bluuebunny/crossref_metadata_2025 huggingface dataset:
Appearance of peanut agglutinin in the blood circulation after peanut ingestion promotes endothelial secretion of metastasis-promoting cytokines
Authors: Wang Weikun , Sindrewicz-Goral Paulina , Chen Chen , Duckworth Carrie A , Pritchard David Mark , Rhodes Jonathan M , Yu Lu-Gang
Published: July 2021

Peanut agglutinin (PNA) is a carbohydrate-binding protein in peanuts that accounts for ~0.15% peanut weight. PNA is highly resistant to cooking and digestion and is rapidly detectable in the blood after peanut consumption. Our previous studies have shown that circulating PNA mimics the actions of endogenous galactoside-binding protein galectin-3 by interaction with tumour cell-associated MUC1 and promotes circulating tumour cell metastatic spreading. The present study shows that circulating PNA interacts with micro- as well as macro-vascular endothelial cells and induces endothelial secretion of cytokines MCP-1 (CCL2) and IL-6 in vitro and in vivo. The increased secretion of these cytokines autocrinely/paracrinely enhances the expression of endothelial cell surface adhesion molecules including integrins, VCAM and selectin, leading to increased tumour cell-endothelial adhesion and endothelial tubule formation. Binding of PNA to endothelial surface MCAM (CD146), via N-linked glycans, and subsequent activation of PI3K-AKT-PREAS40 signalling is here shown responsible for PNA-induced secretion of MCP-1 and IL-6 by vascular endothelium. Thus, in addition to its influence on promoting tumour cell spreading by interaction with tumour cell-associated MUC1, circulating PNA might also influence metastasis by enhancing the secretion of metastasis-promoting MCP-1 and IL-6 from the vascular endothelium.
CHARGE syndrome and related disorders: a mechanistic link
Authors: Ufartes Roser , Grün Regina , Salinas Gabriela , Sitte Maren , Kahl Fritz , Wong Monica T Y , van Ravenswaaij-Arts Conny M A , Pauli Silke
Published: July 2021

CHARGE syndrome is an autosomal dominant malformation disorder caused by pathogenic variants in the chromatin remodeler CHD7. Affected are craniofacial structures, cranial nerves and multiple organ systems. Depending on the combination of malformations present, its distinction from other congenital disorders can be challenging.

To gain a better insight into the regulatory disturbances in CHARGE syndrome, we performed RNA-Seq analysis on blood samples of 19 children with CHARGE syndrome and a confirmed disease-causing CHD7 variant in comparison with healthy control children. Our analysis revealed a distinct CHARGE syndrome pattern with downregulation of genes that are linked to disorders described to mimic the CHARGE phenotype, i.e. KMT2D and KDM6A (Kabuki syndrome), EP300 and CREBBP (Rubinstein-Taybi syndrome) and ARID1A and ARID1B (Coffin-Siris syndrome).

Furthermore, by performing protein–protein interaction studies using co-immunoprecipitation, direct yeast-two hybrid and in situ proximity ligation assays, we could demonstrate an interplay between CHD7, KMT2D, KDM6A and EP300.

In summary, our data demonstrate a mechanistic and regulatory link between the developmental disorders CHARGE-, Kabuki- and Rubinstein Taybi-syndrome providing an explanation for the overlapping phenotypes.
The importance of regional differences in vulnerability to climate change for demersal fisheries
Authors: Aragão Guilherme Martins , López-López Lucía , Punzón Antonio , Guijarro Elena , Esteban Antonio , García Encarnación , González-Irusta José Manuel , Polo Julia , Vivas Miguel , Hidalgo Manuel
Published: July 2021

Regional differences in climate vulnerability are particularly important in many countries with socio-ecological gradients or geographical and environmental spatial segregation. Many studies are regularly performed at the national level, but regional assessments can provide more detailed information and important insights into intra-national vulnerabilities. They require detailed information of many socio-ecological components that are often neglected at the regional scale but are meaningful and operational at national and international levels. In this work, we developed a climate vulnerability assessment (CVA) to investigate the vulnerability of demersal fisheries based on 19 indicators covering exposure, fisheries sensitivity, species sensitivity (SS) and adaptive capacity (AC) for nine coastal regions of Spain, contrasting the Mediterranean to Atlantic areas. Exposure was consistently larger in the Mediterranean than Atlantic regions, while AC showed the opposite trend. While fisheries and SS did not display a clear Atlantic-Mediterranean pattern, they were critical for capturing regional differences that have an impact on fisheries vulnerability. Our results highlight the generally higher vulnerability of Mediterranean demersal fisheries, mainly due to the lower AC and higher exposure of Mediterranean regions, while providing key regional elements for guiding national and international actions for adaptation. This study demonstrates that the spatial scale considered in the development of CVAs must recognise the spatial heterogeneity in the socio-ecological system within its unit of analysis in order to be a relevant tool for management and policy makers.
Peripheral T cell lymphopenia in COVID-19: potential mechanisms and impact
Authors: Zhang Sifan , Asquith Becca , Szydlo Richard , Tregoning John S , Pollock Katrina M
Published: July 2021

Immunopathogenesis involving T lymphocytes, which play a key role in defence against viral infection, could contribute to the spectrum of COVID-19 disease and provide an avenue for treatment. To address this question, a review of clinical observational studies and autopsy data in English and Chinese languages was conducted with a search of registered clinical trials. Peripheral lymphopenia affecting CD4 and CD8 T cells was a striking feature of severe COVID-19 compared with non-severe disease. Autopsy data demonstrated infiltration of T cells into organs, particularly the lung. Seventy-four clinical trials are on-going that could target T cell-related pathogenesis, particularly IL-6 pathways. SARS-CoV-2 infection interrupts T cell circulation in patients with severe COVID-19. This could be due to redistribution of T cells into infected organs, activation induced exhaustion, apoptosis, or pyroptosis. Measuring T cell dynamics during COVID-19 will inform clinical risk-stratification of hospitalised patients and could identify those who would benefit most from treatments that target T cells.
Epidemiologic, Immunologic, and Virus Characteristics in Patients With Paired Severe Acute Respiratory Syndrome Coronavirus 2 Serology and Reverse-Transcription Polymerase Chain Reaction Testing
Authors: Shragai Talya , Smith-Jeffcoat Sarah E , Koh Mitsuki , Schechter Marcos C , Rebolledo Paulina A , Kasinathan Vyjayanti , Wang Yun , Hoffman Adam , Miller Halie , Tejada-Strop Alexandra , Jain Shilpi , Tamin Azaibi , Harcourt Jennifer L , Thornburg Natalie J , Wong Phili , Medrzycki Magdalena , Folster Jennifer M , Semenova Vera , Steward-Clark Evelene , Drobenuic Jan , Biedron Caitlin , Stewart Rebekah J , da Silva Juliana , Kirking Hannah L , Tate Jacqueline E ,   Centers for Disease Control and Prevention COVID-19 Emergency Response GA-10 Field Team, Adeyemo AdeSubomi O , Moorman Anne , Bauman Brenda L , Joseph Kahaliah , O’Hegarty Michelle , Kamal Nazia , Cohen Mila , Rosetti Rebecca , Britton Amadea , Aholou Tiffiany M , Callahan Courtney T , Fonseka Jamila , Agyemang Elfriede , Lawson Miriam J , Deutsch-Feldman Molly , Tiwari Tejpratap S P , Sami Samira , Tao Hong
Published: July 2021

Background

The natural history and clinical progression of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections can be better understood using combined serological and reverse-transcription polymerase chain reaction (RT-PCR) testing.

Methods

Nasopharyngeal swabs and serum were collected at a single time-point from patients at an urban, public hospital during August–November 2020 and tested for SARS-CoV-2 using RT-PCR, viral culture, and anti-spike pan-immunoglobulin antibody testing. Participant demographics and symptoms were collected through interview. The χ 2 and Fisher exact tests were used to identify associations between RT-PCR and serology results with presence of viable virus and frequency of symptoms.

Results

Among 592 participants, 129 (21.8%) had evidence of SARS-CoV-2 infection by RT-PCR or serology. Presence of SARS-CoV-2 antibodies was strongly associated with lack of viable virus (P = .016). COVID-19 symptom frequency was similar for patients testing RT-PCR positive/seronegative and patients testing RT-PCR positive/seropositive. Patients testing RT-PCR positive/seronegative reported headaches, fatigue, diarrhea, and vomiting at rates not statistically significantly different from those testing RT-PCR negative/seropositive.

Conclusions

While patients testing SARS-CoV-2 seropositive were unlikely to test positive for viable virus and were therefore at low risk for forward transmission, coronavirus disease 2019 (COVID-19) symptoms were common. Paired SARS-CoV-2 RT-PCR and antibody testing provides more nuanced understanding of patients’ COVID-19 status.
The Effect of Intermittent Preventive Treatment of Malaria During Pregnancy and Placental Malaria on Infant Risk of Malaria
Authors: Andronescu Liana R , Sharma Ankur , Peterson Ingrid , Kachingwe Martin , Kachepa Witness , Liang Yuanyuan , Gutman Julie R , Mathanga Don P , Chinkhumba Jobiba , Laufer Miriam K
Published: July 2021

Background

Intermittent preventive treatment of malaria during pregnancy (IPTp) with dihydroartemisinin-piperaquine (DP) provides greater protection from placental malaria than sulfadoxine-pyrimethamine (SP). Some studies suggest placental malaria alters risk of malaria infection in infants, but few have quantified the effect of IPTp on infant susceptibility to malaria.

Methods

Infants born to women enrolled in a randomized clinical trial comparing IPTp-SP and IPTp-DP in Malawi were followed from birth to 24 months to assess effect of IPTp and placental malaria on time to first malaria episode and Plasmodium falciparum incidence.

Results

In total, 192 infants born to mothers randomized to IPTp-SP and 195 randomized to IPTp-DP were enrolled. Infants in IPTp exposure groups did not differ significantly regarding incidence of clinical malaria (incidence rate ratio [IRR], 1.03; 95% confidence interval [CI], .58–1.86) or incidence of infection (IRR, 1.18; 95% CI, .92–1.55). Placental malaria exposure was not associated with incidence of clinical malaria (IRR, 1.03; 95% CI, .66–1.59) or infection (IRR, 1.15; 95% CI, .88–1.50). Infant sex, season of birth, and maternal gravidity did not confound results.

Conclusions

We did not find evidence that IPTp regimen or placental malaria exposure influenced risk of malaria during infancy in this population.

Clinical Trials Registration. NCT03009526
A New Family of Stoneflies (Insecta: Plecoptera), Kathroperlidae, fam. n., with a Phylogenomic Analysis of the Paraperlinae (Plecoptera: Chloroperlidae)
Authors: South Eric J , Skinner Rachel K , Edward DeWalt R , Davis Mark A , Johnson Kevin P , Teslenko Valentina A , Lee Jonathan J , Malison Rachel L , Hwang Jeong Mi , Bae Yeon Jae , Myers Luke W
Published: July 2021

Recent molecular analyses of transcriptome data from 94 species across 92 genera of North American Plecoptera identified the genus Kathroperla Banks, 1920 as sister group to Chloroperlidae + Perlodidae. Given that the genus Kathroperla has historically been included as a member of the family Chloroperlidae, this discovery indicated further investigation of the genus and the subfamily Paraperlinae was needed. Both transcriptome and genome sequencing datasets were generated from 32 species of the infraorder Systellognatha, including all described species of the Paraperlinae, to test the phylogenetic placement of these taxa. From these datasets, a large phylogenomic data matrix of 800 orthologous genes was produced, and multiple analyses were conducted, including both concatenated and coalescent analyses. Morphological comparisons were made among all Paraperlinae using light microscopy. All molecular results support a monophyletic Kathroperla, which is supported as sister taxon to the remaining Perloidea by five of six molecular analyses. Postocular head length is determined to be a distinct morphological character of this genus. Combined molecular and morphological evidence support the designation of Kathroperlidae, fam. n., as the seventeenth family of extant Plecoptera.
The association of remdesivir and in-hospital outcomes for COVID-19 patients treated with steroids
Authors: Kuno Toshiki , Miyamoto Yoshihisa , Iwagami Masao , Ishimaru Miho , Takahashi Mai , Egorova Natalia N
Published: July 2021

Background

Remdesivir has been shown to decrease SARS-CoV-2 viral loads and the duration of COVID-19 symptoms. However, current evidence regarding the association between remdesivir and in-hospital mortality for patients with COVID-19 steroid treatments is limited. We aimed to investigate whether remdesivir reduces in-hospital mortality among patients with COVID-19 treated with steroids.

Methods

In this retrospective multicentre study, we reviewed the medical records of 3372 patients discharged between 1 March 2020 and 30 March 2021, with laboratory confirmed COVID-19 in the Mount Sinai Health System and treated with steroids. We evaluated the effect of remdesivir on the outcomes using propensity score analyses. Subgroup analyses were conducted by stratification of patients by endotracheal intubation and COVID-19 antibody status. Acute kidney injury (AKI) was defined as an absolute serum creatinine increase of 0.3 mg/dL or a relative increase of 50%.

Results

Of the 3372 eligible patients, 1336 (39.6%) received remdesivir. After 1:1 propensity score matching (N = 999 pairs), in-hospital mortality was similar between those with and without remdesivir (21.4% versus 21.6%, respectively, P = 0.96). Remdesivir was not significantly associated with in-hospital mortality regardless of endotracheal intubation or COVID-19 antibody status. However, there was a signal that remdesivir was associated with a reduced risk of AKI in the propensity matched analysis (17.5% versus 23.4%, respectively, P = 0.001).

Conclusions

Remdesivir was not associated with reduced risk of in-hospital mortality in patients with COVID-19 treated with steroids but potentially associated with decreased risk of AKI. These findings should be confirmed in prospective studies focusing on COVID-19 patients treated with steroids.
Safety and efficacy of intravenously administered cidofovir in adult haematopoietic cell transplant recipients: a retrospective multicentre cohort study
Authors: Stern Anat , Alonso Carolyn D , Garcia-Vidal Carolina , Cardozo Celia , Slavin Monica , Yong Michelle K , Ho Su Ann , Mehta Steinke Seema , Avery Robin K , Koehler Philipp , Scheid Christof , Cornely Oliver A , Maertens Johan , Abi Aad Yasmine , Epstein David J , Papanicolaou Genovefa A , Neofytos Dionysios
Published: July 2021

Objectives

To evaluate the safety and efficacy of cidofovir for the treatment of double-stranded DNA (dsDNA) viral infections following allogeneic haematopoietic cell transplant (HCT).

Methods

This was a retrospective multicentre cohort study including adult HCT recipients who received ≥1 dose of IV-administered cidofovir for any dsDNA viral infection from 2006 to 2019. The objectives were to describe the rate of and risk factors for nephrotoxicity and virological response by the end of treatment (EOT).

Results

We included 165 patients from nine centres. Cidofovir was administered at 5 mg/kg/week (N = 115; 69.7%), 1 mg/kg/week (18; 10.9%), 3 mg/kg/week (12; 7.3%) or 1 mg/kg three times/week (11; 6.7%). Cidofovir was administered for adenovirus, cytomegalovirus (CMV) and BK virus infection in 75 (45.5%), 64 (38.8%) and 51 (30.9%) patients, respectively. Among 158 patients with renal function data at baseline and EOT, 40 (25.3%) developed nephrotoxicity. In multivariable analyses, age (OR 1.04; P = 0.05), weight (OR 1.05; P = 0.01), CMV infection (OR 3.6; P = 0.02), liposomal amphotericin B (OR 8.06; P = 0.05) and IV voriconazole/posaconazole (OR 13.0; P = 0.003) were predictors of nephrotoxicity. Creatinine concentration was significantly higher at EOT (1.16 ± 0.95 mg/dL) compared with baseline (0.91 ± 0.39 mg/dL; P < 0.001), but improved by 2 weeks (0.91 ± 0.84 mg/dL; P = 0.007) and 4 weeks (0.96 ± 0.89 mg/dL; P = 0.03) post-EOT. Median viral load significantly declined for patients with adenovirus DNAaemia by EOT (P < 0.0001) and for patients with CMV DNAaemia by EOT + 4 weeks (P = 0.003), but not for patients with BK virus DNAaemia.

Conclusions

One in four HCT recipients treated with IV cidofovir developed largely reversible nephrotoxicity. Careful selection of patients and close follow-up of renal function may minimize toxicity.
Crohn’s and Colitis Canada’s 2021 Impact of COVID-19 and Inflammatory Bowel Disease in Canada: Seniors With IBD
Authors: Bernstein Charles N , Singh Harminder , Murthy Sanjay K , Nguyen Geoffrey C , Benchimol Eric I , Bitton Alain , Kuenzig M Ellen , Huang James Guoxian , Jones Jennifer L , Lee Kate , Targownik Laura E , Windsor Joseph W , Mukhtar Mariam S , Tandon Parul , Kaplan Gilaad G
Published: July 2021

The risk of hospitalization and death from Coronavirus disease-19 (COVID-19) increases with age. The extreme elderly have been particularly vulnerable, with those above the age of 80 having a case-fatality rate as high as 15%. Aging of the immune system can lead to impaired inflammatory responses where eradication of an organism such as Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV2) is inadequate but is exaggerated in such a way as to enhance pneumonia and acute respiratory distress syndrome. Frailty and comorbidity are both more common in the elderly, and these can enhance the morbidity and mortality from COVID-19. Studies from Northern California and Italy suggest that elderly persons with inflammatory bowel disease (IBD) were more likely to acquire SARS-CoV-2 infection than youths with IBD. While the specific impact of age-related comorbidity is less well established among people with IBD who acquire COVID-19, data from the Surveillance Epidemiology of Coronavirus Under Research Exclusion (SECURE-IBD) database reported that having two or more chronic illnesses was independently associated with developing severe COVID-19 among people with IBD. Despite having exaggerated auto-inflammatory responses, people with IBD do not appear to have an overall increased risk of developing severe COVID-19 than the general population. However, whether seniors with IBD do worse once they acquire COVID-19 compared with seniors without IBD is not known. The advent of telehealth care has posed an information technology challenge for many seniors with and without IBD. Most persons with IBD have expressed satisfaction with virtual IBD health care (phone or video-based visits). While the elderly may have less robust immune responses to vaccinations, learning from experiences with other vaccination programs, especially influenza, have shown that vaccinating seniors decreases both morbidity and mortality and, in turn, healthcare resources.
Arthroscopic treatment for femoroacetabular impingement syndrome (FAIS) in adolescents—5-year follow-up
Authors: Winge Søren , Winge Sophie , Kraemer Otto , Dippmann Christian , Hölmich Per
Published: July 2021

To report the minimum 5-year outcome after hip arthroscopy with labral repair in adolescents. From 2011 to 2014, 29 consecutive patients with a mean age 16.3 years (range 12.7–19.8 years) underwent hip arthroscopy treatment for femoroacetabular impingement syndrome. Patient-related outcome measures (PROMs) including modified Harris Hip Score (mHHS), Visual Analog Scale (VAS) for pain and Copenhagen Hip and Groin Outcome Score (HAGOS) were used preoperatively and at follow-up (FU). Percentage of patients achieving minimum clinically important difference (MCID) and substantial clinical benefit (SCB) for mHHS and HAGOS were determined. Mean FU was 6.7 years (range 5–9.6 years), and a 100% FU was accomplished. Significant improvements were seen for all PROMs at FU in patients not having a periacetabular osteotomy (PAO) with VAS pain score improving from mean 62 to 9, mHHS from 58 to 94 and HAGOS improved in all subgroups. For mHHS, SCB changes were achieved by 76% and MCID by 76% of the patients. Percentage of patients achieving MCID for HAGOS subgroups were 81% for pain, 67% for symptoms, 76% for physical function in daily living, 76% for physical function in sport and recreation, 81% for participation in physical activities and 81% for hip-related quality of life. Two patients had revision hip arthroscopy. PAO was later performed in three patients. The risk of further surgery with center edge (CE) bony edge (CEB) <30° was 42% and 0% with CEB ≥30°. Adolescents having hip arthroscopy with labral repair and resection of cam and pincer morphology achieve significant improvements at mean 6.7 years of FU. CEB < 30° increases the risk of further surgery.
Neutralization of Beta and Delta variant with sera of COVID-19 recovered cases and vaccinees of inactivated COVID-19 vaccine BBV152/Covaxin
Authors: Yadav Pragya D , Sapkal Gajanan N , Ella Raches , Sahay Rima R , Nyayanit Dimpal A , Patil Deepak Y , Deshpande Gururaj , Shete Anita M , Gupta Nivedita , Mohan V Krishna , Abraham Priya , Panda Samiran , Bhargava Balram
Published: July 2021

SARS-CoV-2 variant of concern mainly Delta and Beta is global public health concern due to its impact on existing vaccines. Here, we assessed the neutralization of sera from COVID-19 recovered cases and BBV152 vaccinees against Beta and Delta variants. BBV152 vaccine found to confer significant protection against both the variants.
General-relativistic treatment of tidal g-mode resonances in coalescing binaries of neutron stars – I. Theoretical framework and crust breaking
Authors: Kuan Hao-Jui , Suvorov Arthur G , Kokkotas Kostas D
Published: July 2021

During the final stages of a neutron-star binary coalescence, stellar quasi-normal modes can become resonantly excited by tidal fields. If the strain exerted by the excited modes exceeds the extent to which the crust can respond linearly, localized crustal failures may occur. In this work, we re-examine resonant g-mode excitations of relativistic neutron stars in the last ∼10 s of an inspiral. We adopt realistic equations of state that pass constraints from GW170817, include third-order post-Newtonian terms for the conservation orbital motion, and employ a 2.5 post-Newtonian scheme for gravitational back-reaction. Frequency modulations of the modes due to tidal fields, Lorentz forces, and (slow) rotation are also considered to investigate the maximal strain achievable by resonantly excited g modes. Depending on the equation of state, degree of stratification, and stellar magnetic field, we find that certain g-mode excitations may be able to break the crust some seconds prior to coalescence.
On the detection of free-floating planets through microlensing towards the Magellanic Clouds
Authors: Sajadian Sedighe
Published: July 2021

In this work, we study detecting free-floating planets (FFPs) by microlensing observations towards the Magellanic Clouds (MCs). In comparison to similar events towards the Galactic bulge, an FFP in the Galactic halo produces on average longer microlensing events with smaller projected source radii towards these clouds. For these microlensing events, the relative lens-source velocities are on average smaller. The MC self-lensing events due to FFPs suffer from severe finite-source effects. We first simulate microlensing events due to FFPs towards MCs and assume a log-uniform step function for their mass. The efficiencies for capturing their lensing signatures (with signal-to-noise greater than 50) are found to be 0.1–0.6 per cent and 3–6 per cent through ground-based optical surveys and space-based near-infrared surveys, respectively. We then promote these simulations and assume the Roman telescope continuously observes each MC during one 72-d season with the 15 min observing cadence. From simulated microlensing events with the resolvable source stars at the baseline due to FFPs with the masses ∼0.01–104M⊕, Roman discovers their lensing effects with the efficiencies $\sim 10\!-\!80{{\ \rm per\ cent}}$, respectively. By adopting $5{{\ \rm per\ cent}}$ as haloes fraction from FFPs, we estimate the expected number of events. The highest number of detectable FFPs which is ∼1700–2200 per season per square degree happens for ones with masses ∼0.01M⊕. Our simulations show that Roman potentially extends the mass range of detectable FFPs in haloes down to 5.9 × 10−7M⊕ with continuous observations during one observing season from the Large Magellanic Cloud.
Follow-up genotoxicity assessment of Ames-positive/equivocal chemicals using the improved thymidine kinase gene mutation assay in DNA repair-deficient human TK6 cells
Authors: Sassa Akira , Fukuda Takayuki , Ukai Akiko , Nakamura Maki , Sato Ryosuke , Fujiwara Sho , Hirota Kouji , Takeda Shunichi , Sugiyama Kei-ichi , Honma Masamitsu , Yasui Manabu
Published: July 2021

Genotoxicity testing plays an important role in the safety assessment of pharmaceuticals, pesticides and chemical substances. Among the guidelines for various genotoxicity tests, the in vitro genotoxicity test battery comprises the bacterial Ames test and mammalian cell assays. Several chemicals exhibit conflicting results for the bacterial Ames test and mammalian cell genotoxicity studies, which may stem from the differences in DNA repair capacity or metabolism, between different cell types or species. For better understanding the mechanistic implications regarding conflict outcomes between different assay systems, it is necessary to develop in vitro genotoxicity testing approaches with higher specificity towards DNA-damaging reagents. We have recently established an improved thymidine kinase (TK) gene mutation assay (TK assay) i.e. deficient in DNA excision repair system using human lymphoblastoid TK6 cells lacking XRCC1 and XPA (XRCC1−/−/XPA−/−), the core factors of base excision repair (BER) and nucleotide excision repair (NER), respectively. This DNA repair-deficient TK6 cell line is expected to specifically evaluate the genotoxic potential of chemical substances based on the DNA damage. We focussed on four reagents, N-(1-naphthyl)ethylenediamine dihydrochloride (NEDA), p-phenylenediamine (PPD), auramine and malachite green (MG) as the Ames test-positive chemicals. In our assay, assessment using XRCC1−/−/XPA−/− cells revealed no statistically significant increase in the mutant frequencies after treatment with NEDA, PPD and MG, suggesting the chemicals to be non-genotoxic in humans. The observations were consistent with that of the follow-up in vivo studies. In contrast, the mutant frequency was markedly increased in XRCC1−/−/XPA−/− cells after treatment with auramine. The results suggest that auramine is the genotoxic reagent that preferentially induces DNA damages resolved by BER and/or NER in mammals. Taken together, BER/NER-deficient cell-based genotoxicity testing will contribute to elucidate the mechanism of genotoxicity and therefore play a pivotal role in the accurate safety assessment of chemical substances.
Acidosis and alkali therapy in patients with kidney transplant is associated with transcriptional changes and altered abundance of genes involved in cell metabolism and acid–base balance
Authors: Imenez Silva Pedro H , Wiegand Anna , Daryadel Arezoo , Russo Giancarlo , Ritter Alexander , Gaspert Ariana , Wüthrich Rudolf P , Wagner Carsten A , Mohebbi Nilufar
Published: July 2021

Background

Metabolic acidosis occurs frequently in patients with kidney transplant and is associated with a higher risk for and accelerated loss of graft function. To date, it is not known whether alkali therapy in these patients improves kidney function and whether acidosis and its therapy are associated with altered expression of proteins involved in renal acid–base metabolism.

Methods

We retrospectively collected kidney biopsies from 22 patients. Of these patients, nine had no acidosis, nine had metabolic acidosis [plasma bicarbonate (HCO3− <22 mmol/L) and four had acidosis and received alkali therapy. We performed transcriptome analysis and immunohistochemistry for proteins involved in renal acid–base handling.

Results

We found that the expression of 40 transcripts significantly changed between kidneys from non-acidotic and acidotic patients. These genes are mostly involved in proximal tubule (PT) amino acid and lipid metabolism and energy homoeostasis. Three transcripts were fully recovered by alkali therapy: the Kir4.2 potassium channel, an important regulator of PT HCO3− metabolism and transport, acyl-CoA dehydrogenase short/branched chain and serine hydroxymethyltransferase 1, genes involved in beta oxidation and methionine metabolism. Immunohistochemistry showed reduced staining for the PT NBCe1 HCO3− transporter in kidneys from acidotic patients who recovered with alkali therapy. In addition, the HCO3− exchanger pendrin was affected by acidosis and alkali therapy.

Conclusions

Metabolic acidosis in kidney transplant recipients is associated with alterations in the renal transcriptome that are partly restored by alkali therapy. Acid–base transport proteins mostly from PT were also affected by acidosis and alkali therapy, suggesting that the downregulation of critical players contributes to metabolic acidosis in these patients.
Protease inhibitor plasma concentrations associate with COVID-19 infection
Authors: Medjeral-Thomas Nicholas R , Troldborg Anne , Hansen Annette G , Pihl Rasmus , Clarke Candice L , Peters James E , Thomas David C , Willicombe Michelle , Palarasah Yaseelan , Botto Marina , Pickering Matthew C , Thiel Steffen
Published: July 2021

Protease inhibitors influence a range of innate immunity and inflammatory pathways. We quantified plasma concentrations of key anti-inflammatory protease inhibitors in chronic haemodialysis patients with coronavirus disease 2019 (COVID-19). The samples were collected early in the disease course to determine whether plasma protease inhibitor levels associated with the presence and severity of COVID-19. We used antibody-based immunoassays to measure plasma concentrations of C1 esterase inhibitor, alpha2-macroglobulin, antithrombin and inter-alpha-inhibitor heavy chain 4 (ITIH4) in 100 serial samples from 27 haemodialysis patients with COVID-19. ITIH4 was tested in two assays, one measuring intact ITIH4 and another also detecting any fragmented ITIH4 (total ITIH4). Control cohorts were 32 haemodialysis patients without COVID-19 and 32 healthy controls. We compared protease inhibitor concentration based on current and future COVID-19 severity and with C-reactive protein. Results were adjusted for repeated measures and multiple comparisons. Analysis of all available samples demonstrated lower plasma C1 esterase inhibitor and α2M and higher total ITIH4 in COVID-19 compared with dialysis controls. These differences were also seen in the first sample collected after COVID-19 diagnosis, a median of 4 days from diagnostic swab. Plasma ITIH4 levels were higher in severe than the non-severe COVID-19. Serum C-reactive protein correlated positively with plasma levels of antithrombin, intact ITIH4 and total ITIH4. In conclusion, plasma protease inhibitor concentrations are altered in COVID-19.
Can we predict if patients with SLE will require more than one cycle of rituximab?
Authors: Fernández González Raquel , Abida Rym , Gisca Eugeniu , Duarte Leila , Isenberg David A
Published: July 2021

Objective

To identify clinical and serological features that distinguish patients with SLE who require single as opposed to repeated rituximab (RTX) cycles.

Methods

All 175 SLE patients followed up at University College Hospital from 2000 onwards were retrospectively reviewed. They were divided into a one-RTX-cycle group and a multiple-cycle group (2 or more cycles). Patients included had a follow-up of at least 3 years after their first RTX cycle, unless they needed a second infusion sooner.

Results

A total of 131 patients were included; 44 (33.6%) received one cycle of RTX and 87 (66.4%) received two or more. The former were older at diagnosis (31.4 vs 21 years, P < 0.001) and at first RTX infusion (39.9 vs 29 years, P < 0.001). This group of patients had more organs/systems involved (P = 0.044), more leukopenia, lymphopenia and thrombocytopenia (P = 0.001, P < 0.0001 and P = 0.003, respectively) and lower C3 levels (P = 0.035). They also had fewer immunosuppressive drugs before RTX therapy compared with those who required multiple RTX cycles (P = 0.003). There was no statistical difference in either the clinical or serological response after the first RTX cycle between both groups. Furthermore, patients who had received more immunosuppressive treatments were more likely to require more than one cycle of RTX infusions (P = 0.007).

Conclusions

RTX is an effective option for SLE patients with severe flares. Patients who received more immunosuppressive drugs were more likely to receive more than one set of RTX infusions. This suggests that RTX is best used for SLE patients with no history of refractory disease.
QRISK3 relation to carotid plaque is higer than that of score in patients with systemic lupus erythematosus
Authors: Quevedo-Abeledo Juan Carlos , Caceres Laura , Palazuelos Camilo , Llorca Javier , González-Gay Miguel Á , Ferraz-Amaro Iván
Published: July 2021

Introduction

SLE has been described as an independent risk factor for the development of cardiovascular (CV) disease. Recently, the QRESEARCH risk estimator version 3 (QRISK3) calculator has been launched for CV risk assessment in the general population. QRISK3 now includes the presence of SLE as one of its variables for calculating CV risk. Our objective was to compare the predictive capacity between QRISK3 and the Systematic Coronary Risk Evaluation (SCORE) for the presence of subclinical carotid atherosclerosis in patients with SLE.

Methods

Two hundred and ninety-six patients with SLE were recruited. The presence of subclinical atherosclerosis was evaluated by carotid ultrasound to identify carotid plaque and the thickness of the carotid intima–media (cIMT). QRISK3 and SCORE were calculated. The relationship of QRISK3 and SCORE with each other and with the presence of subclinical carotid atherosclerosis (both carotid plaque and cIMT) was studied.

Results

There was no correlation between SCORE and QRISK3 in patients with SLE (Spearman’s rho = −0.008, P = 0.90). Although QRISK3 showed a statistically significant correlation with cIMT (Spearman’s rho = 0.420, P = 0.000), this relationship was not found between SCORE and cIMT (Spearman’s rho = −0.005, P = 0.93). The discrimination capacity of QRISK3 for the presence of carotid plaque was statistically significant and superior to that of SCORE (AUC 0.765 [95% CI: 0.711, 0.820] vs 0.561 [95% CI: 0.494, 0.629], P = 0.000).

Conclusion

QRISK3 discrimination for subclinical atherosclerosis is higher than that of SCORE. QRISK3, and not SCORE, should be used for the calculation of CV risk in patients with SLE.
Interactive Effects of Soybean Cyst Nematode, Arbuscular-Mycorrhizal Fungi, and Soil pH on Chlorophyll Content and Plant Growth of Soybean
Authors: Sun Manhong , Chen Senyu , Kurle James E.
Published: July 2021

Nutritional deficiency chlorosis, especially iron-deficiency chlorosis, and the soybean cyst nematode (SCN) limit soybean yield. Arbuscular mycorrhizal fungi (MF) generally have beneficial effects on plant growth. The interactive effects of SCN, MF, and soil pH on leaf chlorophyll content (LCC) and growth of soybean were examined in a greenhouse experiment. The experiment was a randomized complete block design with three factors: SCN population densities, MF inoculation, and soil pH levels. SCN reduced LCC, and the effect increased with increasing time during 5 to 9 weeks after planting, especially in the high-pH (pH 8) soil. MF increased LCC in low-pH (pH 5.6) soil regardless of SCN population density and in the high-pH soil without SCN. However, MF reduced LCC if both pH and SCN population density were high. The high-SCN population density (inoculation with 10,000 eggs per 100 cm3 of soil) reduced soybean shoot weight in all soils regardless of MF. MF increased shoot weight at pH 6.9 and pH 8 but not at pH 5.6. When MF was present, shoot weight was generally highest at pH 6.9. At high SCN when MF was absent, plant growth was better in pH 5.6 than pH 6.9 and pH 8 soils. This study demonstrates that SCN causes greater damage to soybean when interacting with high pH, and MF had a beneficial effect on soybean growth regardless of SCN infection in all pH soils, in spite of the negative effect of MF on LCC at approximately 5 to 9 weeks after planting in high-pH soil at high SCN population density.
Pangenomic Analysis of Dickeya dianthicola Strains Related to the Outbreak of Blackleg and Soft Rot of Potato in the United States
Authors: Ge Tongling , Jiang He , Tan Ek Han , Johnson Steven B. , Larkin Robert P. , Charkowski Amy O. , Secor Gary , Hao Jianjun
Published: July 2021

Dickeya dianthicola has caused an outbreak of blackleg and soft rot of potato in the eastern half of the United States since 2015. To investigate genetic diversity of the pathogen, a comparative analysis was conducted on genomes of D. dianthicola strains. Whole genomes of 16 strains from the United States outbreak were assembled and compared with 16 previously sequenced genomes of D. dianthicola isolated from potato or carnation. Among the 32 strains, eight distinct clades were distinguished based on phylogenomic analysis. The outbreak strains were grouped into three clades, with the majority of the strains in clade I. Clade I strains were unique and homogeneous, suggesting a recent incursion of this strain into potato production from alternative hosts or environmental sources. The pangenome of the 32 strains contained 6,693 genes, 3,377 of which were core genes. By screening primary protein subunits associated with virulence from all U.S. strains, we found that many virulence-related gene clusters, such as plant cell wall degrading enzyme genes, flagellar and chemotaxis related genes, two-component regulatory genes, and type I/II/III secretion system genes, were highly conserved but that type IV and type VI secretion system genes varied. The clade I strains encoded two clusters of type IV secretion systems, whereas the clade II and III strains encoded only one cluster. Clade I and II strains encoded one more VgrG/PAAR spike protein than did clade III. Thus, we predicted that the presence of additional virulence-related genes may have enabled the unique clade I strain to become predominant in the U.S. outbreak.
Biallelic Editing of the LOB1 Promoter via CRISPR/Cas9 Creates Canker-Resistant ‘Duncan’ Grapefruit
Authors: Jia Hongge , Omar Ahmad A. , Orbović Vladimir , Wang Nian
Published: July 2021

Citrus canker caused by Xanthomonas citri subsp. citri is one of the most devastating citrus diseases worldwide. Generating disease-resistant citrus varieties is considered one of the most efficient and environmentally friendly measures for controlling canker. X. citri subsp. citri causes canker symptoms by inducing the expression of canker susceptibility gene LOB1 via PthA4, a transcription activator-like (TAL) effector, by binding to the effector binding element (EBE) in the promoter region. In previous studies, canker-resistant plants were generated by mutating the coding region or the EBE of LOB1. However, homozygous or biallelic canker-resistant plants have not been generated for commercial citrus varieties, such as grapefruit (Citrus paradisi), which usually contain two alleles of LOB1 and thus, have two types of LOB1 promoter sequences: TI LOBP and TII LOBP. Two different sgRNAs were used to target both EBE types. Both 35S promoter and Yao promoter were used to drive the expression of SpCas9p to modify EBEPthA4-LOBP in grapefruit. Using ‘Duncan’ grapefruit epicotyls as explants, 19 genome-edited grapefruit plants were generated with one biallelic mutant line (#DunYao7). X. citri subsp. citri caused canker symptoms on wild-type and nonbiallelic mutant plants but not on #DunYao7. XccPthA4 mutant containing the designer TAL effector dLOB1.5, which recognizes a conserved sequence in both wild-type and #DunYao7, caused canker symptoms on both wild-type and #DunYao7. No off-target mutations were detected in #DunYao7. This study represents the first time that CRISPR-mediated genome editing has been successfully used to generate disease-resistant plants for ‘Duncan’ grapefruit, paving the way for using disease-resistant varieties to control canker.
Plasmodiophora brassicae CBM18 Proteins Bind Chitin and Suppress Chitin-Triggered Immunity
Authors: Muirhead Kevin , Pérez-López Edel
Published: July 2021

Plants have a sophisticated and multilayered immune system. However, plant pathogens, helped by effector proteins, have found several strategies to evade plant immunity. For instance, the clubroot pathogen Plasmodiophora brassicae is able to turn the roots of susceptible hosts into nutrient-sink galls suppressing pattern-triggered immunity (PTI) and effector-triggered immunity. Chitin, the main component of P. brassicae spore cell walls and a well-known pathogen-associated molecular pattern, can elicit PTI but is also the target of plant chitinases and chitin deacetylases. The fact that P. brassicae does not trigger PTI during infection of susceptible hosts motivated a genome-wide search of genes coding for secreted proteins with domains previously associated with chitin binding. We found that the P. brassicae genome encodes a repertoire of candidate-secreted effectors containing the chitin-binding domain carbohydrate-binding module family 18 (CBM18), chitinase, and chitin deacetylase domains. The role of these proteins in the pathogenicity of the clubroot pathogen is unknown. Here, we characterized two CBM18 proteins, PbChiB2 and PbChiB4, which are transcriptionally activated during infection. Through coprecipitation, we found that recombinant PbChiB2 and PbChiB4 bind to spores and to chitin oligomers. We also showed that both proteins suppress chitin-triggered activation of the map kinase proteins MPK3 and MPK6 in the host Brassica napus. These findings suggest that P. brassicae CBM18 proteins act as effectors for protecting the clubroot pathogen and for suppressing chitin-triggered immunity during infection.

[Formula: see text] Copyright © 2022 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .
Real-time RT-PCR Allelic Discrimination Assay for Detection of N501Y Mutation in the Spike Protein of SARS-CoV-2 Associated with Variants of Concern
Authors: Abdulnoor Mariana , Eshaghi AliReza , Perusini Stephen J. , Corbeil Antoine , Cronin Kirby , Fittipaldi Nahuel , Forbes Jessica D. , Guthrie Jennifer L. , Kus Julianne V. , Majury Anna , Mazzulli Tony , Melano Roberto G. , Olsha Romy , Sullivan Ashleigh , Tran Vanessa , Patel Samir N. , Allen Vanessa G. , Gubbay Jonathan B.
Published: July 2021

The N501Y amino acid mutation caused by a single point substitution A23063T in the spike gene of SARS-CoV2 is possessed by the three most common variants of concern - B.1.1.7, B.1.351, and P.1. A rapid screening tool using this mutation is important for surveillance during the COVID-19 pandemic.

We developed and validated a single nucleotide polymorphism real-time reverse transcription polymerase chain reaction assay using allelic discrimination of the spike gene N501Ymutation to screen for potential variants of concern and differentiate them from wild-type SARS-CoV-2. A total of 160 clinical specimens positive for SARS-CoV-2 were characterized as mutant (N501Y) or wild-type by Sanger sequencing and were subsequently tested with the N501Y single nucleotide polymorphism real time reverse transcriptase polymerase chain reaction assay. Our assay compared to sequencing, the gold standard for SNP detection and lineage identification, demonstrated clinical sensitivity of 100% for all 57 specimens displaying N501Y mutant, which were confirmed by Sanger sequencing to be typed as A23063T, including one specimen with mixed signal for wildtype and mutant. Clinical specificity was 100% in all 103 specimens typed as wild-type, with A23063 identified as wild-type by Sanger sequencing. The identification of circulating SARS-CoV-2 lineages carrying an N501Y mutation is critical for surveillance purposes. Current identification methods rely primarily on Sanger sequencing or whole genome sequencing which are time-consuming, labor-intensive and costly. The assay described herein is an efficient tool for high-volume specimen screening for SARS-CoV-2 VOCs and for selecting specimens for confirmatory Sanger or whole genome sequencing.
Heterogeneity of hypoxemia severity according to oxygenation index in COVID-19 pneumonia
Authors: Núñez Isaac , Soto-Mota Adrian
Published: July 2021

Objective

To compare hypoxemia severity of patients with COVID-19 pneumonia that arrive at an emergency department as classified by three oxygenation indexes.

Design

Retrospective analysis of pulse oximeter saturation and arterial blood gas analysis obtained at arrival.

Setting

Tertiary referral hospital in Mexico City converted early in the pandemic to a COVID-19 center.

Patients and measurements

A total of 2,960 patients with suspected COVID-19 pneumonia were admitted to the emergency department from April 2020 until March 2021. Pulse oximeter saturation and arterial blood gas analysis was obtained in all of them. Pulse oximeter saturation (SpO2) to inspired oxygen fraction ratio (FiO2), oxygen saturation in arterial blood (SatO2) to FiO2 ratio, and oxygen pressure in arterial blood to FiO2 ratio were calculated for every patient.

Interventions

None.

Main Results

A strong correlation was seen between PaO2/FiO2 & SpO2/FiO2 (rho = 0.6, p < 0.001), and SatO2/FiO2 & SpO2/FiO2 (rho = 0.65, p < 0.001), while a very strong correlation was seen between PaO2/FiO2 & SatO2/FiO2 (rho = 0.88, p < 0.001). When classifying severity by quantiles, considerable cross-over was observed when comparing oxygenation indexes, as only 785 (26.5%) patients were in the same quintile across the three indexes.

Conclusions

Hypoxemia severity is heterogeneous according to the oxygenation index utilized. This limits their usefulness as sole markers of severity, as inter-observer variability, especially on FiO2 estimation, and different practices limit consistent follow up and treatment decisions.
Change in disease dynamics and health care utilisation in children during COVID 19 in a tertiary care hospital of Eastern India
Authors: Sahoo Bandya , Kanyari S Suneeti , Pradhan Deepti Damayanty , Patnaik Sibabratta , Behera Manas Ranjan
Published: July 2021

This retrospective, observational study was conducted by collecting data from medical records during COVID 19 pandemic from March 2020 till August 2020. This was compared with the data of 2019 during similar months. The impact of COVID 19 on use of preventive and curative paediatric health care service units like outpatient department, casualty, intensive care and immunization clinic were assessed. Data from 2019 to 2020 were compared using standard parametric and nonparametric tests. There was a significant decline in routine OPD (68%) attendance during the COVID 19 period as compared to pre-COVID period. Paediatric ward admissions and PICU admissions were decreased by 55% and 42% respectively. We also observed a significant 43% decline in the number of children attending immunization clinic in the year 2020. The fear of COVID 19 pandemic and the measures taken to control the pandemic has affected the health seeking behaviour of patients. This evaluation of trends in healthcare use may help in planning the delivery of healthcare service delivery in future.