Category: Nevin Manimala

Hum Brain Mapp. 2022 May 16. doi: 10.1002/hbm.25907. Online ahead of print.

ABSTRACT

Children with perinatally acquired HIV (CPHIV) have poor cognitive outcomes despite early combination antiretroviral therapy (cART). While CPHIV-related brain alterations can be investigated separately using proton magnetic resonance spectroscopy (¹ H-MRS), structural magnetic resonance imaging (sMRI), diffusion tensor imaging (DTI), and functional MRI (fMRI), a set of multimodal MRI measures characteristic of children on cART has not been previously identified. We used the embedded feature selection of a logistic elastic-net (EN) regularization to select neuroimaging measures that distinguish CPHIV from controls and measured their classification performance via the area under the receiver operating characteristic curve (AUC) using repeated cross validation. We also wished to establish whether combining MRI modalities improved the models. In single modality analysis, sMRI volumes performed best followed by DTI, whereas individual EN models on spectroscopic, gyrification, and cortical thickness measures showed no class discrimination capability. Adding DTI and ¹ H-MRS in basal measures to sMRI volumes produced the highest classification performance validation accuracy=85%AUC=0.80$$ left(mathrm{validation} mathrm{accuracy}=85%,mathrm{AUC}=0.80right) $$ . The best multimodal MRI set consisted of 22 DTI and sMRI volume features, which included reduced volumes of the bilateral globus pallidus and amygdala, as well as increased mean diffusivity (MD) and radial diffusivity (RD) in the right corticospinal tract in cART-treated CPHIV. Consistent with previous studies of CPHIV, select subcortical volumes obtained from sMRI provide reasonable discrimination between CPHIV and controls. This may give insight into neuroimaging measures that are relevant in understanding the effects of HIV on the brain, thereby providing a starting point for evaluating their link with cognitive performance in CPHIV.

PMID:35575438 | DOI:10.1002/hbm.25907

J Natl Cancer Inst. 2022 May 16:djac101. doi: 10.1093/jnci/djac101. Online ahead of print.

ABSTRACT

BACKGROUND: There is growing evidence for the inherited basis of susceptibility to childhood acute lymphoblastic leukemia (ALL). Genome-wide association studies have identified non-coding ALL risk variants at the ARID5B gene locus, but their exact functional effects and the molecular mechanism linking ARID5B to B-ALL leukemogenesis remain largely unknown.

METHODS: We performed targeted sequencing of ARID5B in germline DNA of 5,008 children with ALL. Variants were evaluated for association with ALL susceptibility using 3,644 subjects from the UK10K cohort as non-ALL controls, under an additive model. Cis-regulatory elements in ARID5B were systematically identified using CRISPRi enhancer screen in ALL cells. Disruption of transcription factor binding by ARID5B variant was predicted informatically and then confirmed using chromatin immunoprecipitation and co-immunoprecipitation. ARID5B variant association with hematological traits was examined using UK Biobank dataset. All statistical tests are two-sided.

RESULTS: We identified 54 common variants in ARID5B significantly associated with leukemia risk, all of which were non-coding. Six cis-regulatory elements at the ARID5B locus were discovered using CRISPR-based high-throughput enhancer screening. Strikingly, the top ALL risk variant (rs7090445, P=5.57 × 10-45) is located precisely within the strongest enhancer element, which is also distally tethered to the ARID5B promoter. The variant allele disrupts the MEF2C binding motif sequence, resulting in reduced MEF2C affinity and decreased local chromosome accessibility. MEF2C influences ARID5B expression in ALL, likely via a transcription factor complex with RUNX1. Using the UK Biobank dataset (n = 349,861), we showed that rs7090445 was also associated with lymphocyte percentage and count in the general population (P=8.6 × 10-22 and 2.1 × 10-18, respectively).

CONCLUSION: Our results indicate that ALL risk variants in ARID5B function by modulating cis-regulatory elements at this locus.

PMID:35575404 | DOI:10.1093/jnci/djac101

Klin Lab Diagn. 2022 Apr 17;67(4):244-249. doi: 10.51620/0869-2084-2022-67-4-244-249.

ABSTRACT

To carry the comparative analysis of sample preparation methods for the most effective identification of Candida yeast by mass spectrometric analysis. 265 strains of yeast and yeast-like fungi isolated from the sputum of patients with pneumonia were investigated. The selected strains were identified by conventional methods (cultural, morphological, tinctorial, enzymatic properties) and MALDI-ToF MS using the Autoflex speed III Bruker Daltonics mass spectrometer (Germany) and Flex Control software. To evaluate the effectiveness of fungi species determinination, the comparative analysis of sample preparation was performed using 4 methods: direct application to the target, an extended direct application method, protein extraction using ethanol/formic acid or trifluoroacetic acid. The accelerated scheme of identification of fungi by the culture method does not provide clear and unambiguous results. When using mass spectrometric analysis, the reliability of the results depended on the sample preparation. A comparative study of the effectiveness of fungi species determination by various methods of the sample preparation of 50 clinical isolates was carried out. It was revealed that the extraction of cells using TFC acid does not lead to the appearance of the recordable protein spectra. The use of direct and extended direct application methods made it possible to establish the species only in 32-44% of the strains. The most effective method of sample preparation was the method using formic acid and ethanol, which allowed us to determine the species affiliation in 100% of the studied fungi (Score 2.0). Depending on the yeast species, a high statistical indicator (Score≥2.3) was registered for 42-100% of samples. The results of present study show that the use of MALDI-ToF MS is the most reliable and informative method of Candida spp.identification.

PMID:35575399 | DOI:10.51620/0869-2084-2022-67-4-244-249

ACS Macro Lett. 2022 Mar 15;11(3):323-328. doi: 10.1021/acsmacrolett.1c00774. Epub 2022 Feb 16.

ABSTRACT

Statistical copolypeptides comprising lysine and tyrosine with unprecedented ion-induced gelation behavior are reported. Copolypeptides are obtained by one-step N-carboxyanhydride (NCA) ring-opening polymerization. The gelation mechanism is studied by in situ SAXS analyses, in addition to optical spectroscopy and transmission electron microscopy (TEM). It is found that the gelation of these statistically polymerized polypeptides is due to the formation of stable intermolecular β-sheet secondary structures induced by the presence of salt ions as well as the aggregation of an α-helix between the copolypeptides. This behavior is unique to the statistical lysine/tyrosine copolypeptides and was not observed in any other amino acid combination or arrangement. Furthermore, the diffusion and mechanical properties of these hydrogels can be tuned through tailoring the polypeptide chain length and ion strength.

PMID:35575374 | DOI:10.1021/acsmacrolett.1c00774

Klin Lab Diagn. 2022 Apr 17;67(4):204-206. doi: 10.51620/0869-2084-2022-67-4-204-206.

ABSTRACT

Fabry disease is an X-linked hereditary lysosomal storage disorder caused by mutations in the GLA gene. Neonatal screening for Fabry disease in males is feasible by measurement of α-galactosidase A activity in DBS using either the mass spectrometric or fluorigenic substrate. The aim of the study: to assess the possibility of introducing the compared methods into the practice of neonatal screening. In the both assays performed a statistically significant difference of the enzyme activity between affected individuals and controls is reported. The slight modification of the fluorimetric method by centrifugation of a 96-well microplate before measurement could improve signal to noise ratio.

PMID:35575392 | DOI:10.51620/0869-2084-2022-67-4-204-206

Bioinformatics. 2022 May 16:btac325. doi: 10.1093/bioinformatics/btac325. Online ahead of print.

ABSTRACT

MOTIVATION: Interactions between peptide fragments and protein receptors are vital to cell function yet difficult to experimentally determine in structural details of. As such, many computational methods have been developed to aid in peptide-protein docking or structure prediction. One such method is Rosetta FlexPepDock which consistently refines coarse peptide-protein models into sub-Ångström precision using Monte-Carlo simulations and statistical potentials. Deep learning has recently seen increased use in protein structure prediction, with graph neural networks used for protein model quality assessment.

RESULTS: Here, we introduce a graph neural network, InterPepScore, as an additional scoring term to complement and improve the Rosetta FlexPepDock refinement protocol. InterPepScore is trained on simulation trajectories from FlexPepDock refinement starting from thousands of peptide-protein complexes generated by a wide variety of docking schemes. The addition of InterPepScore into the refinement protocol consistently improves the quality of models created, and on an independent benchmark on 109 peptide-protein complexes its inclusion results in an increase in the number of complexes for which the top-scoring model had a DockQ-score of 0.49 (Medium quality) or better from 14.8% to 26.1%.

AVAILABILITY: InterPepScore is available online at http://wallnerlab.org/InterPepScore.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID:35575349 | DOI:10.1093/bioinformatics/btac325

ACS Macro Lett. 2022 Apr 19;11(4):580-587. doi: 10.1021/acsmacrolett.2c00046. Epub 2022 Apr 7.

ABSTRACT

Overexpression of epidermal growth factor receptor (EGFR) is observed in multiple cancers such as colorectal, lung, and cervical solid tumors. Regulating the EGFR expression is an efficient strategy to manage these malignancies, and it can be achieved by using short interfering RNA (siRNA). Cell-penetrating peptides (CPPs) demonstrated an excellent capability to enhance the cellular uptake of siRNA, but high knockdown efficiencies have not been achieved due to endosomal entrapment. In this work, Schiff’s base reaction was used to modify a block {P[LAEMA(2-lactobionamidoethyl methacrylamide)₃₇]-b-P[FPMA(4-formyl phenyl methacrylate)₂–st-DMA(N,N-dimethylacrylamide)₂], P2} and two statistical [P(LAEMA₂₃–st-FPMA₃) (P3) and P(LAEMA₂₅–st-FPMA₂–st-DMA₂) (P4)] aldehyde-based and galactose-based polymers, prepared via reversible addition-fragmentation chain-transfer (RAFT) polymerization. An arginine-rich peptide (ARP, KRRKRRRRRK) was used as a cell-penetrating peptide (CPP) and conjugated to the polymers via a Schiff base reaction. The resulting glycopolymer-peptide conjugates were utilized to condense the siRNA to prepare polyplexes with multivalent CPPs (MCPPs, a nanoparticle with multiple copies of the CPP) to enhance the endosomal escape. The polyplexes have different surface properties as determined by the architecture of polymers and the insertion of dimethyl amide moieties. The enhancement of cellular internalization of ARP was observed by labeling the polyplexes with fluorescein isothiocyanate (FITC)-siRNA showing a localization of polyplexes in the cytoplasm of a HeLa (cervical cancer) cell line. In the in vitro EFGR silencing study, the statistical glycopolymer-peptide (P3-P) polyplexes had superior EGFR silencing efficiency in comparison with the other polymers that were studied. Furthermore, P3-P polyplexes led to less off-targeting silencing than lipofectamine 3000. These encouraging results confirmed the potency of decorating galactose-based polymers with CPP, like ARP for their application in siRNA delivery and management of cervical carcinomas.

PMID:35575337 | DOI:10.1021/acsmacrolett.2c00046

ACS Macro Lett. 2022 Apr 19;11(4):498-503. doi: 10.1021/acsmacrolett.1c00776. Epub 2022 Mar 22.

ABSTRACT

Polymers that exhibit a lower critical solution temperature (LCST) have been of great interest for various biological applications such as drug or gene delivery, controlled release systems, and biosensing. Tuning the LCST behavior through control over polymer composition (e.g., upon copolymerization of monomers with different hydrophobicity) is a widely used method, as the phase transition is greatly affected by the hydrophilic/hydrophobic balance of the copolymers. However, the lack of a general method that relates copolymer hydrophobicity to their temperature response leads to exhaustive experiments when seeking to obtain polymers with desired properties. This is particularly challenging when the target copolymers are comprised of monomers that individually form nonresponsive homopolymers, that is, only when copolymerized do they display thermoresponsive behavior. In this study, we sought to develop a predictive relationship between polymer hydrophobicity and cloud point temperature (T_CP). A series of statistical copolymers were synthesized based on hydrophilic N,N-dimethyl acrylamide (DMA) and hydrophobic alkyl acrylate monomers, and their hydrophobicity was compared using surface area-normalized octanol/water partition coefficients (Log P_oct/SA). Interestingly, a correlation between the Log P_oct/SA of the copolymers and their T_CPs was observed for the P(DMA-co-RA) copolymers, which allowed T_CP prediction of a demonstrative copolymer P(DMA-co-MMA). These results highlight the strong potential of this computational tool to improve the rational design of copolymers with desired temperature responses prior to synthesis.

PMID:35575334 | DOI:10.1021/acsmacrolett.1c00776

Palliat Support Care. 2022 Apr;20(2):264-274. doi: 10.1017/S1478951521001279.

ABSTRACT

BACKGROUND: The significance of spiritual care needs among chronic diseases patients has been emphasized across countries and cultures in many studies. However, there were few studies on spiritual care needs among elderly patients with moderate-to-severe chronic heart failure (CHF) in China.

OBJECTIVE: To investigate spiritual care needs and associated influencing factors among elderly patients with moderate-to-severe CHF, and to examine the relationships among spiritual care needs, self-perceived burden, symptom management self-efficacy, and perceived social support.

METHODS: A cross-sectional design was implemented, and the STROBE Checklist was used to report the study. A convenience sample of 474 elderly patients with moderate-to-severe CHF were selected from seven hospitals in Tianjin, China. The sociodemographic characteristics questionnaire, the Spiritual Needs Questionnaire Scale, the Self-Perceived Burden Scale, the Self-efficacy for Symptom Management Scale, and the Perceived Social Support Scale were used. Descriptive statistics, univariate, multiple linear regression, and Pearson’s correlation analysis were used to analyze data.

RESULTS: The total score of spiritual care needs among 474 elderly patients with moderate-to-severe CHF was 37.95 ± 14.71, which was moderate. Religious belief, educational background, self-perceived burden, symptom management self-efficacy, and perceived social support were the main factors affecting spiritual care needs, and spiritual care needs were negatively correlated with self-perceived burden (r = -0.637, p < 0.01) and positively correlated with symptom management self-efficacy (r = 0.802, p < 0.01) and social support (r = 0.717, p < 0.01).

SIGNIFICANCE OF RESULTS: The spiritual care needs of elderly patients with moderate-to-severe CHF were moderate, which were influenced by five factors. It is suggested that clinical nurses, families, and society should take targeted spiritual care measures to improve patients’ symptom management self-efficacy and perceived social support from many aspects, and reduce self-perceived burden to meet their spiritual care needs and improve the quality and satisfaction of spiritual care in nursing practice.

PMID:35574915 | DOI:10.1017/S1478951521001279

J Health Care Poor Underserved. 2022;33(2):790-805. doi: 10.1353/hpu.2022.0064.

ABSTRACT

OBJECTIVES: Determine if United States graduates of the Latin American Medical School in Cuba: 1) provide primary health care to disadvantaged populations; 2) complete licensing exams and obtain residencies; and 3) accrue additional debt during their medical education.

METHODS: A Qualtrics secure web-based survey was provided to 158 graduates via email, completed anonymously. Responses were compiled and descriptive statistics generated.

RESULTS: Fifty-six valid surveys were returned, for a response rate of 35.4%. Chi-square analysis showed no statistically significant differences between survey respondents and the sampling frame. Most graduates are people of color; 68% work in clinical medicine; of these, 90% are in primary care, with 100% serving disadvantaged populations. Most accrued no further educational loan debt.

CONCLUSIONS: United States graduates of the Latin American Medical School work in primary care with disadvantaged populations. Graduates accrue little additional student loan debt.

PMID:35574877 | DOI:10.1353/hpu.2022.0064