bluuebunny/crossref_metadata_2025 huggingface dataset:
Ocular Anatomical and Functional Characteristics in Anisometropic Chinese Children
Authors: Zhong Yuanyuan , Zeng Li , Chen Zhi , Yang Jianlong , Liu Jiang
Published: May 2021

SIGNIFICANCE

This research found that anterior and posterior biometrics differ in many aspects between fellow eyes of anisometropic children. This might shed light on the mechanisms underlying the onset and progression of anisometropia and myopia.

PURPOSE

This study aimed to investigate the ocular biometric parameters, peripheral refraction, and accommodative lag of fellow eyes in anisometropic children.

METHODS

Anisometropic children were recruited. Axial length (AL), vitreous chamber depth (VCD), central corneal thickness, anterior chamber depth (ACD), lens thickness (LT), simulated K readings, central and peripheral refractive errors, and accommodative lag were measured in both eyes. The subfoveal choroidal thickness, average choroidal thickness, and choroid vessel density of the 6 × 6-mm macular area were measured by optical coherence tomography.

RESULTS

Thirty-two children aged 11.1 ± 1.7 years were enrolled. The average degree of anisometropia was 2.49 ± 0.88 D. The AL, VCD, ACD, and simulated K reading values were significantly larger in the more myopic eyes, whereas the LT value was significantly smaller. Subfoveal choroidal thickness (P = .001) and average choroidal thickness (P = .02) were smaller in the more myopic eyes than in the contralateral eyes, whereas choroid vessel density (P = .03) was larger. The amount of anisometropia had a significant positive correlation with the difference in AL (r = 0.869, P < .001), VCD (r = 0.853, P < .001), and ACD (r = 0.591, P < .001) and a negative correlation with the difference in LT (r = −0.457, P = .009).

CONCLUSIONS

Ocular biometrics differ in many aspects between the fellow eyes of anisometropic Chinese children, and the difference is correlated with the degree of anisometropia.
Nutritional Factors and Myopia: An Analysis of National Health and Nutrition Examination Survey Data
Authors: Harb Elise N. , Wildsoet Christine F.
Published: May 2021

SIGNIFICANCE

The rise in the prevalence of myopia, a significant worldwide public health concern, has been too rapid to be explained by genetic factors alone and thus suggests environmental influences.

PURPOSE

Relatively little attention has been paid to the possible role of nutrition in myopia. The availability of the large National Health and Nutrition Examination Survey data set, which includes results from vision examinations, offers the opportunity to investigate the relationship between several nutrition-related factors, including body metrics, and the presence and magnitude of myopia.

METHODS

Cross-sectional survey data sets with vision examination, demographic, body metrics, and nutritional data, collected as part of the National Health and Nutrition Examination Survey over the years of 2003 to 2008, were extracted for analysis. Based on already published basic and epidemiological studies, the following parameters were selected for study: body height and body mass index, demographics, serum vitamin D and glucose/insulin levels, and caffeine intake, using multivariable models and objectively measured refractive errors as the main outcome measure.

RESULTS

Data from a total of 6855 ethnically diverse Americans aged 12 to 25 years were analyzed. In final multivariate models, female sex and age were the most significant factors related to myopia status and refractive error. In general, neither body metrics (body mass index) nor nutritional factors (serum vitamin D, glucose levels, and caffeine intake) were found to be associated with refractive error or myopia status; however, increased insulin levels were related to increased odds of having myopia.

CONCLUSIONS

These largely negative findings suggest that other environmental factors, such as those related to the visual environment, may contribute more to the development and/or progression of myopia and would argue for continued research in these areas in support of more evidence-based myopia clinical management.
The Profunda Artery Perforator Flap: A Versatile Option for Head and Neck Reconstruction
Authors: Largo Rene D. , Bhadkamkar Mohin A. , Asaad Malke , Chu Carrie K. , Garvey Patrick B. , Butler Charles E. , Yu Peirong , Hanasono Matthew M. , Chang Edward I.
Published: May 2021

Background:

Although the profunda artery perforator flap has gained popularity in breast reconstruction, it has not been well described for reconstruction of head and neck defects. The authors report their experience with free profunda artery perforator flaps in postoncologic head and neck reconstruction.

Methods:

A retrospective review of all free profunda artery perforator flaps used for head and neck reconstruction from 2016 to 2019 was performed.

Results:

Overall, 61 profunda artery perforator flap reconstructions were performed: 45 single independent flaps, 12 in conjunction with a second free flap, and four in combination with two other free flaps. The profunda artery perforator flaps were most commonly used for reconstruction of the tongue (n = 19), cheek (n = 11), parotid (n = 10), and maxilla (n = 6). The profunda artery perforator flaps averaged 7.1 × 12.1 × 1.9 cm, with a mean pedicle length of 11.5 cm. The A, B, and C perforators were located at mean distances of 7.4 cm (range, 4 to 11.5 cm), 11.7 cm (range, 8 to 18 cm), and 16.1 cm (range, 14 to 20.5 cm) from the pubic tubercle along the axis of the adductor longus muscle and 7.9 cm (range, 7 to 11cm), 7.6 cm (range, 7 to 15.5 cm), and 7.2 cm (range, 6 to 16 cm) posterior and perpendicular to the axis. There were three partial flap losses. Eight patients (13 percent) had recipient-site complications necessitating operative intervention: four for vascular compromise of the profunda artery perforator flap, two for hematoma evacuation, and two for infection. Donor-site complications were noted in seven patients (11 percent), two of whom required operative intervention.

Conclusions:

The profunda artery perforator flap is a versatile and reliable flap with consistent anatomy and a low complication rate. The profunda artery perforator flap seems to be a reasonable alternative for reconstruction of head and neck defects.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, IV.
Initiating antiretroviral treatment for newly diagnosed HIV patients in sexual health clinics greatly improves timeliness of viral suppression
Authors: Pathela Preeti , Jamison Kelly , Braunstein Sarah L. , Borges Christine M. , Lazar Rachael , Mikati Tarek , Daskalakis Demetre , Blank Susan
Published: May 2021

Objective:

The ‘JumpstART’ program in New York City (NYC) public Sexual Health Clinics (SHC) provides patients newly diagnosed with human immunodeficiency virus (HIV) with antiretroviral medication (ART) (1-month supply) on day of diagnosis and active linkage to HIV care (LTC). We examined viral suppression (VS) among patients who did and did not receive JumpstART services.

Design:

Retrospective cohort.

Methods:

Among newly diagnosed SHC patients (23 November 2016–30 September 2018) who were matched to the NYC HIV surveillance registry to obtain HIV laboratory test results through 30 June 2019, we compared 230 JumpstART and 73 non-JumpstART patients regarding timely LTC (≤30 days), probability of VS (viral load < 200 copies/ml) by 3 months post-diagnosis, and time to and factors associated with achieving VS within the follow-up period.

Results:

Of 303 patients, 76% (230/303) were JumpstART and the remaining were non-JumpstART patients; 36 (11%) had acute HIV infections. LTC ≤30 days was observed for 63% of JumpstART and 73% of non-JumpstART patients. By 3 months post-diagnosis, 83% of JumpstART versus 45% of non-JumpstART patients achieved VS (log-rank, P < .0001). Median times to VS among virally suppressed JumpstART and non-JumpstART patients were 31 (interquartile range [IQR]: 24–51) and 95 days (IQR: 52–153), respectively. For groups with and without timely LTC, JumpstART was associated with viral suppression within 3 months post-diagnosis, after adjusting for age and baseline viral load.

Conclusions:

Prompt ART initiation among SHC patients, some with acute HIV infections, resulted in markedly shortened intervals to VS. Immediate ART provision and active LTC can be key contributors to improved HIV treatment outcomes and the treatment-as-prevention paradigm, with potential for downstream, population-level benefit.
Identification of hepatitis delta superinfection when investigating transaminitis in HIV/hepatitis B virus co-infection
Authors: Hamady Ali , Cooke Graham S. , Garvey Lucy J.
Published: May 2021

Hepatitis delta virus (HDV) is a highly pathogenic virus which can cause rapidly progressive liver disease in individuals with chronic hepatitis B virus and for which treatment options are limited. The incidence of sexually transmitted HDV infection is unknown. Here we report the case of a HDV seronegative man with pre-existent HIV/hepatitis B virus, taking effective tenofovir-containing antiretroviral therapy, who experienced a significant acute transaminitis with HDV antibody seroconversion and viraemia and no other identifiable cause.
Potential reduction in female sex workers’ risk of contracting HIV during coronavirus disease 2019
Authors: Machingura Fortunate , Chabata Sungai T. , Busza Joanna , Jamali Gracious , Makamba Memory , Dirawo Jeffrey , Yekeye Raymond , Mugurungi Owen , Matambanadzo Primrose , Cowan Frances Mary
Published: May 2021

Female sex workers’ livelihoods in Zimbabwe have been severely impacted by the coronavirus disease 2019 pandemic due to closure of entertainment venues. Competition over fewer clients has reduced ability to negotiate condom use. At the same time as partner numbers have decreased, frequency of reported condomless sex has not increased, suggesting potential reduction in overall HIV and sexually transmitted infection risk and an opportunity for programmes to reach sex workers with holistic social and economic support and prevention services.
Everyday Abilities Scale for India in Screening for Poststroke Dementia Among Young Stroke Survivors
Authors: Done Indira P. , Aghoram Rajeswari , Narayan Sunil K.
Published: May 2021

Introduction:

Cognitive dysfunction after stroke is an important concern. We explored the utility of everyday abilities scale for India (EASI) for screening for dementia among young stroke survivors.

Methods:

We interviewed 150 young stroke survivors and caregivers. Vascular dementia was diagnosed according to American Heart Association-American Stroke Association (ASA-AHA) criteria. EASI was administered to all caregivers. Receiver operating characteristic curve analysis was used to determine the area under the curve and optimum cut-points for EASI for the identification of dementia.

Results:

Median EASI scores among subjects with dementia (n=35; 23.3%) was 2 (interquartile range: 0-4) and significantly different from those without (median: 0; interquartile range: 0-1; P<0.001). The area under the curve was 0.768 (95% confidence interval: 0.674-0.863), and at the optimum cut-point of 2 on EASI, a sensitivity of 60% and specificity of 91.3% was achieved for the identification of dementia.

Conclusion:

EASI appears to be a promising tool to screen for dementia among young stroke survivors.
Bone Mineral Density Measurements and Association With Brain Structure and Cognitive Function
Authors: Stefanidou Maria , O’Donnell Adrienne , Himali Jayandra J. , DeCarli Charles , Satizabal Claudia , Beiser Alexa S. , Seshadri Sudha , Zaldy Tan
Published: May 2021

Background:

Bone mineral density (BMD) is a potential surrogate marker of lifetime estrogen exposure previously linked to increased risk of Alzheimer dementia among elderly women. We examine the association between BMD in the “young old” with imaging biomarkers of brain aging and cognitive performance.

Methods:

Offspring participants (N=1905, mean age 66) of a population-based cohort who had BMD, brain imaging and detailed cognitive assessment were included in the study. Sex-stratified, linear, and logistic regression models were used for analysis.

Results:

Higher femoral neck BMD was associated with lower white matter hyperintensity burden and better performance on Trails B-A in both sexes, even after adjustment for cerebrovascular risk factors. Among women, the positive association with Trails B-A performance was seen only in APOE4 allele carriers. Higher BMD measurements were linked to better visual reproductions test performance in men. Finally, among women, higher femoral trochanter BMD was associated with better logical memory and Hooper visual organization test performance.

Conclusion:

Among the “young old,” higher BMD is associated with less white matter hyperintensity burden and better, domain-specific, cognitive performance. This suggests that lifetime estrogen exposure may modulate the degree of cumulative vascular brain injury independent of cerebrovascular risk factors.
Corynebacterium lizhenjunii sp. nov., isolated from the respiratory tract of Marmota himalayana, and Corynebacterium qintianiae sp. nov., isolated from the lung tissue of Pseudois nayaur
Authors: Zhou Juan , Xu Mingchao , Guo Wentao , Yang Jing , Pu Ji , Lai Xin-He , Jin Dong , Lu Shan , Zhang Sihui , Huang Yuyuan , Zhu Wentao , Huang Ying , Zheng Han , Xu Jianguo
Published: May 2021

Four Gram-stain-positive, non-motile and asporous bacilli (strains ZJ-599T, ZJ-621, MC1420T and MC1482), isolated from animal tissue and environmental samples collected on the Qinghai-Tibet Plateau, PR China, were taxonomically characterized. Based on the results of 16S rRNA gene sequence analyses, the closest relatives of strains ZJ-599T and ZJ-621 were

Corynebacterium endometrii

LMM-1653T (97.5 %),

Corynebacterium phocae

M408/89/1T (96.5 %) and

Corynebacterium flavescens

OJ8T (96.3 %), whereas strains MC1420T and MC1482 were closest to

Corynebacterium sanguinis

CCUG 58655T (98.9 %),

Corynebacterium mycetoides

DSM 20632T (98.4 %) and

Corynebacterium lipophiloflavum

DSM 44291T (97.9 %). The results of rpoB gene sequence similarity analysis indicated that

C. phocae

M408/89/1T and

C. sanguinis

CCUG 58655T were closest to strains ZJ-599T/ZJ-621 (83.5 %) and MC1420T/MC1482 (91.8 %), respectively. The two novel type strains shared a similarity of 95.2 % in 16S rRNA and 81.3 % in rpoB gene sequences. The TAP-PCR DNA fingerprint and MALDI-TOF MS spectrum patterns clearly differentiated the novel isolates within and between each pair of strains. Strain ZJ-599T had 21.9–22.4 % digital DNA–DNA hybridization (dDDH) scores with

C. endometrii

LMM-1653T,

C. phocae

M408/89/1T and

C. flavescens

OJ8T, and 72.3–72.9 % of average nucleotide identity (ANI) with them. Similarly, strain MC1420T had 22.9–23.7 % dDDH values with

C. sanguinis

CCUG 58655T,

C. mycetoides

DSM 20632T and

C. lipophiloflavum

DSM 44291T, and 80.4–81.3 % ANI scores with them. Strain ZJ-599T had a 23.1 % dDDH value and 70.5 % ANI score with strain MC1420T, both below the corresponding thresholds for species delineation. Strains ZJ-599T and MC1420T both contain mycolic acids and have MK-8(H2) and MK-9(H2) as the predominant respiratory quinones, meso-diaminopimelic acid as the diagnostic diamino acid, and C18 : 1
 ω9c as the main fatty acid. C17 : 1
 ω8c and C15 : 1
 ω8c were predominant in strain ZJ-599T in contrast to C17 : 1
 ω7c being predominant in strain MC1420T. The main polar lipids in strain ZJ-599T were diphosphatidylglycerol, phosphatidylinositol and one unidentified glycolipid, while strain MC1420T had diphosphatidylglycerol, phosphatidylglycerol and one unidentified lipid as the major components. Since the two pairs of novel strains (ZJ-599T/ZJ-621, MC1420T/MC1482) distinctly differ from each other and from their nearest relatives, two novel species of the genus

Corynebacterium

are proposed, namely Corynebacterium lizhenjunii (type strain ZJ-599T=GDMCC 1.1779T=JCM 34341T) and Corynebacterium qintianiae (type strain MC1420T=GDMCC 1.1783T=JCM 34340T), respectively.
Cerebral venous thrombosis and portal vein thrombosis: a retrospective cohort study of 537,913 COVID-19 cases
Authors: Taquet Maxime , Husain Masud , Geddes John R , Luciano Sierra , Harrison Paul J
Published: May 2021

Objectives

To estimate the absolute risk of cerebral venous thrombosis (CVT) and portal vein thrombosis (PVT) in the two weeks following a diagnosis of COVID-19, and to assess the relative risks (RR) compared to influenza or the administration of an mRNA vaccine against COVID-19.

Design

Retrospective cohort study based on an electronic health records network

Setting

Linked records between primary and secondary care centres within 59 healthcare organisations, primarily in the USA

Participants

All patients with a confirmed diagnosis of COVID-19 between January 20, 2020 and March 25, 2021 were included (N=537,913, mean [SD] age: 46.2 [21.4] years; 54.9% females). Cohorts (matched for age, sex, and race) of participants diagnosed with influenza (N=392,424) or receiving the BNT162b2 or mRNA-1273 vaccine (N=366,869) were used for comparison.

Main outcome measures

Diagnosis of CVT (ICD-10 code I67.6) or PVT (ICD-10 code I81) within 2 weeks after a diagnosis of COVID-19.

Results

The incidence of CVT after COVID-19 diagnosis was 42.8 per million people (95% CI 28.5–64.2) including 35.3 per million (95% CI 22.6–55.2) first diagnoses. This was significantly higher than the CVT incidence in a matched cohort of patients with influenza (RR=3.83, 95% CI 1.56–9.41, P<0.001) and people who received an mRNA vaccine (RR=6.67, 95% CI 1.98–22.43, P<0.001). The incidence of PVT after COVID-19 diagnosis was 392.3 per million people (95% CI 342.8–448.9) including 175.0 per million (95% CI 143.0–214.1) first diagnoses. This was significantly higher than the PVT incidence in a matched cohort of patients with influenza (RR=1.39, 95% CI 1.06–1.83, P=0.02) and people who received an mRNA vaccine (RR=7.40, 95% CI 4.87–11.24, P<0.001). Mortality after CVT and PVT was 17.4% and 19.9% respectively.

Conclusions

The incidence of CVT and PVT is significantly increased after COVID-19. The data highlight the risk of serious thrombotic events in COVID-19 and can help contextualize the risks and benefits of vaccination in this regard.

What is known

‐

A systematic review of cohort studies suggested an incidence of CVT among hospitalised patients with COVID-19 to be about 800 per million patients. There was evidence of selection, ascertainment, and reporting bias in all included studies.

‐

The incidence of CVT and PVT among both hospitalised and non-hospitalised patients with COVID-19 is unknown.

‐

It is unknown if COVID-19 increases the risk of CVT and PVT.

What this study adds

Our study estimates that the absolute risk of CVT and PVT are respectively 42.8 and 392.3 per million patients (both hospitalised and non-hospitalised) in the 2 weeks after a diagnosis of COVID-19. COVID-19 increases the risk of CVT and PVT compared to patients diagnosed with influenza, and to people who have received a COVID-19 mRNA vaccine.
SARS-CoV-2 infection induces autoimmune antibody secretion more in lean than in obese COVID-19 patients
Authors: Frasca Daniela , Reidy Lisa , Romero Maria , Diaz Alain , Cray Carolyn , Kahl Kristin , Blomberg Bonnie B.
Published: May 2021

Background/Objectives

Obesity decreases the secretion of SARS-CoV-2-specific IgG antibodies in the blood of COVID-19 patients. How obesity impacts the secretion of autoimmune antibodies in COVID-19 patients, however, is not understood. The serum of adult COVID-19 patients contains autoimmune antibodies generated in response to virus-induced tissue damage and cell death leading to the release of intracellular antigens not known to be immunogenic autoantigens. The objective of this study is to evaluate the presence of autoimmune antibodies in COVID-19 patients with obesity.

Subjects/Methods

Thirty serum samples from individuals who tested positive for SARS-CoV-2 infection by RT-PCR were collected from inpatient and outpatient settings. Of these, 15 were lean (BMI<25), and 15 were obese (BMI ≥30). Control serum samples were from 30 uninfected individuals, age-gender- and BMI-matched, recruited before the current pandemic. Serum IgG antibodies against two autoimmune specificities, as well as against SARS-CoV-2 Spike protein, were measured by ELISA. IgG autoimmune antibodies were specific for malondialdehyde (MDA), a marker of oxidative stress and lipid peroxidation, and for adipocyte-derived protein antigens (AD), markers of virus-induced cell death in the obese AT.

Results

Our results show that SARS-CoV-2 infection induces anti-MDA and anti-AD autoimmune antibodies more in lean than in obese patients as compared to uninfected controls. Serum levels of these autoimmune antibodies, however, are always higher in obese versus lean COVID-19 patients. Moreover, because the autoimmune antibodies found in serum samples of COVID-19 patients have been correlated with serum levels of C-reactive protein (CRP), a general marker of inflammation, we also evaluated the association of anti-MDA and anti-AT antibodies with serum CRP and found a significant association between CRP and autoimmune antibodies in our cohort of lean and obese COVID-19 patients.

Conclusions

Our results highlight the importance of evaluating the quality of the antibody response in COVID-19 patients with obesity, particularly the presence of autoimmune antibodies, and identify biomarkers of self-tolerance breakdown. This is crucial to protect this vulnerable population that is at higher risk of responding poorly to infection with SARS-CoV-2 compared to lean controls.
Design of the SARS-CoV-2 RBD vaccine antigen improves neutralizing antibody response
Authors: Dickey Thayne H. , Tang Wai Kwan , Butler Brandi , Ouahes Tarik , Orr-Gonzalez Sachy , Salinas Nichole D. , Lambert Lynn E. , Tolia Niraj H.
Published: May 2021

The receptor binding domain (RBD) of the SARS-CoV-2 spike protein is the primary target of neutralizing antibodies and is a component of almost all vaccine candidates. Here, RBD immunogens were created with stabilizing amino acid changes that improve the neutralizing antibody response, as well as characteristics for production, storage, and distribution. A computational design andin vitroscreening platform identified three improved immunogens, each with approximately nine amino acid changes relative to the native RBD sequence and four key changes conserved between immunogens. The changes are adaptable to all vaccine platforms, are compatible with established changes in SARS-CoV-2 vaccines, and are compatible with mutations in emerging variants of concern. The immunogens elicit higher levels of neutralizing antibodies than native RBD, focus the immune response to structured neutralizing epitopes, and have increased production yields and thermostability. Incorporating these variant-independent amino acid changes in next-generation vaccines may enhance the neutralizing antibody response and lead to pan-SARS-CoV-2 protection.
Humoral immunogenicity of the seasonal influenza vaccine before and after CAR-T-cell therapy
Authors: Walti Carla S. , Loes Andrea N. , Shuey Kiel , Krantz Elizabeth M. , Boonyaratanakornkit Jim , Keane-Candib Jacob , Loeffelholz Tillie , Wolf Caitlin R. , Taylor Justin J. , Gardner Rebecca A. , Green Damian J. , Cowan Andrew J. , Maloney David G. , Turtle Cameron J. , Pergam Steven A. , Chu Helen Y. , Bloom Jesse D. , Hill Joshua A.
Published: May 2021

Recipients of chimeric antigen receptor-modified T (CAR-T) cell therapies for B-cell malignancies are immunocompromised and at risk for serious infections. Vaccine immunogenicity is unknown in this population. We conducted a prospective observational study of the humoral immunogenicity of 2019-2020 inactivated influenza vaccines (IIV) in children and adults immediately prior to (n=7) or 13-57 months after (n=15) CD19-, CD20-, or BCMA-targeted CAR-T-cell therapy, as well as controls (n=8). Individuals post-CAR-T-cell therapy were in remission. We tested for antibodies to 4 vaccine strains at baseline and ≥1 time point after IIV using neutralization and hemagglutination inhibition assays. An antibody response was defined as a ≥4-fold titer increase from baseline at the first post-vaccine time point. Baseline A(H1N1) titers in the CAR-T cohorts were significantly lower compared to controls. Antibody responses to ≥1 vaccine strain occurred in 2 (29%) individuals before CAR-T-cell therapy; one individual maintained a response for >3 months post-CAR-T-cell therapy. Antibody responses to ≥1 vaccine strain occurred in 6 (40%) individuals vaccinated after CAR-T-cell therapy. An additional 2 (29%) and 6 (40%) individuals had ≥2-fold increases (at any time) in the pre- and post-CAR-T cohorts, respectively. There were no identified clinical or immunologic predictors of antibody responses. Neither severe hypogammaglobulinemia nor B-cell aplasia precluded antibody responses. These data support consideration for vaccination before and after CAR-T-cell therapy for influenza and other relevant pathogens such as SARS-CoV-2, irrespective of hypogammaglobulinemia or B-cell aplasia. Larger studies are needed to determine correlates of vaccine immunogenicity and durability in CAR-T-cell therapy recipients.

Key Points

Influenza vaccination was immunogenic pre- and post-CAR-T-cell therapy, despite hypogammaglobulinemia and B-cell aplasia.

Vaccination with inactivated vaccines can be considered before CAR-T-cell therapy and in individuals with remission after therapy.
Autoantibody screening in Guillain-Barré Syndrome
Authors: Lleixà Cinta , Martín-Aguilar Lorena , Pascual-Goñi Elba , Franco Teresa , Caballero Marta , Diaz-Manera Jordi , Rojas-García Ricard , de Luna Noemí , Gallardo Eduard , Cortés-Vicente Elena , Turón Joana , Suárez-Calvet Xavier , Casasnovas Carlos , Homedes Christian , Gutiérrez-Gutiérrez Gerardo , Jimeno-Montero María Concepción , Berciano José , Sedano Tous Maria José , Garcia-Sobrino Tania , Pardo-Fernandez Julio , Márquez-Infante Celedonio , Rojas-Marcos Iñigo , Jericó-Pascual Ivonne , Martínez-Hernández Eugenia , Morís de la Tassa Germán , Domínguez-González Cristina , Martínez-Martínez Laura , Juárez Cándido , Illa Isabel , Querol Luis
Published: May 2021

Abstract

Guillain-Barré Syndrome (GBS) is an acute inflammatory neuropathy with a heterogeneous presentation and pathogenesis. Serum antibodies against various gangliosides can be found in less than half of all patients in the acute phase of GBS but the target antigens remain unknown for the remaining half. Our work describes a comprehensive screening for serum autoantibodies targeting peripheral nerve tissue, cells, and purified antigens in a prospective GBS cohort including 100 patients. Our study confirms that (1) GBS patients display a very heterogeneous repertoire of autoantibodies targeting nerve cells and structures, (2) gangliosides are the most frequent antigens in GBS patients and have prognostic value, (3) a small subset of patients display antibodies targeting the myelin sheath, and (4) further antigen-discovery experiments are needed to elucidate other potential disease-specific autoantibodies in GBS.
Multi-omics characterization of mesenchymal stem/stromal cells for the identification of putative critical quality attributes
Authors: Maughon Ty S. , Shen Xunan , Huang Danning , Michael Adeola O Adebayo , Shockey William A. , Andrews Seth H. , McRae Jon M. , Platt Manu O , Fernández Facundo M. , Edison Arthur S. , Stice Steven L. , Marklein Ross A.
Published: May 2021

Background

Mesenchymal stromal cells (MSCs) have shown great promise in the field of regenerative medicine as many studies have shown that MSCs possess immunomodulatory function. Despite this promise, no MSC therapies have been granted licensure from the FDA. This lack of successful clinical translation is due in part to MSC heterogeneity and a lack of critical quality attributes (CQAs). While MSC Indoleamine 2,3-dioxygnease (IDO) activity has been shown to correlate with MSC function, multiple CQAs may be needed to better predict MSC function.

Methods

Three MSC lines (two bone marrow, one iPSC) were expanded to three passages. At the time of harvest for each passage, cell pellets were collected for nuclear magnetic resonance (NMR) and ultra-performance liquid chromatography mass spectrometry (UPLC-MS), and media was collected for cytokine profiling. Harvested cells were also cryopreserved for assessing function using T cell proliferation and IDO activity assays. Linear regression was performed on functional and multiomics data to reduce the number of important features, and partial least squares regression (PLSR) was used to obtain putative CQAs based on variable importance in projection (VIP) scores.

Results

Significant functional heterogeneity (in terms of T cell suppression and IDO activity) was observed between the three MSC lines, as well as donor-dependent differences based on passage. Omics characterization revealed distinct differences between cell lines using principal component analysis (PCA). Cell lines separated along principal component 1 based on tissue source (bone marrow vs. iPSC-derived) for NMR, MS, and cytokine profiles. PLSR modeling of important features predicts MSC functional capacity with NMR (R2=0.86), MS (R2=0.83), cytokines (R2=0.70), and a combination of all features (R2=0.88).

Discussion

The work described here provides a platform for identifying putative CQAs for predicting MSC functional capacity using PLSR modeling that could be used as release criteria and guide future manufacturing strategies for MSCs and other cell therapies.
Rab35 and glucocorticoids regulate APP and BACE1 trafficking to modulate Aβ production
Authors: Zhuravleva Viktoriya , Vaz-Silva João , Zhu Mei , Gomes Patricia , Silva Joana M. , Sousa Nuno , Sotiropoulos Ioannis , Waites Clarissa L.
Published: May 2021

Chronic stress and elevated glucocorticoids (GCs), the major stress hormones, are risk factors for Alzheimer’s disease (AD) and promote AD pathomechanisms, including overproduction of toxic amyloid-β (Aβ) peptides and intraneuronal accumulation of hyperphosphorylated Tau protein. The latter is linked to downregulation of the small GTPase Rab35, which mediates Tau degradation via the endolysosomal pathway. Whether Rab35 is also involved in Aβ overproduction remains an open question. Here, we find that hippocampal Rab35 levels are decreased not only by stress/GC but also by aging, another AD risk factor. Moreover, Rab35 negatively regulates Aβ production by sorting amyloid precursor protein (APP) and β-secretase (BACE1) out of the endosomal network, where they interact to produce Aβ. Interestingly, Rab35 coordinates distinct intracellular trafficking events for BACE1 and APP, mediated by its effectors OCRL and ACAP2, respectively. Finally, we show that Rab35 overexpression prevents the amyloidogenic trafficking of APP and BACE1 induced by high GC levels. These studies identify Rab35 as a key regulator of APP processing and suggest that its downregulation may contribute to stress- and AD-related amyloidogenesis.
Lifespan prolonging mechanisms and insulin upregulation without fat accumulation in long-lived reproductives of a higher termite
Authors: Séité Sarah , Harrison Mark C. , Sillam-Dussès David , Lupoli Roland , Van Dooren Tom J. M. , Robert Alain , Poissonnier Laure-Anne , Lemainque Arnaud , Renault David , Acket Sébastien , Andrieu Muriel , Viscarra José , Sul Hei Sook , de Beer Z. Wilhelm , Bornberg-Bauer Erich , Vasseur-Cognet Mireille
Published: May 2021

Kings and queens of eusocial termites can live for decades, while queens sustain a nearly maximal fertility. To investigate the molecular mechanisms underlying their long lifespan, we carried out transcriptomics, lipidomics and metabolomics inMacrotermes natalensison sterile short-lived workers, long-lived kings and five stages spanning twenty years of adult queen maturation. Reproductives share gene expression differences from workers in agreement with a reduction of several aging-related processes, involving upregulation of DNA damage repair and mitochondrial functions. Anti-oxidant gene expression is downregulated, while peroxidability of membranes in queens decreases. Against expectations, we observed an upregulated gene expression in fat bodies of reproductives of several components of the IIS pathway, including an insulin-like peptide,Ilp9.This pattern does not lead to deleterious fat storage in physogastric queens, while simple sugars dominate in their hemolymph and large amounts of resources are allocated towards oogenesis. Our findings support the notion that all processes causing aging need to be addressed simultaneously in order to prevent it.
Noise-Transfer2Clean: Denoising cryo-EM images based on noise modeling and transfer
Authors: Li Hongjia , Zhang Hui , Wan Xiaohua , Yang Zhidong , Li Chengmin , Li Jintao , Han Renmin , Zhu Ping , Zhang Fa
Published: May 2021

Motivation

Cryo-electron microscopy (cryo-EM) is a widely-used technology for ultrastructure determination, which constructs the three-dimensional (3D) structures of protein and macromolecular complex from a set of two-dimensional (2D) micrographs. However, limited by the electron beam dose, the micrographs in cryo-EM generally suffer from extremely low signal-to-noise ratio (SNR), which hampers the efficiency and effectiveness of downstream analysis. Especially, the noise in cryo-EM is not simple additive or multiplicative noise whose statistical characteristics are quite different from the ones in natural image, extremely shackling the performance of conventional denoising methods.

Results

Here, we introduce the Noise-Transfer2Clean (NT2C), a denoising deep neural network (DNN) for cryo-EM to enhance image contrast and restore specimen signal, whose main idea is to improve the denoising performance by correctly discovering the noise model of cryo-EM images and transferring the statistical nature of noise into the denoiser. Especially, to cope with the complex noise model in cryo-EM, we design a contrast-guided noise and signal re-weighted algorithm to achieve clean-noisy data synthesis and data augmentation, making our method authentically achieve signal restoration based on noise’s true properties. To our knowledge, NT2C is the first denoising method that resolves the complex noise model in cryo-EM images. Comprehensive experimental results on simulated datasets and real datasets show that NT2C achieved a notable improvement in image denoising and specimen signal restoration, comparing with the state-of-art methods. A real-world case study shows that NT2C can improve the recognition rate on hard-to-identify particles by 19% in the particle picking task.
Concerns regarding vaccination as a management strategy against koala retrovirus
Authors: Joyce Briony A. , Watterson Daniel , Isaacs Ariel , Chappell Keith J.
Published: May 2021

Koalas are of great cultural, ecological and economic significance to Australia. However, they are in steep decline throughout much of their geographic range, with the recently endogenized koala retrovirus (KoRV) presumed to be a contributing factor. Olagoke, et al. 1 have proposed vaccination against KoRV as a suitable control mechanism to reduce the severity of KoRV infections and suggest that their recombinant vaccine is effective at invoking a neutralising immune response and significantly reducing viral loads. Here, we report the findings of our own attempts to detect antibodies specific to the KoRV envelope protein (Env) in infected animals. Antibodies against Env were undetectable in all animals, as would be expected in the case of an endogenous virus antigen which should proceed towards a pathway of self-tolerance. This finding calls into question the results of Olagoke, et al. 1, and prior work by this team 2,3. Following a critical review of this work 1–3, we have identified a number of assay inaccuracies and possible over interpretations of the data and conclude that further work to develop and test a vaccine against KoRV in koalas is not supported by evidence.
A Keller-Segel model for C elegans L1 aggregation
Authors: Avery Leon , Ingalls Brian , Dumur Catherine , Artyukhin Alexander
Published: May 2021

We describe a mathematical model for the aggregation of starved first-stage C elegans larvae (L1s). We propose that starved L1s produce and respond chemotactically to two labile diffusible chemical signals, a short-range attractant and a longer range repellent. This model takes the mathematical form of three coupled partial differential equations, one that describes the movement of the worms and one for each of the chemical signals. Numerical solution of these equations produced a pattern of aggregates that resembled that of worm aggregates observed in experiments. We also describe the identification of a sensory receptor gene, srh–2, whose expression is induced under conditions that promote L1 aggregation. Worms whose srh–2 gene has been knocked out form irregularly shaped aggregates. Our model suggests this phenotype may be explained by the mutant worms slowing their movement more quickly than the wild type.

Author summary

Among the most complex of animal behaviors are collective behaviors, in which animals interact with each other so as to produce large-scale organization. Starved first-stage larvae of the nematode Caenorhabditis elegans exhibit such a behavior: they come together to form aggregates of several hundred worms. How and why they do this are unknown. To address these questions, we developed a mathematical model of starved L1 aggregation. This model reproduced the main features of the behavior.
Orc6 at replication fork enables efficient mismatch repair
Authors: Lin Yo-Chuen , Chakraborty Arindam , Liu Dazhen , Mitra Jaba , Kadyrova Lyudmila Y , Hsu Rosaline Y.C. , Arif Mariam K. , Adusumilli Sneha , Ha Taekjip , Kadyrov Farid A , Prasanth Kannanganattu V. , Prasanth Supriya G.
Published: May 2021

In eukaryotes, the Origin Recognition Complex (ORC) is required for the initiation of DNA replication. The smallest subunit of ORC, Orc6, is essential for pre-replication complex (pre-RC) assembly and cell viability in yeast and for cytokinesis in metazoans. However, unlike other ORC components, the role of human Orc6 in replication remains to be resolved. Here, we identify an unexpected role for hOrc6, which is to promote S-phase progression post pre-RC assembly and DNA damage response. Orc6 localizes at the replication fork and is an accessory factor of the mismatch repair (MMR) complex. In response to oxidative damage during S-phase, often repaired by MMR, Orc6 facilitates MMR complex assembly and activity, without which the checkpoint signaling is abrogated. Mechanistically, Orc6 directly binds to MutSα and enhances the chromatin-association of MutLα, thus enabling efficient mismatch repair. Based on this, we conclude that hOrc6 plays a fundamental role in genome surveillance during S-phase.

Abstract Figure

Highlights

Human Orc6 is dispensable for G1 licensing, but required for S-phase progression

Human Orc6 at the replication fork is an accessory factor for MMR complex

Depletion of hOrc6 sensitizes cells to DNA damage and impairs ATR activation

Human Orc6 regulates MMR complex assembly and activity
Topography of corticopontine projections is controlled by postmitotic expression of the area-mapping gene Nr2f1
Authors: Tocco Chiara , Øvsthus Martin , Bjaalie Jan G. , Leergaard Trygve B. , Studer Michèle
Published: May 2021

Axonal projections from layer V neurons of distinct neocortical areas are topographically organized into discrete clusters within the pontine nuclei during the establishment of voluntary movements. However, the molecular determinants controlling corticopontine connectivity are insufficiently understood. Here, we show that an intrinsic cortical genetic program driven by Nr2f1 graded expression is directly implicated in the organization of corticopontine topographic mapping. Transgenic mice lacking cortical expression of Nr2f1 and exhibiting areal organization defects were used as model systems to investigate the arrangement of corticopontine projections. Combining three-dimensional digital brain atlas tools, Cre-dependent mouse lines, and axonal tracing, we show that Nr2f1 expression in postmitotic neurons spatially and temporally controls somatosensory topographic projections, whereas expression in progenitor cells influences the ratio between corticopontine and corticospinal fibres passing the pontine nuclei. We conclude that cortical gradients of area patterning genes are directly implicated in the establishment of a topographic somatotopic mapping from the cortex onto pontine nuclei.

Summary statement

Cortical gradient expression of the area patterning gene Nr2f1 spatially and temporally controls corticopontine topographic connectivity in layer V projection neurons.
Improved protein contact prediction using dimensional hybrid residual networks and singularity enhanced loss function
Authors: Si Yunda , Yan Chengfei
Published: May 2021

Deep residual learning has shown great success in protein contact prediction. In this study, a new deep residual learning-based protein contact prediction model was developed. Comparing with previous models, a new type of residual block hybridizing 1D and 2D convolutions was designed to increase the effective receptive field of the residual network, and a new loss function emphasizing the easily misclassified residue pairs was proposed to enhance the model training. The developed protein contact prediction model referred to as DRN-1D2D was first evaluated on 105 CASP11 targets, 76 CAMEO hard targets and 398 membrane proteins together with two in house-developed reference models based on either the standard 2D residual block or the traditional BCE loss function, from which we confirmed that both the dimensional hybrid residual block and the singularity enhanced loss function can be employed to improve the model performance for protein contact prediction. DRN-1D2D was further evaluated on 39 CASP13 and CASP14 free modeling targets together with the two reference models and six state-of-the-art protein contact prediction models including DeepCov, DeepCon, DeepConPred2, SPOT-Contact, RaptorX-Contact and TripleRes. The result shows that DRN-1D2D consistently achieved the best performance among all these models.
Rapid inactivation of SARS-CoV-2 variants by continuous and intermittent irradiation with a deep-ultraviolet light-emitting diode (DUV-LED) device
Authors: Inagaki Hiroko , Saito Akatsuki , Kaneko Chiho , Sugiyama Hironobu , Okabayashi Tamaki , Fujimoto Shouichi
Published: May 2021

More than 1 year has passed since social activities have been restricted due to the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). More recently, novel SARS-CoV-2 variants have been spreading around the world, and there is growing concern of higher transmissibility of the variants and weaker protective efficacy of vaccine against the variants. Immediate measures are needed to reduce human exposure to the virus. In this study, the antiviral efficacy of deep-ultraviolet light-emitting diode (DUV-LED) irradiation (280 ± 5 nm, 3.75 mW/cm2) against three SARS-CoV-2 variants was evaluated. For the B.1.1.7, B.1.351, and P.1 strains, the infectious titer reduction rates of 96.3%, 94.6%, and 91.9%, respectively, were already recognized with the irradiation of virus stocks for 1 s, and the rates increased to 99.9%, 99.9%, and 99.8%, respectively, with irradiation for 5 s. We also tested the effect of pulsed DUV-LED irradiation (7.5 mW/cm2, duty rate: 50%, frequency: 1 KHz) under the same output conditions as continuous irradiation, and found that the antiviral efficacy of pulsed and continuous irradiation was the same. These findings suggest that SARS-CoV-2 may be instantly inactivated by DUV-LED irradiation if the DUV-LED device is further developed and optimized to increase its output.
Increased abundance of Cbl E3 ligases alters PDGFR signaling in recessive dystrophic epidermolysis bullosa
Authors: Martínez-Martínez Esther , Tölle Regine , Donauer Julia , Gretzmeier Christine , Bruckner-Tuderman Leena , Dengjel Jörn
Published: May 2021

In recessive dystrophic epidermolysis bullosa (RDEB), loss of collagen VII, the main component of anchoring fibrils critical for epidermal-dermal cohesion, affects several intracellular signaling pathways and leads to impaired wound healing and fibrosis. In skin fibroblasts, wound healing is also affected by platelet-derived growth factor receptor (PDGFR) signaling. To study a potential effect of loss of collagen VII on PDGFR signaling we performed unbiased disease phosphoproteomics. Whereas RDEB fibroblasts exhibited an overall weaker response to PDGF, Cbl E3 ubiquitin ligases, negative regulators of growth factor signaling, were stronger phosphorylated. This increase in phosphorylation was linked to higher Cbl protein levels due to increased TGFβ signaling in RDEB. In turn, increased Cbl levels led to increased PDGFR ubiquitination, internalization, and degradation negatively affecting MAPK and AKT downstream signaling pathways. Thus, our results indicate that elevated TGFβ signaling leads to an attenuated response to growth factors, which contribute to impaired dermal wound healing in RDEB.
The sum of two halves may be different from the whole. Effects of splitting sequencing samples across lanes
Authors: Williams Eleanor C. , Chazarra-Gil Ruben , Shahsavari Arash , Mohorianu Irina
Published: May 2021

The advances in high throughput sequencing (HTS) enabled the characterisation of biological processes at an unprecedented level of detail; the majority of hypotheses in molecular biology rely on analyses of HTS data. However, achieving increased robustness and reproducibility of results remains one of the main challenges. Although variability in results may be introduced at various stages, e.g. alignment, summarisation or detection of differences in expression, one source of variability was systematically omitted: the sequencing design which propagates through analyses and may introduce an additional layer of technical variation.

We illustrate qualitative and quantitative differences arising from splitting samples across lanes, on bulk and single-cell sequencing. For bulk mRNAseq data, we focus on differential expression and enrichment analyses; for bulk ChIPseq data, we investigate the effect on peak calling, and peaks’ properties. At single-cell level, we concentrate on identifying cell subpopulations. We rely on markers used for assigning cell identities; both smartSeq and 10x data are presented.

The observed reduction in the number of unique sequenced fragments reduces the level of detail on which the different prediction approaches depend. Further, the sequencing stochasticity adds in a weighting bias corroborated with variable sequencing depths and (yet unexplained) sequencing bias.