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PLoS Genetics Jun 2024The outer membrane of gram-negative bacteria is a barrier to chemical and physical stress. Phospholipid transport between the inner and outer membranes has been an area...
The outer membrane of gram-negative bacteria is a barrier to chemical and physical stress. Phospholipid transport between the inner and outer membranes has been an area of intense investigation and, in E. coli K-12, it has recently been shown to be mediated by YhdP, TamB, and YdbH, which are suggested to provide hydrophobic channels for phospholipid diffusion, with YhdP and TamB playing the major roles. However, YhdP and TamB have different phenotypes suggesting distinct functions. It remains unclear whether these functions are related to phospholipid metabolism. We investigated a synthetic cold sensitivity caused by deletion of fadR, a transcriptional regulator controlling fatty acid degradation and unsaturated fatty acid production, and yhdP, but not by ΔtamB ΔfadR or ΔydbH ΔfadR. Deletion of tamB recuses the ΔyhdP ΔfadR cold sensitivity further demonstrating the phenotype is related to functional diversification between these genes. The ΔyhdP ΔfadR strain shows a greater increase in cardiolipin upon transfer to the non-permissive temperature and genetically lowering cardiolipin levels can suppress cold sensitivity. These data also reveal a qualitative difference between cardiolipin synthases in E. coli, as deletion of clsA and clsC suppresses cold sensitivity but deletion of clsB does not. Moreover, increased fatty acid saturation is necessary for cold sensitivity and lowering this level genetically or through supplementation of oleic acid suppresses the cold sensitivity of the ΔyhdP ΔfadR strain. Together, our data clearly demonstrate that the diversification of function between YhdP and TamB is related to phospholipid metabolism. Although indirect regulatory effects are possible, we favor the parsimonious hypothesis that YhdP and TamB have differential phospholipid-substrate transport preferences. Thus, our data provide a potential mechanism for independent control of the phospholipid composition of the inner and outer membranes in response to changing conditions based on regulation of abundance or activity of YhdP and TamB.
PubMed: 38913742
DOI: 10.1371/journal.pgen.1011335 -
PloS One 2024With a globally aging population, there is a need to better understand how brain structure relates to function in healthy older and younger adults. (Comparative Study)
Comparative Study
OBJECTIVE
With a globally aging population, there is a need to better understand how brain structure relates to function in healthy older and younger adults.
METHODS
34 healthy participants divided into older (17; Mean = 70.9, SD = 5.4) and younger adults (17; Mean = 28.1, SD = 2.8) underwent diffusion-weighted imaging and neuropsychological assessment, including the California Verbal Learning Test 2nd Edition and the Trail Making Test (TMT-A and TMT-B). Differences in white matter microstructure for older and younger adults and the association between DTI metrics (fractional anisotropy, FA; mean diffusivity, MD) and cognitive performance were analyzed using tract-based spatial statistics (p < 0.05, corrected).
RESULTS
Older adults had significantly lower FA and higher MD than younger adults in widespread brain regions. There was a significant negative correlation between executive function (TMT-B) and MD for older adults in the right superior/anterior corona radiata and the corpus callosum. No significant relationship was detected between DTI metrics and executive function in younger adults or with memory performance in either group.
CONCLUSIONS
The findings underscore the need to examine brain-behaviour relationships as a function of age. Future studies should include comprehensive assessments in larger lifespan samples to better understand the aging brain.
Topics: Humans; White Matter; Aged; Male; Female; Adult; Neuropsychological Tests; Diffusion Tensor Imaging; Aging; Middle Aged; Executive Function; Cognition; Young Adult; Diffusion Magnetic Resonance Imaging; Brain; Aged, 80 and over; Anisotropy
PubMed: 38913655
DOI: 10.1371/journal.pone.0305818 -
Journal of Applied Biomedicine Jun 2024Diffuse large B-cell lymphoma (DLBCL) stands out as the most common type of malignant cancer, representing the majority of cases of non-Hodgkin's lymphoma. Ethyl...
Diffuse large B-cell lymphoma (DLBCL) stands out as the most common type of malignant cancer, representing the majority of cases of non-Hodgkin's lymphoma. Ethyl pyruvate (EP) is a derivative of pyruvic acid and found to have potent anti-tumor properties. Despite its potential benefits, the impact of EP on DLBCL remains ambiguous. Our objective is to elucidate the role of EP in modulating the development of DLBCL. Analysis of cholecystokinin-8 (CCK-8) revealed that treatment with EP significantly diminished the viability of DLBCL cells. Furthermore, EP administration suppressed colony formation and hindered cell adhesion and invasion in DLBCL cells. Examination of cell cycle progression showed that EP treatment induced arrest at the G1 phase and subsequently reduced the S phase population in DLBCL cells. EP treatment consistently exhibited apoptosis-inducing properties in Annexin-V assays, and notably downregulated the expression of Bcl-2 while increasing levels of proapoptotic cleaved caspase 3 and BAX in DLBCL cells. Additionally, EP treatment decreased the overexpression of c-Jun in c-Jun-transfected DLBCL cells. Further, EP demonstrated DNA-damaging effects in TUNEL assays. In vivo, xenograft animal models revealed that EP treatment significantly mitigated DLBCL tumor growth and suppressed DLBCL cell adhesion to bone marrow stromal cells. In summary, these findings suggest that EP mitigates DLBCL progression by inducing apoptosis, inducing cell cycle arrest, and promoting DNA damage.
Topics: Pyruvates; Lymphoma, Large B-Cell, Diffuse; Humans; Animals; Cell Adhesion; Cell Proliferation; Cell Line, Tumor; Mice; Apoptosis; Proto-Oncogene Proteins c-jun; Xenograft Model Antitumor Assays
PubMed: 38912866
DOI: 10.32725/jab.2024.014 -
JCI Insight Jun 2024The diffuse axonal damage in white matter and neuronal loss, along with excessive neuroinflammation, hinder long-term functional recovery after traumatic brain injury...
The diffuse axonal damage in white matter and neuronal loss, along with excessive neuroinflammation, hinder long-term functional recovery after traumatic brain injury (TBI). MicroRNAs (miRs) are small noncoding RNAs that negatively regulate protein-coding target genes in a posttranscriptional manner. Recent studies have shown that loss of function of the miR-15a/16-1 cluster reduced neurovascular damage and improved functional recovery in ischemic stroke and vascular dementia. However, the role of the miR-15a/16-1 cluster in neurotrauma is poorly explored. Here, we report that genetic deletion of the miR-15a/16-1 cluster facilitated the recovery of sensorimotor and cognitive functions, alleviated white matter/gray matter lesions, reduced cerebral glial cell activation, and inhibited infiltration of peripheral blood immune cells to brain parenchyma in a murine model of TBI when compared with WT controls. Moreover, intranasal delivery of the miR-15a/16-1 antagomir provided similar brain-protective effects conferred by genetic deletion of the miR-15a/16-1 cluster after experimental TBI, as evidenced by showing improved sensorimotor and cognitive outcomes, better white/gray matter integrity, and less inflammatory responses than the control antagomir-treated mice after brain trauma. miR-15a/16-1 genetic deficiency and miR-15a/16-1 antagomir also significantly suppressed inflammatory mediators in posttrauma brains. These results suggest miR-15a/16-1 as a potential therapeutic target for TBI.
Topics: Animals; MicroRNAs; Brain Injuries, Traumatic; Mice; Recovery of Function; Disease Models, Animal; Male; Mice, Knockout; Mice, Inbred C57BL; Brain
PubMed: 38912585
DOI: 10.1172/jci.insight.178650 -
Annals of Indian Academy of Neurology May 2024Epileptic spasms are a unique, age-dependent manifestation of epilepsies in infancy and early childhood, commonly occurring as part of infantile epileptic spasms...
Epileptic spasms are a unique, age-dependent manifestation of epilepsies in infancy and early childhood, commonly occurring as part of infantile epileptic spasms syndrome. Developmental stagnation and subsequent decline may occur in children with epileptic spasms, partly due to the abundant high-amplitude interictal epileptiform and slow wave abnormalities. Early recognition and treatment of epileptic spasms, along with the reversal of the electroencephalography (EEG) findings, are critical for improving outcomes. Recognizing hypsarrhythmia and its variations is key to confirming the diagnosis. The various patterns of hypsarrhythmia are not etiology specific, but could indicate the severity of the disease. Several scoring systems have been proposed to improve the inter-rater reliability of recognizing hypsarrhythmia and to assess EEG progress in response to treatment. Ictal patterns during spasms are brief and composed of slow waves, sharp transients, fast activity, and voltage attenuation, either in isolation or more commonly as a combination of these waveforms. Ictal patterns are commonly diffuse, but may be lateralized to one hemisphere in children with structural etiology. A subset of patients with epileptic spasms has a surgically remediable etiology, with readily identifiable lesions on neuroimaging in most cases. Asymmetry in epileptic spasms, concurrent focal seizures, and asymmetric interictal and ictal EEG findings may be present, but a lack of focality in electrophysiological findings is not uncommon. Intracranial EEG features of epileptic spasms have been described, but the utility of intracranial EEG monitoring in surgical candidates with overt focal epileptogenic lesions on magnetic resonance imaging is questionable, and surgery could be performed using noninvasive data.
PubMed: 38912539
DOI: 10.4103/aian.aian_445_24 -
Heliyon Jun 2024The security of images is one of the predominant pivotal aspects in the mammoth and still expanding digital domain. Due to chaotic system properties i.e. randomness and...
The security of images is one of the predominant pivotal aspects in the mammoth and still expanding digital domain. Due to chaotic system properties i.e. randomness and unpredictability is very appropriate to encrypt the images. In this research article, we construct an encryption model via 6D hyperchaotic map and a symmetric matrix for both color and grayscale images. We utilize the 6D hyperchaotic map in the confusion stage to change the pixel location and the symmetric matrix is used for changing the pixel value in the diffusion step for each RGB channel extraction from plain or original image. The image encryption model is checked over differential attacks (NPCR and UACI). Histogram analysis, correlation coefficients, and entropy analysis are also performed as statistical attacks. In conclusion, the image pixels are uniformly distributed, and the average entropy value are 7.9992 and 7.9973 for color and grayscale images, subsequently. The average NPCR and UACI for color images are 99.5956 and 33.4061, correspondingly, while the values for grayscale images are 99.5934 and 33.3054, respectively. These values are in the vicinity of optimal ranges. The suggested scheme's great efficiency and the proposed algorithm's resilience to a wide range of cryptanalytic attacks are implied by experimental results, statistical analysis, and differential attacks.
PubMed: 38912513
DOI: 10.1016/j.heliyon.2024.e31618 -
Heliyon Jun 2024Clinical benefit of Alpha-Proteinase Inhibitor (Human) (A-PI) products for Alpha-antitrypsin deficiency (AATD) is uncertain, based on a systematic review of... (Review)
Review
Clinical benefit of Alpha-Proteinase Inhibitor (Human) (A-PI) products for Alpha-antitrypsin deficiency (AATD) is uncertain, based on a systematic review of observational studies and randomized controlled trials (RCTs) in AATD of Alpha-Proteinase Inhibitor (Human) (A-PI) products. At the recommended dose, A-PI products raise its serum concentration but do not normalize levels. Observational studies suggest A-PI might modestly slow progression of airflow limitation in patients with intermediate airflow obstruction, a finding not confirmed by three placebo-controlled RCTs of limited power, which showed non-significant rates of forced expiratory volume in 1 s (FEV) change favoring placebo. These RCTs found trends favoring A-PI in loss of high-resolution computerized tomographic (HRCT) lung density. While two meta-analyses of HRCT lung density change in RCTs achieved significance favoring A-PI arms, clinical benefit remains uncertain. HRCT lung density measurements don't distinguish changes in measured density due to fluid shifts into and out of the lungs and changes in lung inflammation from those due to progressive loss of alveolar mass. A meta-analysis of RCTs found exacerbations significantly increased in A-PI groups compared to placebo. No RCTs have shown favorable effects of A-PI on mortality, FEV, 6-min walking distance, quality of life, change in diffusion capacity of carbon monoxide (DL, or exacerbation frequency. A fourth RCT comparing two dose regimens of A-PI is underway. RCTs have not provided evidence of clinical benefit in terms of how patients feel, function, or survive. Results have implications for the design of future clinical trials of A-PI and potentially other products targeting AATD-associated emphysema.
PubMed: 38912501
DOI: 10.1016/j.heliyon.2024.e31183 -
International Journal of Pharmaceutics:... Jun 2024Vincristine (VCR), as a cytotoxic drug, is used clinically to treat acute lymphatic leukemia and breast cancer, and commonly used clinically as vincristine sulfate...
Vincristine (VCR), as a cytotoxic drug, is used clinically to treat acute lymphatic leukemia and breast cancer, and commonly used clinically as vincristine sulfate (VCRS). However, its clinical use is limited by unpredictable pharmacologic characteristics, a narrow therapeutic index, and neurotoxicity. The pH gradient method was used for active drug loading of VCRS, and the process route mainly includes the preparation of blank liposomes and drug-loaded liposomes. VCRS liposomes had suitable particle size, high encapsulation efficiency and good stability. The loading and release kinetics of VCRS liposomes were explored. By calculating the changes of encapsulation efficiency with time at different temperatures, it was confirmed that the drug-loading process of liposomes exhibited a first-order kinetic feature, and the activation energy required for the reaction was determined as 20.6 kcal/mol. The release behavior at different pH was also investigated, and it was demonstrated that the release behavior conformed to the first-order model, suggesting that the release mechanism of VCRS was simple transmembrane diffusion. VCRS liposomes also enhanced and antitumor activity. Thus, VCRS liposomes showed great potential for VCRS delivery, and the loading and release kinetics were well researched to provide a reference for investigating active drug loading liposomes.
PubMed: 38912324
DOI: 10.1016/j.ijpx.2024.100258 -
The Indian Journal of Radiology &... Jul 2024Intracranial cavernous malformations (CMs), commonly known as cavernomas or cavernous angiomas, are low-flow, well-circumscribed vascular lesions composed of... (Review)
Review
Intracranial cavernous malformations (CMs), commonly known as cavernomas or cavernous angiomas, are low-flow, well-circumscribed vascular lesions composed of sinusoidal spaces lined by a single layer of endothelium and separated by a collagenous matrix without elastin, smooth muscle, or other vascular wall elements. A diameter greater than 3 cm for a CM is unlikely. These lesions may have atypical appearances on magnetic resonance imaging (MRI). MRI with advanced techniques such as a susceptibility-weighted image or T2-gradient echo, a diffusion-weighted image and corresponding apparent diffusion coefficient map, and diffusion tensor tractography have revolutionized the diagnostic approach to these lesions. The present study reviews the etiopathogenesis, clinical manifestations, MRI strategy, and MRI appearances of the CMs, with a few examples of the giant CMs from our archive. Intracranial giant CMs may have unexpected locations, sizes, numbers, and varied imaging appearances due to repeated hemorrhages, unusual enhancement patterns, intense perifocal edema, and unusual associations, making the differential diagnosis difficult. Familiarity with the MRI appearances of the giant intracranial CMs and the differential diagnosis improves diagnostic accuracy and patient management.
PubMed: 38912256
DOI: 10.1055/s-0044-1779587 -
The Indian Journal of Radiology &... Jul 2024: Despite documented correlation between glioma grades and dynamic contrast-enhanced (DCE) magnetic resonance (MR) perfusion-derived parameters, and its inherent...
Diagnostic Utility of Integration of Dynamic Contrast-Enhanced and Dynamic Susceptibility Contrast MR Perfusion Employing Split Bolus Technique in Differentiating High-Grade Glioma.
: Despite documented correlation between glioma grades and dynamic contrast-enhanced (DCE) magnetic resonance (MR) perfusion-derived parameters, and its inherent advantages over dynamic susceptibility contrast (DSC) perfusion, the former remains underutilized in clinical practice. Given the inherent spatial heterogeneity in high-grade diffuse glioma (HGG) and assessment of different perfusion parameters by DCE (extravascular extracellular space volume [Ve] and volume transfer constant in unit time [k-trans]) and DSC (rCBV), integration of the two into a protocol could provide a holistic assessment. Considering therapeutic and prognostic implications of differentiating WHO grade 3 from 4, we analyzed the two grades based on a combined DCE and DSC perfusion. : Perfusion sequences were performed on 3-T MR. Cumulative dose of 0.1 mmol/kg of gadodiamide, split into two equal boluses, was administered with an interval of 6 minutes between the DCE and DSC sequences. DCE data were analyzed utilizing commercially available GenIQ software. : Of the 41 cases of diffuse gliomas analyzed, 24 were WHO grade III and 17 grade IV gliomas (2016 WHO classification). To differentiate grade III and IV gliomas, Ve cut-off value of 0.178 provided the best combination of sensitivity (88.24%) and specificity (87.50%; AUC: 0.920; < 0.001). A relative cerebral blood volume (rCBV) of value 3.64 yielded a sensitivity of 70.59% and specificity of 62.50% ( = 0.018). The k-trans value, although higher in grade III than in grade IV gliomas, did not reach statistical significance ( = 0.108). : Uniqueness of employed combined perfusion technique, treatment naïve patients at imaging, user-friendly postprocessing software utilization, and ability of Ve and rCBV to differentiate between grade III and IV gliomas ( < 0.05) are the strengths of the present study, contributing to the existing literature and moving a step closer to achieving accurate MR perfusion-based glioma grading.
PubMed: 38912247
DOI: 10.1055/s-0043-1777742