bluuebunny/crossref_metadata_2025 huggingface dataset:
Oscillometric evaluation of the effects of cardiotoxic chemotherapeutic agents on vascular stiffness
Authors: Kertmen Omer , Gulel Okan , Demirag Guzin , Ozatli Duzgun
Published: March 2022

Aim

Several clinical studies have demonstrated that arterial stiffness is an early indicator of cardiovascular events. Our study aimed to detect the potential cardiovascular changes using arterial stiffness parameters and compare these changes with echocardiographic aortic stiffness parameters, in cancer patients treated with cardiotoxic chemotherapeutics.

Methods and Results

Our study is a prospective case-control study. A total of seventy subjects between the ages of 18 and 50 years were included into our study. Thirty of them were newly diagnosed cancer patients and forty constituted the age- and sex-matched control group. Baseline oscillometric arterial and echocardiographic aortic stiffness parameters were measured in all patients. In cancer patients, all of these parameters were measured again, 1 month after chemotherapy protocol was completed. Mean age of the cancer patients was 41.4 ± 5.9 years and mean age of the control group was 39.6 ± 6.6 years (P = 0.258). Before chemotherapy, arterial and aortic stiffness parameters were similar between the study and the control group. After chemotherapy, the oscillometric pulse wave velocity parameter increased compared with the control group and to the prechemotherapy values (P = 0.004 and P < 0.001, respectively). After chemotherapy, the augmentation index parameter increased compared with the control group (P = 0.013). On the other hand, no difference was detected between the groups in terms of echocardiographic aortic stiffness parameters.

Conclusion

In newly diagnosed cancer patients treated with cardiotoxic chemotherapeutics, considerable impairment occurs in some of the oscillometric arterial stiffness parameters, while there is no substantial effect on echocardiographic aortic stiffness. Arterial stiffness parameters in these patients might be useful in evaluating subclinical cardiovascular damage.
Expression of serum long noncoding RNA FAM99A in patients with hypertensive disorder complicating and its clinical significance
Authors: Ge Qiuyan , Zhao Ju , Qu Fujuan
Published: March 2022

Objective

Hypertensive disorder complicating pregnancy (HDCP) consists of various heterogeneous conditions. Long noncoding RNAs (LncRNA) FAM99A is implicated in HDCP diagnosis. This study discussed the diagnostic efficiency of lncRNA FAM99A in HDCP.

Methods

Totally 130 singleton HDCP patients including 50 patients of gestation hypertension (GH), 44 of mild preeclampsia (mPE), and 36 of severe preeclampsia (sPEz) were enrolled, with 70 healthy pregnant women as the control. Serum lncRNA FAM99A expression was detected and its diagnostic efficiency in HDCP was analyzed using the receiver operating characteristic curve. The influencing factors of PE grade were analyzed using the logistic regression model.

Results

Serum lncRNA FAM99A was downregulated in HDCP patients. The SBP/DBP, 24-h urinary protein, and serum creatinine (SCr), AST and ALT contents were elevated, and platelet count (PLT) was diminished in HDCP patients. Relative to the high-expression group, SBP/DBP, 24-h urinary protein, SCr, AST, and ALT contents were raised, and PLT was lowered in the low-expression group. The area under curve of lncRNA FAM99A for HDCP diagnosis was 0.9514, and the cutoff value was 0.8450, with 83.85% sensitivity and 94.29% specificity. LncRNA FAM99A expression was downregulated in the GH group, then mPE group, and sPEz group the least. LncRNA FAM99A had diagnostic efficiency for GH and mPE, and mPE and sPEz. DBP, urinary protein, PLT, and lncRNA FAM99A were independent risk factors for PE severity.

Conclusion

LncRNA FAM99A was diminished in HDCP patients and was related to HDCP severity, which might be used as a potential diagnostic marker of HDCP.
Gender differences in the associations of circulating erythrocytes and hemoglobin with hypertension risk
Authors: Liu Dong , Wang Cuicui , Zhang Ya , Zuo Hui
Published: March 2022

Objective

Studies on associations of erythrocytes parameters with hypertension risk are scarce. We aimed to examine associations of the erythrocytes parameters with the hypertension risk and potential effect modification by gender using data from the China Health and Nutrition Survey.

Methods

A total of 5419 eligible participants (2468 men, 45.5%) without hypertension at baseline in 2009 were included and followed for a median of 6.1 years. Parameters of erythrocytes and hemoglobin were measured at baseline. Multivariable Cox proportional hazards models were used to estimate the hazard ratio for the associations between these parameters and hypertension risk. Data were collected from 2009 to 2015 and analyzed in 2021.

Results

A total of 1178 incident cases of hypertension were identified during the follow-up. In women, erythrocytes and hemoglobin were positively associated with risk of hypertension, yielding the highest hazard ratio in the third quartile of 1.59 (95% confidence interval, 1.28–1.97, P trend < 0.001) for erythrocytes and in the fourth quartile of 1.64 (95% confidence interval, 1.23–2.17, P trend < 0.001) for hemoglobin compared with their first quartile, respectively. In addition, quartiles of erythrocytes and hemoglobin were not associated with risk of hypertension in men (P trend > 0.050).

Conclusion

Erythrocytes and hemoglobin were associated with an increased risk of hypertension in women, but not in men. Our findings suggest that special attention for the prevention of hypertension should be given to those women with the moderate to high level of circulating erythrocytes and higher level of hemoglobin.
Validation of the G.LAB MD41A0 upper arm blood pressure monitor in patients with diabetes mellitus according to the AAMI/ESH/ISO 81060-2:2018 Universal Standard
Authors: Li Lin-Yi , Tian Li , Gao Bin , Ming Jie , Liu Kui , Jiang Jun , Han Zheng-Yuan , Zhao Lu-Yang , Chen Chang-Sheng , Wan Yi
Published: March 2022

Objective

The objective of this study is to determine the accuracy of the G.LAB MD41A0 upper-arm oscillometric blood pressure (BP) monitor for self/home BP measurement in patients with diabetes according to the Association for the Advancement of Medical Instrumentation /European Society of Hypertension /International Organization for Standardization (AAMI/ESH/ISO) Universal Standard (ISO 81060-2:2018).

Methods

Patients with diabetes were recruited according to AAMI/ESH/ISO Universal Standard using the same arm sequential BP measurement method. The standard cuff of the test device was used for arm circumference 22–44 cm.

Results

A total of 92 patients with diabetes were recruited and 85 were analyzed with an average age of 55.1 ± 17.7 years, 48 men, and arm circumference of 32.0 ± 6.0 cm. For the validation Criterion 1, the mean ± SD of the differences between the test device and reference BP readings was 0.89 ± 6.04/−0.84 ± 5.11 mmHg (systolic/diastolic). For Criterion 2, the SD of the averaged BP differences between the test device and reference BP per subject was 4.23/4.19 mmHg (systolic/diastolic).

Conclusion

The G.LAB MD41A0 upper arm BP monitor fulfilled all the requirements of the AAMI/ESH/ISO Universal Standard (ISO 81060-2:2018) in patients with diabetes and can be recommended for self/home use.
Uniparental disomy as a mechanism for X-linked chondrodysplasia punctata
Authors: Woods Emily , Yates Michael , Kanani Farah , Balasubramanian Meena
Published: March 2022

We describe a female infant with X-linked chondrodysplasia punctata (CDPX1) as a result of maternal isodisomy of the X chromosome. Targeted Sanger sequencing and targeted next-generation sequencing of ARSL were used to test for the familial variant. This patient was homozygous for ARSL NM_000047.2: c.1227_1228delinsAT p.(Ser410Cys) familial variant, consistent with a diagnosis of CDPX1. Uniparental disomy is a type of chromosomal variation. Although not necessarily pathogenic, it can cause imprinting disorders and X-linked recessive disorders in females, and be a cause of autosomal recessive conditions when only one parent is a carrier. The patient described highlights that uniparental disomy can be a rare cause of X-linked recessive conditions. This mode of inheritance has not been previously described in this condition.
Asthma diagnosis using patient-reported outcome measures and objective diagnostic tests: now and into the future
Authors: Nawaz Safia F. , Ravindran Mayuran , Kuruvilla Merin E.
Published: March 2022

Purpose of review

The global prevalence of asthma continues to increase; however, asthma remains under-diagnosed and under-treated. This results in a significant burden on the healthcare system and preventable patient morbidity and mortality. Over-diagnosis of asthma based on clinical history alone also complicates patient management. This heightens the importance of a prompt and accurate asthma diagnosis. Therefore, a review of the literature was performed regarding both objective diagnostic testing for asthma and using patient-reported outcome measures.

Recent findings

The cornerstone of asthma diagnosis remains spirometry with testing for bronchodilator reversibility testing for pediatric and adult populations. This test may need to be repeated at multiple time points due to its low sensitivity. Peak flow measurement, fractional exhaled nitric oxide testing, and allergy testing are useful adjuncts to the diagnosis and phenotyping of asthma. Bronchoprovocation testing is reserved for people with high clinical suspicion for asthma, but negative spirometry. Novel noninvasive testing modalities may play a diagnostic role in the future. The advent of remote digital health monitoring technology has resulted in revisiting patient-reported outcome measures for the diagnosis and monitoring of asthma.

Overall, improved diagnostic tools for asthma are crucial for earlier recognition and treatment of the disease and improved patient care outcomes worldwide.
Optimized cocktail of 90Y/177Lu for radionuclide therapy of neuroendocrine tumors of various sizes: a simulation study
Authors: Peer-Firozjaei Milad , Tajik-Mansoury Mohammad Ali , Geramifar Parham , Ghorbani Raheb , Zarifi Shiva , Miller Cassandra , Rahmim Arman
Published: March 2022

Background and objectives

There is significant interest and potential in the treatment of neuroendocrine tumors via peptide receptor radionuclide therapy (PRRT) using one or both of 90Y and 177Lu-labeled peptides. Given the presence of different tumor sizes in patients and differing radionuclide dose delivery properties, the present study aims to use Monte Carlo simulations to estimate S-values to spherical tumors of various sizes with 90Y and 177Lu separately and in combination. The goal is to determine ratios of 90Y to 177Lu that result in the largest absorbed doses per decay of the radionuclides and the most suitable dose profiles to treat tumors of specific sizes.

Material and methods

Particle transfer calculations and simulations were performed using the Monte Carlo GATE simulation software. Spherical tumors of different sizes, ranging from 0.5 to 20 mm in radius, were designed. Activities of 177Lu and 90Y, individually and in combination, were homogeneously placed within the total volume of the tumors. We determined the S-values to the tumors, and to the external volume outside of the tumors (cross-dose) which was used to approximate background tissue. The dose profiles were obtained for each of the different tumor sizes, and the uniformity of dose within each tumor was calculated.

Results

For all tumor sizes, the self-dose and cross-dose per decay from 90Y were higher than that from 177Lu. We observed that 177Lu had the most uniform dose distribution within tumors with radii less than 5 mm. For tumors greater than 5 mm in radius, a ratio of 25% 90Y to 75% 177Lu resulted in the most uniform doses. When the ratio of 177Lu to 90Y was smaller, the uniformity improved more with increasing tumor size. The cross-dose stayed approximately constant for tumors larger than 15 mm for all ratios of 177Lu to 90Y. Finally, as the size of the tumor increased, differences in the S-values between different ratios of 177Lu to 90Y decreased.

Conclusion

Our work showed that to achieve a more uniform dose distribution within the tumor, 177Lu alone is more effective for small tumors. For medium and large tumors, a ratio of 90Y to 177Lu with more or less 177Lu, respectively, is recommended.
Risperidone combination therapy with adalimumab for treatment of chronic schizophrenia: a randomized, double-blind, placebo-controlled clinical trial
Authors: Motamed Mahsa , Karimi Hanieh , Sanjari Moghaddam Hossein , Taherzadeh Boroujeni Sina , Sanatian Zahra , Hasanzadeh Alireza , Khodaei Ardakani Mohammad-Reza , Akhondzadeh Shahin
Published: March 2022

This study aimed to investigate the efficacy and safety of antitumor necrosis factor-alpha (TNF-α) therapy using adalimumab in patients with chronic schizophrenia. This is a randomized, double-blind, placebo-controlled clinical trial carried out at Roozbeh Hospital (Tehran, Iran) from June 2020 to October 2021. The patients were randomly divided into two parallel adalimumab + risperidone and placebo + risperidone groups. Participants in the intervention group received adalimumab subcutaneous injection (40 mg) by pen-injector at weeks 0 and 4. Using the Positive and Negative Symptoms Scale (PANSS), patients’ positive and negative symptoms were assessed at weeks 0, 4, and 8. Forty patients (20 in each group) were included. PANSS total (t = 4.43, df = 38, P < 0.001), negative (t = 2.88, df = 38, P = 0.006), and general psychopathology (t = 4.06, df = 38, P < 0.001) scores demonstrated a significantly greater decline in adalimumab compared with the placebo group from baseline study endpoint. However, improvement of PANSS positive subscale scores showed no significant difference from the baseline study endpoint. There was no significant between-group difference regarding levels of C-reactive protein, interleukin (IL)-1β, TNF-α, IL-6, and IL-8 at baseline and also at the week 8 visit (P > 0.05 for all). The current study found adalimumab adjunctive therapy effective in treating schizophrenia, particularly its negative and general psychopathology symptoms, with no side effects.
Creating a ‘Timeline’ of ductal carcinoma in situ to identify processes and biomarkers for progression towards invasive ductal carcinoma
Authors: Rebbeck Clare A. , Xian Jian , Bornelöv Susanne , Geradts Joseph , Hobeika Amy , Geiger Heather , Alvarez Jose Franco , Rozhkova Elena , Nicholls Ashley , Robine Nicolas , Lyerly Herbert K. , Hannon Gregory J.
Published: March 2022

Ductal carcinoma in situ (DCIS) is considered a non-invasive precursor to breast cancer, and although associated with an increased risk of developing invasive disease, many women with DCIS will never progress beyond their in situ diagnosis. The path from normal duct to invasive disease is not well understood, and efforts to do so are hampered by the substantial heterogeneity that exists between patients and even within patients. Using gene expression analysis, we have generated a ‘Timeline’ of disease progression, utilising the variability within patients and combining >2,000 individually micro-dissected ductal lesions from 145 patients into one continuous trajectory. Using this Timeline we show there is a progressive loss in basal layer integrity, coupled with two epithelial to mesenchymal transitions (EMT), one early in the timeline and a second just prior to cells leaving the duct. We identify early processes and potential biomarkers, includingCAMK2N1,MNX1,ADCY5,HOXC11andANKRD22, whose reduced expression is associated with the progression of DCIS to invasive breast cancer.
A chromosome-level genome assembly enables the identification of the follicle stimulating hormone receptor as the master sex determining gene in Solea senegalensis
Authors: De la Herrán R. , Hermida M. , Rubiolo J. , Gómez-Garrido J. , Cruz F. , Robles F. , Navajas R. , Blanco F. A. , Villamayor P. R. , Torres D. , Sánchez-Quinteiro P. , Ramirez D. , Rodríguez M. E. , Arias-Pérez A. , Cross I. , Duncan N. , Martínez-Peña T. , Riaza A. , Millán A. , Gut M. , Bouza C. , Robledo D. , Rebordinos L. , Alioto T. , Ruíz-Rejón C. , Martínez P.
Published: March 2022

Sex determination (SD) mechanisms are exceptionally diverse and show high evolutionary rates in fish. Pleuronectiformes is an emblematic fish group characterized by its adaptation to demersal life and its compact genomes. Here, we present a chromosome-level genome assembly of Senegalese sole, a promising European aquaculture species. We combined long- and short-read sequencing and a highly dense genetic map to obtain a contiguous assembly of 613 Mb (N50 = 29.0 Mb, 99% of the assembly in the n = 21 chromosomes of its karyotype). The correspondence between this new assembly and the Senegalese sole chromosomes was established by fluorescence in situ hybridization with BAC probes. Orthology within Pleuronectiformes was assessed by using the chromosome-level genomes of six important commercial flatfishes covering a broad phylogenetic spectrum of the order. A total of 7936 single-gene orthologues, shared by the six species, were used to identify syntenies in Pleuronectiformes and to explore chromosome evolutionary patterns in the order. Whole genome resequencing of six males and six females enabled the identification of 41 fixed allelic variants in the follicle stimulating hormone receptor (fshr) gene, homozygous in females and heterozygous in males, consistent with an XX / XY chromosome system. The observed association between fshr SNPs and sex was confirmed at the species level in a broad sample, which allowed tuning up a molecular sexing tool. Fshr demonstrated differential gene expression between male and female gonads since 86 days post-fertilization, when the gonad was still an undifferentiated primordium, concomitant with the activation of other testis and ovary marker genes, such as amh and cyp19a1a genes, respectively. Interestingly, the Y-linked fshr allele, which included 24 non-synonymous variants, expressed to a higher level than the X-linked allele at all stages. We hypothesize a molecular mechanism hampering the action of the follicle stimulating hormone that would drive the undifferentiated gonad toward testis.
A mechanistic understanding of the modes of Ca ion binding to the SARS-CoV-1 fusion peptide and their role in the dynamics of host membrane penetration
Authors: Carten Juliana Debrito , Khelashvili George , Bidon Miya K. , Straus Marco R. , Tang Tiffany , Jaimes Javier A. , Weinstein Harel , Whittaker Gary R. , Daniel Susan
Published: March 2022

The SARS-CoV-1 spike glycoprotein contains a fusion peptide (FP) segment that mediates fusion of the viral and host cell membranes. Calcium ions are thought to position the FP optimally for membrane insertion by interacting with negatively charged residues in this segment (E801, D802, D812, E821, D825, and D830); however, which residues bind to calcium and in what combinations supportive of membrane insertion are unknown. Using biological assays and molecular dynamics studies, we have determined the functional configurations of FP-Ca+2binding which promote membrane insertion. We first mutated the negatively charged residues in the SARS CoV-1 FP to assay their role in cell entry and syncytia formation, finding that charge loss in the D802A or D830A mutants reduced syncytia formation and pseudoparticle transduction. Interestingly, the D812A mutation led to increased pseudoparticle transduction, indicating the Ca2+effect depends on binding at specific FP sites. To interpret mechanistically these results and learn how specific modes of FP-Ca2+binding modulate membrane insertion, we performed molecular dynamics simulations. Preferred residue pairs for Ca2+binding were identified (E801/D802; E801/D830; D812/E821) which promote FP membrane insertion. In contrast, binding to residues E821/D825 inhibited FP membrane insertion, which is also supported by our biological assays. Our findings show that Ca2+binding to SARS-CoV-1 FP residue pairs E801/D802 and D812/E821 facilitates membrane insertion, whereas binding to the E801/D802 and D821/D825 pairs is detrimental. These conclusions provide an improved and nuanced mechanistic understanding of calcium binding modes to FP residues and their dynamic effects on host cell entry.
The mutational steps of SARS-CoV-2 to become like Omicron within seven months: the story of immune escape in an immunocompromised patient
Authors: Sonnleitner Sissy Therese , Prelog Martina , Sonnleitner Stefanie , Hinterbichler Eva , Halbfurter Hannah , Kopecky Dominik B. C. , Almanzar Giovanni , Koblmüller Stephan , Sturmbauer Christian , Feist Leonard , Horres Ralf , Posch Wilfried , Walder Gernot
Published: March 2022

We studied a unique case of prolonged viral shedding in an immunocompromised patient that generated a series of SARS-CoV-2 immune escape mutations over a period of seven months. During the persisting SARS-CoV-2 infection seventeen non-synonymous mutations were observed, thirteen (13/17; 76.5%) of which occurred in the genomic region coding for spike. Fifteen (15/17; 88.2%) of these mutations have already been described in the context of variants of concern and include the prominent immune escape mutations S:E484K, S:D950N, S:P681H, S:N501Y, S:del(9), N:S235F and S:H655Y. Fifty percent of all mutations acquired by the investigated strain (11/22) are found in similar form in the Omicron variant of concern. The study shows the chronology of the evolution of intra-host mutations, which can be seen as the straight mutational response of the virus to specific antibodies and should therefore be given special attention in the rating of immune escape mutations of SARS-CoV-2.
Remdesivir for the treatment of patients hospitalized with COVID-19 receiving supplemental oxygen: a targeted literature review and meta-analysis
Authors: Beckerman Rachel , Gori Andrea , Jeyakumar Sushanth , Malin Jakob J. , Paredes Roger , Póvoa Pedro , Smith Nate , Teixeira-Pinto Armando
Published: March 2022

This network meta-analysis (NMA) assessed the efficacy of remdesivir in hospitalized patients with COVID-19 requiring supplemental oxygen. Randomized controlled trials of hospitalized patients with COVID-19, where patients were receiving supplemental oxygen at baseline and at least one arm received treatment with remdesivir, were identified. Outcomes included mortality, recovery, and no longer requiring supplemental oxygen. NMAs were performed for low-flow oxygen (LFO2); high-flow oxygen (HFO2), including NIV; or oxygen at any flow (AnyO2) at early (day 14/15) and late (day 28/29) time points. Six studies were included (N=5,245 patients) in the NMA. Remdesivir lowered early and late mortality among AnyO2patients (risk ratio (RR) 0.52, 95% credible interval (CrI) 0.34-0.79; RR 0.81, 95%CrI 0.69-0.95) and LFO2patients (RR 0.21, 95%CI 0.09-0.46; RR 0.24, 95%CI 0.11-0.48); no improvement was observed among HFO2patients. Improved early and late recovery was observed among LFO2patients (RR 1.22, 95%CrI 1.09-1.38; RR 1.17, 95%CrI 1.09-1.28). Remdesivir also lowered the requirement for oxygen support among all patient subgroups. Among hospitalized patients with COVID-19 requiring supplemental oxygen at baseline, use of remdesivir compared to best supportive care is likely to improve the risk of mortality, recovery and need for oxygen support in AnyO2and LFO2patients.
Population-based analysis of radiation-induced gliomas after cranial radiotherapy for childhood cancers
Authors: Leary Jacob B. , Anderson-Mellies Amy , Green Adam L.
Published: March 2022

Background

Cranial radiotherapy (RT) is used to treat pediatric central nervous system (CNS) cancers and leukemias. RT carries a risk of secondary CNS malignancies, including radiation-induced gliomas, the epidemiology of which is poorly understood.

Methods

This retrospective study using SEER registry data (1975-2016) included two cohorts. Cohort 1 included patients diagnosed with Grade III/IV or ungraded glioma as a second malignancy at least 2 years after receiving beam radiation and/or chemotherapy for a first malignancy diagnosed at ages 0-19 years, either a primary CNS tumor treated with RT (1a, n=57) or leukemia with unknown RT treatment (1b, n=20). Cohort 2 included patients with possible missed RIG who received RT for a primary CNS tumor diagnosed at 0-19 and then died of presumed progressive disease more than 5 years after diagnosis, since previous studies have documented many missed RIGs in this group (n=296). Controls (n=10,687) included all other patients ages 0-19 who received RT for a first CNS tumor or leukemia who did not fit inclusion criteria above.

Results

For Cohort 1 (likely/definite RIGs), 0.97% of patients receiving cranial RT went on to develop RIG. 3.39% of patients receiving cranial RT for primary CNS tumors fell in Cohort 2 (potential RIGs). Median latency to RIG diagnosis was 11.1 years; latency was significantly shorter for Cohort 1b (median 10.0, range 5.0-16.1) vs. 1a (12.0, 3.6-34.4, p=0.018). Median OS for Cohort 1 was 9.0 months. Receiving surgery, radiation, or chemotherapy were all associated with a non-statistically significant improvement in OS (p 0.1-0.2). 1.8% of brain tumor deaths in the cohort fell in Cohort 1, with an additional 7.9% in Cohort 2.

Conclusion

Within the limitations of a population-based study, 1-4% of patients undergoing cranial RT for pediatric cancers later develop RIG, which is incurable and can occur anywhere from 3-35 years later. 2-10% of pediatric brain tumor deaths are attributable to RIG. Effective treatment of RIG remains unclear and is thus deserving of increased attention in preclinical and clinical studies.
Platelet Dependent Thrombogenicity, Inflammation and Five Year Mortality in Patients with Non-ST Elevation Acute Coronary Syndrome and Type 2 Diabetes Mellitus: An Observational Study
Authors: Viswanathan Girish N , Harper Andrew R. , Badimon Juan J , Marshall Sally M , Zaman Azfar G
Published: March 2022

Platelet dependent thrombogenicity is higher in type 2 diabetes mellitus (T2DM) but there is no data on association between thrombus and mortality or vascular inflammation.

We studied 80 patients who received guideline based therapy (40 T2DM) after NSTE-ACS. Platelet dependent thrombus was assessed using the validated ex vivo Badimon Chamber and all patients were followed up for five years. Bio-markers of coagulation and inflammation were measured.

There were 17 (21.3%) deaths in total (12 in the T2DM, 71% of all deaths), at 5 years. Of the patients who died, thrombus burden was higher (µ2 per mm, Mean ± SD, 12,164 ± 3235 vs 9,751 ± 4333). Serum inflammatory cytokines, P selectin and soluble CD40 ligand were higher in T2DM. Univariate analysis showed thrombus area, diabetic status, age, interleukin 1 and P selectin were independent predictors of mortality. Inflammatory biomarkers were associated with thrombus burden. If these findings can be proven in large scale studies, this will lead on to novel therapeutic strategies especially in the current Covid 19 pandemic which has renewed our interest of this interplay of pathophysiology between thrombus and inflammation.
Prenatal vitamin intake in first month of pregnancy and DNA methylation in cord blood and placenta in two prospective cohorts
Authors: Dou John F. , Middleton Lauren Y.M. , Zhu Yihui , Benke Kelly S. , Feinberg Jason I. , Croen Lisa A. , Hertz-Picciotto Irva , Newschaffer Craig J. , LaSalle Janine M. , Fallin Daniele , Schmidt Rebecca J. , Bakulski Kelly M.
Published: March 2022

Background

Prenatal vitamin use is recommended before and during pregnancies for normal fetal development. Prenatal vitamins do not have a standard formulation, but many contain calcium, folic acid, iodine, iron, omega-3 fatty acids, zinc, and vitamins A, B6, B12, and D, and usually they contain higher concentrations of folic acid and iron than regular multivitamins in the U.S. Nutrient levels can impact epigenetic factors such as DNA methylation, but relationships between maternal prenatal vitamin use and DNA methylation have been relatively understudied. We examined use of prenatal vitamins in the first month of pregnancy in relation to cord blood and placenta DNA methylation in two prospective pregnancy cohorts: the Early Autism Risk Longitudinal Investigation (EARLI) and Markers of Autism Risk Learning Early Signs (MARBLES) studies.

Results

In placenta, prenatal vitamin intake was marginally associated with -0.52% (95% CI: - 1.04, 0.01) lower mean array-wide DNA methylation in EARLI, and associated with -0.60% (−1.08, -0.13) lower mean array-wide DNA methylation in MARBLES. There was little consistency in the associations between prenatal vitamin intake and single DNA methylation site effect estimates across cohorts and tissues, with only a few overlapping sites with correlated effect estimates. However, the single DNA methylation sites with p-value<0.01 (EARLI cord nCpGs=4,068, EARLI placenta nCpGs=3,647, MARBLES cord nCpGs=4,068, MARBLES placenta nCpGs=9,563) were consistently enriched in neuronal developmental pathways.

Conclusions

Together, our findings suggest that prenatal vitamin intake in the first month of pregnancy may be related to lower placental global DNA methylation and related to DNA methylation in brain-related pathways in both placenta and cord blood.
Bladder Cancer Prognosis Using Deep Neural Networks and Histopathology Images
Authors: Barrios Wayner , Abdollahi Behnaz , Goyal Manu , Song Qingyuan , Suriawinata Matthew , Richards Ryland , Ren Bing , Schned Alan , Seigne John , Karagas Margaret , Hassanpour Saeed
Published: March 2022

Recent studies indicate bladder cancer is among the top 10 most common cancer in the world [1]. Bladder cancer frequently reoccurs, and prognostic judgments may vary among clinicians. Classification of histopathology slides is essential for accurate prognosis and effective treatment of bladder cancer patients, as a favorable prognosis might help to inform less aggressive treatment plans. Developing automated and accurate histopathology image analysis methods can help pathologists in determining the prognosis of bladder cancer. In this study, we introduced Bladder4Net, a deep learning pipeline to classify whole-slide histopathology images of bladder cancer into two classes: low-risk (combination of PUNLMP and low-grade tumors) and high-risk (combination of high-grade and invasive tumors). This pipeline consists of 4 convolutional neural network (CNN) based classifiers to address the difficulties of identifying PUNLMP and invasive classes. We evaluated our pipeline on 182 independent whole-slide images from the New Hampshire Bladder Cancer Study (NHBCS) [22] [23] [24] collected from 1994 to 2004 and 378 external digitized slides from The Cancer Genome Atlas (TCGA) database [26]. The weighted average F1-score of our approach was 0.91 (95% confidence interval (CI): 0.86–0.94) on the NHBCS dataset and 0.99 (95% CI: 0.97–1.00) on the TCGA dataset. Additionally, we computed Kaplan-Meier survival curves for patients predicted as high-risk versus those predicted as low-risk. For the NHBCS test set, patients predicted as high-risk had worse overall survival than those predicted as low-risk, with a Log-rank P-value of 0.004. If validated through prospective trials, our model could be used in clinical settings to improve patient care.
Two new Rhizobiales species isolated from root nodules of common sainfoin (Onobrychis viciifolia) show different plant colonization strategies
Authors: Ashrafi Samad , Kuzmanović Nemanja , Patz Sascha , Lohwasser Ulrike , Bunk Boyke , Spröer Cathrin , Lorenz Maria , Frühling Anja , Neumann-Schaal Meina , Verbarg Susanne , Becker Matthias , Thünen Torsten
Published: March 2022

Root nodules of legume plants are primarily inhabited by rhizobial nitrogen-fixing bacteria. Here we propose two new Rhizobiales species isolated from root nodules of common sainfoin (Onobrychis viciifolia), as shown by core-gene phylogeny, overall genome relatedness indices and pan-genome analysis.

Mesorhizobium onobrychidis sp. nov., actively induces nodules, and achieves atmospheric nitrogen and carbon dioxide fixation. This species appears to be depleted in motility genes, and is enriched in genes for direct effects on plant growth performance. Its genome reveals functional and plant growth-promoting signatures like a large unique chromosomal genomic island with high density of symbiotic genetic traits. Onobrychidicola muellerharveyae gen. nov. sp. nov., is described as type species of the new genus Onobrychidicola in Rhizobiaceae. This species comprises unique genetic features and plant growth-promoting traits (PGPTs), which strongly indicate its function in biotic stress reduction and motility. We applied a newly developed bioinformatics approach for in silico prediction of PGPTs (PGPT-Pred), which supports the different lifestyles of the two new species and the plant growth-promoting performance of M. onobrychidis in the greenhouse trial.
Q3: An ICU Acuity Score for Exploring the Effects of Changing Acuity Throughout the Stay
Authors: Brossette Stephen E. , Zheng Ning , Wong Daisy Y. , Hymel Patrick A.
Published: March 2022

Intro

We develop a straightforward ICU acuity score (Q3) that is calculated every 3 hours throughout the first 10 days of the ICU stay. Q3 uses components of the Oxford Acute Severity of Illness Score (OASIS) and incorporates a new component score for vasopressor use. In well-behaved models of ICU mortality, the marginal effects of Q3 are significant across the first 10 days of the ICU stay. In separate models, Q3 has significant effects on ICU remaining length of stay. The score has implications for work that seeks to explain modifiable mechanisms of changing acuity during the ICU stay.

Methods

From the MIMIC-III database, select ICU stays from 5 adult ICUs were partitioned into consecutive 3-hour segments. For each segment, the number of vasopressors administered and all 10 OASIS component scores were computed. Models of ICU mortality were estimated. OASIS component effects were examined, and vasopressor count bins were weighted. Q3 was defined as the sum of 8 retained OASIS components and a new weighted vasopressor score. Models of ICU mortality quadratic in Q3 were estimated for each of the first 10 ICU days and were subjected to segment-level, location-specific tests of discrimination and calibration on newer ICU stays. Marginal effects of Q3 were computed at different levels of Q3 by ICU day, and average marginal effects of Q3 were computed at each location by ICU day. ICU remaining length of stay (LOS) models were also estimated and the effects of Q3 were similarly examined.

Results

Daily ICU mortality models using Q3 show no evidence of misspecification (Pearson-Windmeijer p>0.05, Stukel p>0.05), discriminate well in all ICUs over the first 10 days (AUROC ∼ 0.72 – 0.85), and are generally well calibrated (Hosemer-Lemeshow p>0.05, Spiegelhalter’s z p>0.05). A one-unit increase in Q3 from typical levels (Q3=15) affects the odds of ICU mortality by a factor of 1.14 to 1.20, depending on ICU day (p<0.001), and the ICU remaining LOS by 5.8 to 9.6% (p<0.001). On average, a one-unit increase in Q3 increases the probability of ICU mortality by 1 to 2 percentage points depending on location and ICU day, and ICU remaining LOS by 5 to 10 hours depending on location and ICU day.

Conclusion

Q3 significantly affects ICU mortality and ICU remaining LOS in different ICUs across the first 10 days of the ICU stay. Depending on location and ICU day, a one-unit increase in Q3 increases the probability of ICU mortality by or 1-2 percentage points and ICU remaining LOS by 5 to 10 hours. Unlike static acuity scores or those updated infrequently, Q3 could be used in explanatory models to help elucidate mechanisms of changing ICU acuity.
Genetic heritage of the BaPhuthi highlights an over ethnicised notion of ‘Bushman’ in the Maloti-Drakensberg, Southern Africa
Authors: Daniels Ryan Joseph , D’Amato Maria Eugenia , Lesaoana Mpasi , Kasu Mohaimin , Ehlers Karen , Chauke Paballo Abel , Lecheko Puseletso , Challis Sam , Rockett Kirk , Montinaro Francesco , González-Santos Miguel , Capelli Cristian
Published: March 2022

Using contemporary people as proxies for ancient communities is a contentious but necessary practice in anthropology. In Southern Africa, the distinction between the Cape KhoeSan and eastern KhoeSan remains unclear as ethnicity labels are continually changed through time and most communities were extirpated. The eastern KhoeSan may reflect an ‘essentialistic’ biological distinction from neighbouring Bantu-speaking communities or it may not be tied to ‘race’ and instead denote communities with a nomadic ‘life-way’ distinct from agro-pastoralism. The BaPhuthi of the 1800s in the Maloti-Drakensberg, Southern Africa had a substantial San constituency and a life-way of nomadism, cattle raiding, and horticulture. The BaPhuthi heritage could provide insights into the history of the eastern KhoeSan. We examine for the first time genetic affinities of 23 BaPhuthi to distinguish if KhoeSan ancestry reflects biologically distinct heritage or a shared life-way. Data were merged with 52 global populations. The Principle Component Analysis, ADMIXTURE clustering and F3 tests show no support for a unique eastern KhoeSan ancestry distinct from other KhoeSan or southern Bantu-speaking communities. The BaPhuthi have strong affinities with Nguni communities, as the non-Nguni show strong evidence of recent African admixture possibly related to late-iron age migrations. The BaPhuthi may have an interesting connection to the early iron-age Bantu-speaking communities as MALDER detected no signals for late-iron age admixture. We demonstrate how the ‘essentialistic’ understanding of references in historic literature creates misconstrued notions of ethnic/biological distinctions when ‘San’ and ‘Bushman’ may have reflected ambiguous references to the non-sedentary polities and practices.
Defining Factors that Influence vaccine-induced, cross-variant neutralizing antibodies for SARS-CoV-2 in Asians
Authors: Gu Yue , Shunmuganathan Bhuvaneshwari D/O , Qian Xinlei , Gupta Rashi , Tan Rebecca S.W. , Kozma Mary , Purushotorman Kiren , Murali Tanusya M. , Tan Nikki Y.J. , Preiser Peter R. , Lescar Julien , Nasir Haziq , Somani Jyoti , Tambyah Paul A. ,   SCOPE Cohort Study Group, Smith Kenneth G.C. , Renia Laurent , Ng Lisa F.P. , Lye David C. , Young Barnaby E. , MacAry Paul A.
Published: March 2022

The scale and duration of neutralizing antibody responses targeting SARS-CoV-2 viral variants represents a critically important serological parameter that predicts protective immunity for COVID-19. In this study, we present longitudinal data illustrating the impact of age, sex and comorbidities on the kinetics and strength of vaccine-induced neutralizing antibody responses for key variants in an Asian volunteer cohort. We demonstrate a reduction in neutralizing antibody titres across all groups six months post-vaccination and show a marked reduction in the serological binding and neutralizing response targeting Omicron compared to other viral variants. We also highlight the increase in cross-protective neutralizing antibody responses against Omicron induced by a third dose (booster) of vaccine. These data illustrate how key virological factors such as immune escape mutation combined with host factors such as age and sex of the vaccinated individuals influence the strength and duration of cross-protective serological immunity for COVID-19.
Yeast galactokinase in closed conformation can switch between catalytic and signal transducer states
Authors: Giri Nandinee , Bhat Paike Jayadeva
Published: March 2022

S.cerevisiae galactokinase (ScGal1p), in closed conformation catalyzes the phosphorylation of galactose to galactose 1-phopshate using ATP as the phosphate donor as well as allosterically activates the GAL genetic switch in response to galactose and ATP as ligands. How both kinase and signaling activities of ScGal1p are associated with closed conformation of the protein is not understood. Conformational sampling of ScGal1p indicated that this protein samples closed kinase and closed non-kinase conformers. Closed non-kinase conformers are catalytically incompetent to phosphorylate galactose and act as a bonafide signal transducer. It was observed that toggling of side chain of highly conserved K266 of ScGal1p between S171and catalytic base D217 is responsible for transitioning of ScGal1p between signal transducer and kinase states. Interestingly in ScGal3p, the paralog of ScGal1p, which has only signal transduction activity and lacks kinase activity, a H bond between a non-conserved Y433, and a highly conserved Y57, gets broken during MD simulation. The corresponding H-bond present in ScGal1p between residues Y441 and Y63 respectively, remains intact throughout the simulations of ScGal1p.Therefore, we predicted that K266 and Y441 have a role in bifunctionality of ScGal1p. To test the above predictions, we monitored the signaling and kinase activity of ScGal1K266Rp and ScGal1Y441Ap variants. Signaling activity increased in both ScGal1Y441Ap and ScGal1K266Rp variants as compared to ScGal1wtp, whereas the kinase activity increased in ScGal1Y441Ap, but decreased in ScGal1K266Rp Based on the above, we propose that K266 and Y441 are crucial for conferring bifunctionality to ScGal1p.

Author summary

Galactokinase of S.cerevisiae(ScGal1p), the first enzyme of Leloir pathway of galactose metabolism, phosphorylates galactose using ATP as the phosphate donor. ScGal1p also functions as a signal transducer of GAL regulon wherein galactose and ATP allosterically activate galactokinase. The active form of galactokinase, then sequesters the repressor ScGal80p, to activate the GAL switch. ScGal1p has a single site each for binding to galactose and ATP. How ScGal1p, a monomeric protein, performs the above two mutually exclusive activities using the same set of substrates/ligands, with the same site acting as the active site for enzymatic activity as well as allosteric site for signal transduction activity is unclear. Our findings are that this protein has a distinct conformational state for functioning as a signal transducer and a distinct conformational state for functioning as a kinase. A highly conserved lysine residue (K266) present only in fungal galactokinases, triggers the interconversion between catalysis and signal transduction states. This interconversion is subdued by H bond between Y441 and Y63. These studies suggest that the two activities of ScGal1p are fine tuned by evolution to regulate metabolism through transcriptional control.
A simple geometrical model of the electrostatic environment around the catalytic center of the ribosome
Authors: Joiret Marc , Rapino Francesca , Close Pierre , Geris Liesbet
Published: March 2022

The central function of the large subunit of the ribosome is to catalyze peptide bond formation. This biochemical reaction is conducted at the peptidyl transferase center (PTC). Experimental evidence shows that the catalytic activity is affected by the electrostatic environment around the peptidyl transferase center. The electrostatic field originates from the particular 3-dimensional space distribution in the phosphate moieties of the 23S (archea and bacteria) or 28S (eukarya) rRNA of the large ribosomal subunit as well as the funnel shape of the cavity at its connection with the ribosome exit tunnel. Here, we set up a minimal geometrical model fitting the available x-ray solved structure of the ribonucleoproteic cavity around the catalytic center of the large subunit of the ribosome. The purpose of this phenomenological model is to estimate quantitatively the electrostatic potential and electric field that are experienced during the peptidyl transfer reaction. At least two reasons motivate the need for developing this quantification. First, we inquire whether the electric field in this particular catalytic environment, made only of nucleic acids, is of the same order of magnitude as the one prevailing in catalytic centers of the proteic enzymes counterparts. Second, the protein synthesis rate is dependent on the nature of the amino acid sequentially incorporated in the nascent chain. The activation energy of the catalytic reaction and its detailed kinetics are expected to be dependent on the mechanical work exerted on the amino acids by the electric field, especially when one of the four charged amino acid residues (R, K, E, D) is newly incorporated in the nascent chain. Physical values of the electric field will provide quantitative knowledge of mechanical work, activation energy and kinetics of the peptide bond formation catalysed by the ribosome.
An affinity-matured DLL4 ligand for broad-spectrum activation and inhibition of Notch signaling
Authors: Gonzalez-Perez David , Das Satyajit , Medina Elliot , Antfolk Daniel , Egan Emily D. , Blacklow Stephen C. , Rodriguez Paulo C. , Luca Vincent C.
Published: March 2022

The Notch pathway regulates cell fate decisions and is an emerging target for regenerative and cancer therapies. Recombinant Notch ligands are attractive candidates for modulating Notch signaling; however, their intrinsically low receptor-binding affinity restricts their utility in biomedical applications. To overcome this limitation, we evolved variants of the ligand Delta-like 4 (DLL4) with enhanced affinity and cross-reactivity. A consensus variant with maximized binding affinity, DeltaMAX, engages human and murine Notch receptors with 500- to 1000-fold increased affinity compared to wild-type human DLL4. DeltaMAX also potently activates human Notch in plate-bound, bead-bound, and cellular formats. When administered as a soluble decoy, DeltaMAX inhibits Notch activation in response to either Delta-like (DLL) or Jagged (Jag) ligands, highlighting its utility as both an agonist and antagonist. Finally, we demonstrate that DeltaMAX stimulates increased proliferation and expression of effector mediators in primary activated human T cells. Taken together, our data defines DeltaMAX as a versatile biotechnological tool for broad-spectrum activation or inhibition of Notch signaling.