure of traditional antibiotics in biofilm-associated
S. aureus
infections remains a serious challenge.
iTRAQ-Based Quantitative Proteomic Analysis of Acinetobacter baumannii under Hypoxia and Normoxia Reveals the Role of OmpW as a Virulence Factor
Authors: Gil-Marqués María Luisa , Pachón Jerónimo , Smani Younes
Published: March 2022

Acinetobacter baumannii
causes infections that are very difficult to treat due to the high rate of resistance to most and sometimes all of the antimicrobials used in the clinical setting. There is an important need to develop new strategies to combat
A. baumannii
infections.
VPipe: an Automated Bioinformatics Platform for Assembly and Management of Viral Next-Generation Sequencing Data
Authors: Wagner Darlene D. , Marine Rachel L. , Ramos Edward , Ng Terry Fei Fan , Castro Christina J. , Okomo-Adhiambo Margaret , Harvey Krysten , Doho Gregory , Kelly Reagan , Jain Yatish , Tatusov Roman L. , Silva Hideky , Rota Paul A. , Khan Agha N. , Oberste M. Steven
Published: March 2022

Computational infrastructure and bioinformatics analysis are bottlenecks in the application of NGS to viral pathogens. As of September 2021, VPipe has been used by the U.S.
Streptococcus intermediuscausing cellulitis of the penile shaft complicated with abscess formation and rupture after dry humping sex
Authors: Shen Fang , Thevarajah Gowribahan , Cheng Janice
Published: March 2022

Penile cellulitis with abscess formation then rupture is an extremely rare presentation. This is a case report of a penile shaft abscess caused byStreptococcus intermediusafter ‘dry humping’ sexual activities. A 34-year-old healthy man was presented with painful penile swelling for 3 weeks after initial ‘dry humping’ and later penovaginal intercourse. He was admitted to the hospital for intravenous antibiotics treatment, but a penile abscess was developed and ruptured within 24 hours. Urgent penile exploration revealed localised abscess andS. intermediuswas isolated. The wound healed by secondary intention. However, his admission was complicated by acute kidney injury, probably due to vancomycin. Therefore, longer inpatient supportive care was required before discharge. Given this severe complication of primary penile cutaneous infection byS. intermedius, our case would raise awareness of this normal flora in abscess development at the male genital region, and the importance for the patient seeking prompt medical advice and physicians administrating appropriate antibiotics.
Novel likely pathogenicSLC20Avariant in primary familial brain calcification
Authors: Sharma Rishi , Stitt Derek
Published: March 2022

A woman in her 30s was referred to our neurology outpatient clinic following an incidental finding of significant bilateral and symmetric basal ganglia, thalamic, cerebellar and subcortical white matter calcification on brain CT and MRI. A diagnosis of asymptomatic primary familial brain calcification (PFBC) was made. Targeted genetic testing revealed a likely pathogenic variant in theSLC20A2gene, the most common gene in which pathogenic variants have been implicated in PFBC. These findings prompted genetic testing and brain CT of our patient’s asymptomatic 64-year-old father. These tests revealed the same variant inSLC20A2and similar brain calcification on CT in the patient’s father.
Marked increase of interferon-β after BNT162b2 mRNA vaccination: a case of polyarthritis with pleurisy
Authors: Shimagami Hiroshi , Yamaguchi Yuta , Kato Yasuhiro , Kumanogoh Atsushi
Published: March 2022

Exacerbation of rheumatic disease after vaccination against SARS-CoV-2 is being reported. However, there are only a few cases of new-onset rheumatic diseases. We present two cases of new-onset persistent polyarthritis that developed in patients after receiving the mRNA vaccine against SARS-CoV-2. One patient had bilateral pleural effusions with markedly elevated serum interferon (IFN)-β, while the other had no effusion, with serum IFN-β comparable with that in healthy subjects. Other cytokines were unaltered in association with effusion. Both patients responded well to treatment with 20 mg prednisolone. Although more investigations are needed, the marked increase in serum IFN-β levels observed in the case with pleural effusion may reflect an excessive response from the innate immune system to mRNA vaccines.
Herpes zoster meningitis in a rheumatoid arthritis patient treated with tofacitinib
Authors: Nakamura Yoshihiro , Honda Daiyu , Takizawa Naoho , Fujita Yoshiro
Published: March 2022

A man in his 70s with rheumatoid arthritis presented with seizures and coma and was transferred to our emergency department. Two months prior to admission, he started to take tofacitinib 10 mg/day. On admission, we noted a rash with a blister on the forehead, and herpes zoster was diagnosed. Cerebrospinal fluid examination suggested meningitis. An MRI of the brain showed no abnormality. Based on these findings, he was suspected with herpes zoster meningitis. We discontinued tofacitinib and treated the patient with intravenous acyclovir for 2 weeks. He regained complete consciousness, but right forehead skin lesion, severe vision loss in the right eye and right facial nerve paralysis remained as sequelae. Six weeks after admission, we restarted tofacitinib with oral valaciclovir as antiviral prophylaxis. Two years after admission, we administered Shingrix, an adjuvant recombinant vaccine for herpes zoster, and discontinued oral valaciclovir.
Overwhelming cryptococcosis complicated by cryptococcal endocarditis
Authors: Elkhatib Wiaam , Kwon Joshua Y , Phillips Michael B
Published: March 2022

Cryptococcal species endocarditis is infrequently described, carries high mortality and nearly always occurs in immunocompromised states or on prosthetic valves. We report the case of a man in his 70s with multiple recent hospitalisations for pneumonia, hypercalcaemia and septic tank exposure who presented with intermittent fevers, progressive weakness,and worsening encephalopathy, manifested as confusion and word-finding difficulties for 3 weeks. Workup revealed cryptococcal species on blood serum gram stain, native aortic valve endocarditis and meningitis. Cerebrospinal fluid analysis demonstrated lymphocytosis, ultimately found to be secondary to chronic lymphocytic leukaemia. Surgical valve replacement was deemed medically contraindicated and antifungal therapy was initiated. Though poorly understood with very few documented cases, management of cryptococcal endocarditis relies on prompt diagnosis, early surgery when indicated, long-term antifungal therapy and treatment of underlying immunocompromising states where possible.
Large desmoid tumour of the small bowel mesentery
Authors: Michaelides Athena , Ang Andrew , ChinAleong Joanne , Kocher Hemant M
Published: March 2022

A 74-year-old man was being investigated for a pancreatic insulinoma when an incidental mesenteric mass measuring 2.6 cm x 2.5 cm was noticed on CT imaging. A wait-and-see approach was decided on. Thirty-nine months later, the patient presented with symptoms of abdominal obstruction. CT images revealed the mesenteric mass filled majority of the abdominal cavity and measured 29 cm x 26 cm x 16 cm. The patient underwent an open bypass gastrojejunostomy which stopped working a few weeks later due to further compression by the tumour. A debulking surgery was performed: a right hemicolectomy and small bowel resection with excision of the desmoid tumour and bypass gastrojejunostomy. The tumour measured 12.6 kg and was macroscopically visualised to have a white cut surface with a focal translucent area. Microscopic analysis revealed bland spindle cells with pale eosinophilic cytoplasm showing no cytological atypia, in keeping with a mesenteric desmoid tumour. Currently, two and a half years from the debulking surgery, the patient remains well and in remission with planned surveillance.
Pretreatment of choriocarcinoma syndrome: a rare complication of metastatic germ cell tumours
Authors: Soputro Nicolas Adrianto , Roberts Jay , Wong Shirley , Dias Brendan Hermenigildo
Published: March 2022

A 27-year-old man newly diagnosed with metastatic testicular choriocarcinoma developed a large right perinephric haematoma secondary to a metastatic deposit in his right kidney. His presentation was also complicated by bilateral iliac venous thrombosis and pulmonary embolism identified prior to initiation of chemotherapy. He underwent multiple attempts at angioembolisation of the bleeding vessels and ultimately angioembolisation of the main renal artery had to be performed to control the bleeding. Following resolution and commencement of chemotherapy, the patient also developed spontaneous intracranial haemorrhage requiring craniotomy.
Case of cerebral venous thrombosis on a patient with background of nephrotic syndrome
Authors: Revythis Antonios , Boussios Stergios , Ganesh Vijayakumar , Sarkar Rahuldeb
Published: March 2022

Hypercoagulability is a well-described feature of nephrotic syndrome. The risk of developing a venous thrombus is higher at the time of diagnosis or shortly after. The resulting deep vein thrombosis involves the pulmonary, the deep veins of the lower limbs and renal veins, as described in the literature. We present a case of a man in his 20s with background of nephrotic syndrome, diagnosed at an age of 3 years old, with multiple relapses and on maintenance immunosuppression which is unusual, in two respects: First, the site of thrombosis was in the cerebral venous sinus and second, the onset of the thrombotic episode was years after the initial diagnosis. This case report also focuses on the perspective of the patient, who experienced a rare complication after more than two decades of living with the condition. In a literature search with the search words of ‘nephrotic syndrome’ AND ‘cerebral venous thrombosis in adults’, written in English and published from 1970 to 2/2021, we could only find a review article including 5 cases and 10 individual case reports, of which there were only 16 number of cerebral sinus venous thrombosis reported.
Long-standing hypoxaemia in complex adult congenital heart disease: anatomical and functional interplay in an uncommon presentation
Authors: Silva Cláudia Jesus , Madeira Sergio , Abecasis João , Anjos Rui
Published: March 2022

We report a case of a 28-year-old man lost to follow-up with chronic hypoxaemia and a history of an uncorrected tricuspid hypoplasia, perimembranous ventricular septal defect (VSD) and pulmonary stenosis. Given this initial diagnosis, chronic hypoxaemia was deemed to result from right-to-left shunt through the VSD driven by elevated right ventricle pressures. However, the further investigation identified an inferior sinus venosus atrial septal defect, unveiling the true mechanism behind the clinical scenario. The patient was submitted to surgical correction with clinical improvement. This case illustrates the defiant evaluation of this type of atrial septal defect through echocardiography and underlines the importance of a multimodal evaluation to reach an accurate diagnosis and optimal management.
Tumour to tumour metastasis: case of a carotid body paraganglioma metastatic to a hepatocellular adenoma
Authors: Jedrzejko Nicole , Berg Kyra B , Gurung Ananta , MacKenzie Shawn
Published: March 2022

Tumour to tumour metastases are uncommon, and we report a case of carotid body paraganglioma metastatic to a hepatocellular adenoma. A 54-year-old man presented after a CT chest for chronic cough that incidentally identified two liver lesions in segment 3 and caudate. The imaging findings were suspicious for atypical haemangiomas versus hepatocellular adenoma. The segment 3 lesion was biopsied, demonstrating beta-catenin activated hepatocellular adenoma. He underwent partial hepatectomy with pathology showing the beta-catenin activated hepatocellular adenoma contained a central area of paraganglioma. On closer review, the patient revealed a carotid body paraganglioma with lymph node metastases requiring resection 24 years earlier. He subsequently underwent left hepatectomy including the resection bed and caudate, which confirmed the caudate lesion as metastatic paraganglioma. This case demonstrates how paraganglioma can metastasise to liver decades after initial resection and provide insight into the diagnostic workup for hepatocellular adenoma with neuroendocrine features.
Physical activity and exercise recommendations for patients with valvular heart disease
Authors: Chatrath Nikhil , Papadakis Michael
Published: March 2022

There is a paucity of studies looking at the natural history of valvular heart disease (VHD) in exercising individuals, and exercise recommendations are largely based on expert consensus. All individuals with VHD should be encouraged to avoid sedentary behaviour by engaging in at least 150 min of physical activity every week, including strength training. There are generally no exercise restrictions to individuals with mild VHD. Regurgitant lesions are better tolerated compared with stenotic lesions and as such the recommendations are more permissive for moderate-to-severe regurgitant VHD. Individuals with severe aortic regurgitation can still partake in moderate-intensity exercise provided the left ventricle (LV) and aorta are not significantly dilated and the ejection fraction (EF) remains >50%. Similarly, individuals with severe mitral regurgitation can partake in moderate-intensity exercise if the LV end-diastolic diameter <60 mm, the EF ≥60%, resting pulmonary artery pressure <50 mm Hg and there is an absence of arrhythmias on exercise testing. Conversely, individuals with severe aortic or mitral stenosis are advised to partake in low-intensity exercise. For individuals with bicuspid aortic valve, in the absence of aortopathy, the guidance for tricuspid aortic valve dysfunction applies. Mitral valve prolapse has several clinical, ECG and cardiac imaging markers of increased arrhythmic risk; and if any are present, individuals should refrain from high-intensity exercise.
Soluble CD137 as a dynamic biomarker to monitor agonist CD137 immunotherapies
Authors: Glez-Vaz Javier , Azpilikueta Arantza , Olivera Irene , Cirella Assunta , Teijeira Alvaro , Ochoa Maria C , Alvarez Maite , Eguren-Santamaria Iñaki , Luri-Rey Carlos , Rodriguez-Ruiz Maria E , Nie Xinxin , Chen Lieping , Guedan Sonia , Sanmamed Miguel F , Luis Perez Gracia Jose , Melero Ignacio
Published: March 2022

Background

On the basis of efficacy in mouse tumor models, multiple CD137 (4-1BB) agonist agents are being preclinically and clinically developed. The costimulatory molecule CD137 is inducibly expressed as a transmembrane or as a soluble protein (sCD137). Moreover, the CD137 cytoplasmic signaling domain is a key part in approved chimeric antigen receptors (CARs). Reliable pharmacodynamic biomarkers for CD137 ligation and costimulation of T cells will facilitate clinical development of CD137 agonists in the clinic.

Methods

We used human and mouse CD8 T cells undergoing activation to measure CD137 transcription and protein expression levels determining both the membrane-bound and soluble forms. In tumor-bearing mice plasma sCD137 concentrations were monitored on treatment with agonist anti-CD137 monoclonal antibodies (mAbs). Human CD137 knock-in mice were treated with clinical-grade agonist anti-human CD137 mAb (Urelumab). Sequential plasma samples were collected from the first patients intratumorally treated with Urelumab in the INTRUST clinical trial. Anti-mesothelin CD137-encompassing CAR-transduced T cells were stimulated with mesothelin coated microbeads. sCD137 was measured by sandwich ELISA and Luminex. Flow cytometry was used to monitor CD137 surface expression.

Results

CD137 costimulation upregulates transcription and protein expression of CD137 itself including sCD137 in human and mouse CD8 T cells. Immunotherapy with anti-CD137 agonist mAb resulted in increased plasma sCD137 in mice bearing syngeneic tumors. sCD137 induction is also observed in human CD137 knock-in mice treated with Urelumab and in mice transiently humanized with T cells undergoing CD137 costimulation inside subcutaneously implanted Matrigel plugs. The CD137 signaling domain-containing CAR T cells readily released sCD137 and acquired CD137 surface expression on antigen recognition. Patients treated intratumorally with low dose Urelumab showed increased plasma concentrations of sCD137.

Conclusion

sCD137 in plasma and CD137 surface expression can be used as quantitative parameters dynamically reflecting therapeutic costimulatory activity elicited by agonist CD137-targeted agents.
Long-term exposure to ambient air pollution and asthma symptom score in the CONSTANCES cohort
Authors: Keirsbulck Marion , Savouré Marine , Lequy Emeline , Chen Jie , de Hoogh Kees , Vienneau Danielle , Goldberg Marcel , Zins Marie , Roche Nicolas , Nadif Rachel , Jacquemin Benedicte
Published: March 2022

Background

The asthma symptom score allows to consider asthma as a continuum and to investigate its risk factors. One previous study has investigated the association between asthma score and air pollution and only for nitrogen dioxide (NO2). We aimed to study the associations between particulate matter with an aerodynamic diameter lower than 2.5 µm (PM2.5), black carbon (BC) and NO2and the asthma symptom score in adults from CONSTANCES, a French population-based cohort.

Methods

Asthma symptom score (range: 0–5) was based on the number of five self-reported symptoms of asthma in the last 12 months. Annual individual exposure to PM2.5, BC and NO2was estimated at participants’ residential address using hybrid land-use regression models. Cross-sectional associations of each pollutant with asthma symptom score were estimated using negative binomial regressions adjusted for age, sex, smoking status and socioeconomic position. Associations with each symptom were estimated using logistic regression. The effect of BC independent of total PM2.5was investigated with a residual model.

Results

Analyses were conducted on 135 165 participants (mean age: 47.2 years, 53.3% women, 19.0% smokers, 13.5% ever asthma). The ratio of mean score was 1.12 (95% CI 1.10 to 1.14), 1.14 (95% CI 1.12 to 1.16) and 1.12 (95% CI 1.10 to 1.14) per one IQR increase of PM2.5(4.86 µg/m3), BC (0.88 10−5m−1) and NO2(17.3 µg/m3). Positive and significant associations were also found for each asthma symptom separately. BC effect persisted independently of total PM2.5.

Conclusion

Exposure to each pollutant was associated with increased asthma symptom score in adults. This study highlights that BC could be one of the most harmful particulate matter components.
Effects of nutritional management regimen and residual feed intake (RFI) classification on RFI reranking and feeding behaviour for finishing beef steers
Authors: Ferriman N.N. , Devos J.J. , Edwards A.M. , Wood K.M. , Campbell C.P. , Mandell I.B.
Published: March 2022

Over 2 years, 207 steers were fed an alfalfa/corn silage diet to determine growing phase (GP) residual feed intake (RFI) classification (low, medium, and high) for individual cattle. Steers were then allocated to two finishing management regimens (MR): MR 1 cattle gradually adjusted to an 84.7% concentrate (dry matter (DM) basis) diet; MR 2 included backgrounding on pasture before finishing using the same diet as MR 1 cattle. Treatment differences in growth performance were examined using GP and finishing phase (FP) RFI classifications. Based on GP RFI classification, FP average daily gain was greater in MR 2 cattle (P = 0.01) with no RFI classification differences for most FP performance traits. However, low-RFI steers had lower FP dry matter intake (DMI) and greater G:F (P ≤ 0.05) than high-RFI steers based on FP RFI classification. Low-RFI steers had fewer visits to the feeder with a lower eating rate than high-RFI steers in both production phases (P ≤ 0.05). Extensive RFI reranking occurred between production phases with 64.3% of steers changing RFI classification. Given extensive reranking in the present study, RFI classification was poorly repeatable between growing and finishing production phases when diverse diets are fed and does not accurately predict feed efficiency.
Forage productivity is resilient to timing of post-wildfire defoliation in mixed-grass Prairie
Authors: Bischoff Brendan K. , Bork Edward W. , Carlyle Cameron N.
Published: March 2022

Post-fire rangeland management recommends rest from grazing to allow forage regrowth and litter accumulation. In the first year after wildfire in the mixed-grass Prairie, we examined forage and litter mass responses to variable timing of defoliation in burned and non-burned areas. Total forage biomass did not differ between burned and non-burned areas by the second growing season. The July defoliation in both burned and non-burned areas reduced total forage biomass. Litter mass was decreased by wildfire and was further reduced by all defoliation treatments.
Green islands in a sea of fire: the role of fire refugia in the forests of Alberta
Authors: Sommers Marcus , Flannigan Mike D.
Published: March 2022

Alberta wildfires vary greatly in severity, resulting in a mosaic of burnt, partially burnt, and unburnt forest. These unburnt patches (refugia) within the fire perimeter are critical for the survival of organisms during the fire and the regeneration process. We examined the literature to identify how the fire regimes and landscape features found in Alberta affect the creation and persistence of refugia, the role of refugia for the flora and fauna of Alberta, how climate change is likely to affect refugia, how humans may alter the creation and effectiveness of refugia, and management implications moving forward. Refugia can vary in scale from small areas of unburnt soil or boulders (centimetres to a few metres), to large stands of unburnt trees (many hectares) with different taxa using these refugia across all the spatial scales. Species reliant on habitat connectivity or old growth forest also benefit from refugia as they can use them as stepping-stones between intact habitats or as a lifeboat to recolonize from. The factors influencing what areas remain unburnt are complex and poorly understood but are likely tied to topography, aspect, proximity to waterbodies, weather changes (precipitation and wind direction), time of day during burning, and vegetation type. Areas with the right combination of topography, aspect, and proximity to water have cooler microclimates and higher moisture than the surrounding areas and may remain unburnt throughout multiple fire events, making them persistent refugia. Other areas may remain unburnt by a chance result of weather changes or having the fire pass through at night, making them random refugia. Many of the features that make persistent refugia unlikely to burn (cooler microclimate and higher moisture) will also buffer the effects of climate change. As a result, it is essential we manage the landscape in such a way as to protect areas that act as persistent refugia from industrial activities. In addition, we must restore fire in the landscape to maintain the mosaic of forest caused by mixed-severity fire, especially in the face of climate change, which is projected to increase the severity and frequency of wildfires in Alberta.
Impact of compactlike and asymmetric configurations of thick branes on the scalar–tensor representation of $$f\left( R,T\right) $$ gravity
Authors: Rosa João Luís , Lobão A. S. , Bazeia D.
Published: March 2022

In this work we study braneworld models in generalized $$f\left( R,T\right) $$

f

R
,
T

gravity theories where the action depends on a function of the Ricci scalar R and the trace of the stress–energy tensor T. We explore the so-called scalar–tensor representation of the theory, where the dependence on R and T are exchanged for two auxiliary real scalar fields. We introduce a first-order formalism to relate the auxiliary fields with the source field of brane and analyze four distinct possibilities of current interest regarding compactification and asymmetry of the brane. We investigate the behavior of the auxiliary fields and their stability in each one of the four cases. For the models where the solution of the source field engenders compact behavior, the auxiliary fields exhibit a hybrid structure, behaving differently inside and outside the compact region described by the source configuration. In particular, we found that the solutions of the auxiliary fields are significantly modified in models where the geometry is strongly influenced by the source field. Moreover, for the model capable of engendering asymmetric features, the two auxiliary fields also respond to modifications on the parameter that controls the asymmetry of the system.
Exploring the Potential Pharmacological Mechanism of Hesperidin and Glucosyl Hesperidin against COVID-19 Based on Bioinformatics Analyses and Antiviral Assays
Authors: Huang Yun , Zhou Wei , Sun Jing , Ou Guoliang , Zhong Nan-Shan , Liu Zhigang
Published: March 2022

The development of anti-COVID-19 drugs has become the top priority since the outbreak of the epidemic, and Traditional Chinese medicine plays an important role in reducing mortality. Here, hesperidin and its glycosylation product, glucosyl hesperidin were selected to determine their antiviral activity against SARS-CoV-2 due to their structural specificity as reported. To be specific, their binding ability with ACE2, M, S, RBD and N proteins were verified with both in silico and wet lab methods, i.e., molecular docking and binding affinity tests, including biolayer interferometry assay (BLI) and isothermal titration calorimetry assay (ITC). Moreover, systematic pharmacological analysis was conducted to reveal their pharmacological mechanism in treating COVID-19. Finally, their antiviral activity against SARS-CoV-2 was determined in vitro in a biosafety level 3 (BSL3) laboratory. The results demonstrated their outstanding binding affinity with ACE2, M, S and RBD proteins, while showed barely unobserved binding with N protein, indicating their key roles in influencing the invasion and early replication phase of SARS-CoV-2. In addition, both hesperidin and glucosyl hesperidin were shown to have a great impact on immune, inflammation and virus infection induced by COVID-19 according to the systematic pharmacological analysis. Moreover, the IC50s of hesperidin and glucosyl hesperidin against SARS-CoV-2 were further determined (51.5 [Formula: see text]M and 5.5 mM, respectively) with cell-based in vitro assay, suggesting their great anti-SARS-CoV-2 activity. All in all, present research was the first to verify the binding ability of hesperidin and glucosyl hesperidin with SARS-CoV-2 proteins with both in silico and wet-lab methods and proposed the possibility of applying hesperidin and glucosyl hesperidin to treat COVID-19.
Hierarchical Planning for Dynamic Resource Allocation in Smart and Connected Communities
Authors: Pettet Geoffrey , Mukhopadhyay Ayan , Kochenderfer Mykel J. , Dubey Abhishek
Published: March 2022

Resource allocation under uncertainty is a classic problem in city-scale cyber-physical systems. Consider emergency response, where urban planners and first responders optimize the location of ambulances to minimize expected response times to incidents such as road accidents. Typically, such problems involve sequential decision making under uncertainty and can be modeled as Markov (or semi-Markov) decision processes. The goal of the decision maker is to learn a mapping from states to actions that can maximize expected rewards. While online, offline, and decentralized approaches have been proposed to tackle such problems, scalability remains a challenge for real world use cases. We present a general approach to hierarchical planning that leverages structure in city level CPS problems for resource allocation. We use emergency response as a case study and show how a large resource allocation problem can be split into smaller problems. We then use Monte Carlo planning for solving the smaller problems and managing the interaction between them. Finally, we use data from Nashville, Tennessee, a major metropolitan area in the United States, to validate our approach. Our experiments show that the proposed approach outperforms state-of-the-art approaches used in the field of emergency response.
How to Enable Index Scheme for Reducing the Writing Cost of DNA Storage on Insertion and Deletion
Authors: Lin Yi-Syuan , Liang Yu-Pei , Chen Tseng-Yi , Chang Yuan-Hao , Chen Shuo-Han , Wei Hsin-Wen , Shih Wei-Kuan
Published: March 2022

Recently, the requirement of storing digital data has been growing rapidly; however, the conventional storage medium cannot satisfy these huge demands. Fortunately, thanks to biological technology development, storing digital data into deoxyribonucleic acid (DNA) has become possible in recent years. Furthermore, because of the attractive features (e.g., high storing density, long-term durability, and stability), DNA storage has been regarded as a potential alternative storage medium to store massive digital data in the future. Nevertheless, reading and writing digital data over DNA requires a series of extremely time-consuming processes (i.e., DNA sequencing and DNA synthesis). More specifically, among the two costs, the writing cost is the predominant cost of a DNA data storage system. Therefore, to enable efficient DNA storage, this article proposes an index management scheme for reducing the number of accesses to DNA storage. Additionally, this article introduces a new DNA data encoding format with VERA (Version Editing Recovery Approach) to reduce the total writing bits while inserting and deleting the data. To the best of our knowledge, this work is the first work to provide a total data management solution for DNA storage. According to the experimental results, the proposed design with VERA can reduce the cost by 77% and improve the performance by 71% compared to the append-only methods.
Investigation of the Electrode-Electrolyte Interphase in Ester-Based Electrolytes in NCM523/Graphite Cells
Authors: Rodrigo Nuwanthi D. , Jayawardana Chamithri , Lucht Brett L.
Published: March 2022

The use of methyl acetate (MA) and methyl propionate (MP) as co-solvents in carbonate/LiPF6 electrolytes have been investigated in LiNi0.5Co0.2Mn0.3O2 (NCM523)/graphite cells to improve electrochemical performance at low temperature (−20 °C). Consistent with previous investigations, improved low temperature performance was observed with all electrolyte formulations containing esters. Detailed ex situ surface analysis of the surface films generated with the ester-based electrolytes containing electrolyte additives reveal significant changes to the SEI on graphite upon cycling at moderately elevated temperature (45 °C). In the presence of vinylene carbonate (VC) lithium plating is observed upon cycling at low temperature (−20 °C) which leads to a thicker solid electrolyte interface (SEI) upon cycling at 45 °C. Incorporation of fluoroethylene carbonate (FEC) as an electrolyte additive results in the generation of a thin SEI and alters the structure of the surface film on the NCM523 cathode resulting in stable cycling over a wide temperature range.
Dynamics and mechanistic underpinnings to pharmacology of class A GPCRs: an NMR perspective
Authors: Huang Shuya Kate , Prosser R. Scott
Published: March 2022

One-third of current pharmaceuticals target G protein-coupled receptors (GPCRs), the largest receptor superfamily in humans and mediators of diverse physiological processes. This review summarizes the recent progress in GPCR structural dynamics, focusing on class A receptors and insights derived from nuclear magnetic resonance (NMR) and other spectroscopic techniques. We describe the structural aspects of GPCR activation and the various pharmacological models that capture aspects of receptor signaling behavior. Spectroscopic studies revealed that receptors and their signaling complexes are dynamic allosteric systems that sample multiple functional states under basal conditions. The distribution of states within the conformational ensemble and the kinetics of transitions between states are regulated through the binding of ligands, allosteric modulators, and the membrane environment. This ensemble view of GPCRs provides a mechanistic framework for understanding many of the pharmacological phenomena associated with receptor signaling, such as basal activity, efficacy, and functional bias.
Nephronectin influences EAE development by regulating the Th17/Treg balance via reactive oxygen species
Authors: Honda Machiko , Segawa Tatsuya , Ishikawa Kiyoshi , Maeda Masahiro , Saito Yoshiro , Kon Shigeyuki
Published: March 2022

Blood levels of the extracellular matrix protein nephronectin (Npnt), a protein critical for kidney development, are elevated in autoimmune experimental autoimmune encephalitis (EAE) mice, which are a model for multiple sclerosis. We found here that treatment with anti-Npnt antibody directed against the α8β1 integrin-binding site (Npnt-blocking antibody) inhibits EAE development. The selenium transporter selenoprotein P (SeP) was identified as a novel Npnt-binding partner. In EAE, Npnt induced SeP and glutathione peroxidase 1 (GPx1) expression, followed by reactive oxygen species (ROS) inhibition in CD4+ T cells; these changes were disturbed by Npnt-blocking antibody treatment, which also caused suppressed differentiation of interleukin (IL)-17-producing CD4+ T-helper cells (Th17s) and elevated differentiation of regulatory T cells (Tregs). Treatment of EAE mice with the ROS scavenger N-acetyl cysteine (NAC) blocked the Npnt-blocking antibody-induced decrease in Th17 differentiation and increase in Treg differentiation. In conclusion, the interaction between Npnt and SeP contributes to EAE development by regulating the Th17/Treg balance via the ROS level.
Proactive inhibition is marked by differences in the pattern of motor cortex activity during movement preparation and execution
Authors: Rawji Vishal , Modi Sachin , Rocchi Lorenzo , Jahanshahi Marjan , Rothwell John C.
Published: March 2022

Using directional TMS, we find that the human motor cortex flexibly changes its pattern of neural activity depending on the context in which a movement is due to be made. Interestingly, this occurs despite adjusting for reaction time. We also show that state space and dynamical systems models of movement can be noninvasively visualized in humans using TMS, thereby offering a novel method to study these powerful models in humans.
A systematic review with meta-analysis of the StartReact effect on motor responses in stroke survivors and healthy individuals
Authors: DeLuca Mara , Low Daniel , Kumari Veena , Parton Andrew , Davis Jessica , Mohagheghi Amir A.
Published: March 2022

Control of limb movements may be impaired after stroke due to the loss of connectivity between the cerebral cortex and spinal cord. A notion to improve motor function in stroke survivors is to use alternate motor fibers, such as the reticulospinal tract (RST), which originate from the brainstem and terminate at different levels of spinal cord. One way of targeting the RST is to use a “StartReact” protocol to foster premature release of a preplanned movement in response to a startling stimulus. Our aim was to find support for the preservation of such StartReact effect in stroke survivors. We conducted a systematic review with meta-analysis of literature published in English up to September 2020, to explore differences in motor responses to startling stimuli in StartReact effects. Protocol of the study was registered (PROSPERO Registration No. CRD42020191581). PubMed, Google Scholar, Web of Science, PsycINFO, and Science Direct were searched for relevant literature. The meta-analysis contained six studies involving a total of 151 stroke and healthy participants. Muscle onset latency data were extracted from the qualifying studies and compared using RevMan. StartReact effect was present in both stroke and healthy groups, represented by shortened muscle onset latency when startling stimulus was present. There was considerable heterogeneity of the outcome measures, which was attributed to the range of motor impairments among stroke survivors and methodologies used. Our findings support the notion of preservation of preprogramming ability and suitability of RST and StartReact effect for motor rehabilitation following stroke.