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Background: Despite the effectiveness of antiretroviral therapy, vertical HIV transmission continues. A potent, broadly neutralizing, monoclonal antibody (bNAb) administered to HIV-exposed infants might reduce transmission. VRC07-523LS is 5-fold more potent and has a prolonged half-life compared to VRC01. VRC07-523LS may provide therapeutic levels over the duration of breastfeeding with infrequent doses. Methods: This is an open-label study of VRC07-523LS administered to HIV-exposed infants. Non-breastfed infants receive 80 mg subcutaneous (SC) within 72 hrs of birth. Infants and mothers receive ART to prevent transmission. Infants have safety assessments and VRC07-523LS levels at 24 hrs, week 2, 4, 8, 12 and every 12 weeks through week 96. The target week 12 plasma level is 10 mcg/mL: the leve needed to neutralize > 90% of tier II viruses in a multiclade panel. Plasma VRC07-523LS levels are determined through week 12 and compared to previously reported levels of VRC01. Results: The non-breastfed cohort fully accrued (N = 11) from US sites Jan-Sep, 2019. All infants received 80 mg VRC07-523LS SC within 72 hours of birth (mean 1.5 days), resulting in an average dose of 28 mg/kg (range 23 to 32 mg/kg). Enrollees were 45% male, 73% Black, 18% Hispanic. One infant withdrew after 4 weeks. VRC07-523LS was well tolerated. Local reactions were rare and mild: 1 infant had injection site erythema of 0.5 cm and 1 had tenderness. Five infants developed Grade 3/4 events within 28 days of receipt of VRC07-523LS (vomiting [N = 2], neutropenia, hyperkalemia, and parainfluenza sepsis), none considered related to study treatment. Pharmacokinetic measures through week 12 show average levels of 68.7, 31.1, 16.3mcg/mL at weeks 4, 8, and 12, respectively. Mean VRC07-523LS levels exceeded those previously reported for VRC01 20 mg/kg SC at week 2, 4, and 8. Ongoing growth contributed to the fall in VRC07-523LS concentration but levels remain over the target of 10 mcg/mL at week 12. Conclusions: We identified no safety or tolerability findings when VRC07-523LS is administered to neonates. Week 12 is an appropriate time for a second dose in infants with ongoing breastmilk exposure. VRC07-523LS, with its enhanced potency and extended half-life, could achieve target levels for the duration of breastfeeding with dosing every 3 months., OA03.02 C. Cunningham (1); E. Capparelli (2); E. McFarland (3); P. Muresan (4); C. Perlowski (5); E. Smith (6); R. Hazra (7); L. Purdue (8); P. Harding (3); A. McDermott [...]

A novel analytical representation of bit error rate (BER) performance of an impulse-radio ultra-wideband energy detector on-off keying system using cooperative dual-hop amplify and forward relay technology, with various diversity combining schemes over IEEE 802.15.4a environment is presented in this paper. In particular, the approximate expressions based on energy detection principle are derived for various diversity combining cases, namely linear optimal combining, linear combining, and selective combining. Simulation results depict an improvement in BER performance, with increase in number of relay paths ( L) and decrease in number of frames per symbol ( N f). Furthermore, the BER performance of the impulse-radio ultra-wideband energy detector on-off keying system improves substantially using dual-hop cooperative amplify and forward scheme, compared with that of non-cooperative or single link scenario. Among the diversity combining schemes, linear optimal diversity combining performs better when compared with linear diversity combining and selective combining. The analytical BER expressions are validated with the simulation results, which confirm the accuracy and precision in approximation used in the investigation of BER. Copyright © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Well-Tempered Metadynamics (WT-MetaD) simulations indicate that composite materials made up of Na-Montmorillonite (Na-MMT) coated with ionic liquids (ILs) having hydrophilic cations serve as good adsorbents for a hexameric (1,4) linked b-D-glucopyranoside (BGLC). Hydrophilic IL cations are effectively coated on the negative charges lining the Na-MMT surface while attracting simultaneously the polar oligosaccharides. In this work we have used two less conventional polyethylene glycol (PEG) based IL cations, [mim2 peg1]2+ and [mim2 peg2]2+, paired with [tf2N]- and Cl- anions. Another strongly hydrophilic ion combination, [C2OHmim][Cl], also showed great promise in effective oligosaccharide adsorption on the Na-MMT surface. The study reveals that the topological polar surface area (TPSA), the octanol-water partition coefficient (log PO/W), the length of the cationic side chain and the Debye screening length  of the IL are some of the most important factors affecting the adsorption of hydrophilic oligosaccharides on the clay-IL composites. Among all the systems studied, [mim2 peg2][tf2N]2 having the highest TPSA and a long screening length emerged as the best adsorbent of the oligosaccharide on the IL-coated clay., (© 2024 Wiley‐VCH GmbH.)

Cancer immunotherapy has revolutionized the treatment landscape by harnessing the power of the immune system to combat malignancies. Two of the most promising players in this field are cluster of differentiation 24 (CD24) and sialic acid-binding Ig-like lectin 10 (Siglec-10), and both of them play pivotal roles in modulating immune responses. CD24, a cell surface glycoprotein, emerges as a convincing fundamental signal transducer for therapeutic intervention, given its significant implication in the processes related to tumour progression and immunogenic evasion. Additionally, the immunomodulatory functions of Siglec-10, a prominent member within the Siglec family of immune receptors, have recently become a crucial point of interest, particularly in the context of the tumour microenvironment. Hence, the intricate interplay of both CD24 and Siglec-10 assumes a critical role in fostering tumour growth, facilitating metastasis and also orchestrating immune evasion. Recent studies have found multiple evidences supporting the therapeutic potential of targeting CD24 in cancer treatment. Siglec-10, on the other hand, exhibits immunosuppressive properties that contribute to immune tolerance within the tumour microenvironment. Therefore, we delve into the complex mechanisms through which Siglec-10 modulates immune responses and facilitates immune escape in cancer. Siglec-10 also acts as a viable target for cancer immunotherapy and presents novel avenues for the development of therapeutic interventions. Furthermore, we examine the synergy between CD24 and Siglec-10 in shaping the immunosuppressive tumour microenvironment and discuss the implications for combination therapies. Therefore, understanding the roles of CD24 and Siglec-10 in cancer immunotherapy opens exciting possibilities for the development of novel therapeutics., (© 2024 John Wiley & Sons Ltd.)

Immunotherapy has revolutionized cancer management, with antibody-based treatments leading the charge due to their superior pharmacodynamics, including enhanced effectiveness and specificity. However, these therapies are hampered by limitations such as prolonged half-lives, poor tissue and tumor penetration, and minimal oral bioavailability. Additionally, their immunogenic nature can cause adverse effects. Consequently, the focus is shifting towards small-molecule-based immunotherapies, which potentially overcome these drawbacks. Emerging as a promising alternative, small molecules offer the benefits of therapeutic antibodies and immunomodulators, often yielding synergistic effects when combined. Recent advancements in small-molecule cancer immunotherapy are notable, featuring inhibitors, agonists, and degraders that act as immunomodulators. This article delves into the current landscape of small-molecule immunotherapy in cancer treatment, highlighting novel agents targeting key pathways such as Toll-like receptors (TLR), PD-1/PD-L1, chemokine receptors, and stimulators of interferon genes (STING). The review emphasizes newly discovered molecular entities and their modulatory roles in tumorigenesis, many of which have progressed to clinical trials, that aims to provide a comprehensive snapshot of the evolving frontier in cancer treatment, driven by small-molecule immunomodulators., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

The binding of Thioflavin T (ThT) with various bile salts, a potential host molecule, has been analyzed by steady-state and time-resolved fluorescence spectroscopy. A comparative study has been executed to investigate the influence of confinement of different bile salts, namely, sodium cholate (NaCh), sodium taurocholate (NaTC), and sodium deoxycholate (NaDC) on binding and excited state torsional motion of ThT molecules. The changes in absorption and emission properties of probe molecules were found to be sensitive to increasing bile salt concentration in aqueous 0.2 (M) NaCl solutions. The photophysics of ThT mainly depends on hydrophobicity, morphology, and size of bile salt aggregates in solution. In the presence of bile salts, the emission intensity and emission lifetime of ThT increase significantly, indicating encapsulation of dye. Moreover, we have also investigated the effect of the ionic strength of the medium by sodium chloride (NaCl) on the spectroscopic properties of ThT in the restricted surroundings of aqueous bile salts. It is observed that the fluorescence lifetime of ThT in bile salts increases significantly in the presence of NaCl. The encapsulation efficiency of ThT in bile salt aggregates has been assessed by iodide ( I - ) as an external ionic quencher. We found that NaDC aggregates are more efficient in the modulation of photophysical properties of ThT and also provide better protection efficiency to decrease the nonradiative deactivation processes.

Ferroptosis, a necrotic, iron-dependent controlled cell death mechanism, is distinguished by the development of lipid peroxides to fatal proportions. Malignant tumours, influenced by iron to promote fast development, are vulnerable to ferroptosis. Based upon mounting evidence it has been observed that ferroptosis may be immunogenic and hence may complement immunotherapies. A new approach includes iron oxide-loaded nano-vaccines (IONVs), having supremacy for the traits of the tumour microenvironment (TME) to deliver specific antigens through improving the immunostimulatory capacity by molecular disintegration and reversible covalent bonds that target the tumour cells and induce ferroptosis. Apart from IONVs, another newer approach to induce ferroptosis in tumour cells is through oncolytic virus (OVs). One such oncolytic virus is the Newcastle Disease Virus (NDV), which can only multiply in cancer cells through the p53-SLC7A11-GPX4 pathway that leads to elevated levels of lipid peroxide and intracellular reactive oxygen species leading to the induction of ferroptosis that induce ferritinophagy., (© 2024 John Wiley & Sons Ltd.)

Abstract: Chronic kidney disease (CKD) is a major contributor to morbidity and mortality in sickle cell disease (SCD). Anemia, induced by chronic persistent hemolysis, is associated with the progressive deterioration of renal health, resulting in CKD. Moreover, patients with SCD experience acute kidney injury (AKI), a risk factor for CKD, often during vaso-occlusive crisis associated with acute intravascular hemolysis. However, the mechanisms of hemolysis-driven pathogenesis of the AKI-to-CKD transition in SCD remain elusive. Here, we investigated the role of increased renovascular rarefaction and the resulting substantial loss of the vascular endothelial protein C receptor (EPCR) in the progressive deterioration of renal function in transgenic SCD mice. Multiple hemolytic events raised circulating levels of soluble EPCR (sEPCR), indicating loss of EPCR from the cell surface. Using bone marrow transplantation and super-resolution ultrasound imaging, we demonstrated that SCD mice overexpressing EPCR were protective against heme-induced CKD development. In a cohort of patients with SCD, plasma sEPCR was significantly higher in individuals with CKD than in those without CKD. This study concludes that multiple hemolytic events may trigger CKD in SCD through the gradual loss of renovascular EPCR. Thus, the restoration of EPCR may be a therapeutic target, and plasma sEPCR can be developed as a prognostic marker for sickle CKD., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Glioblastoma poses a formidable challenge among primary brain tumors: its tumorigenic stem cells, capable of self-renewal, proliferation, and differentiation, contribute substantially to tumor initiation and therapy resistance. These glioblastoma stem cells (GSCs), resembling conventional stem and progenitor cells, adopt pathways critical for tissue development and repair, promoting uninterrupted tumor expansion. Long non-coding RNAs (lncRNAs), a substantial component of the human transcriptome, have garnered considerable interest for their pivotal roles in normal physiological processes and cancer pathogenesis. They display cell- or tissue-specific expression patterns, and extensive investigations have highlighted their impact on regulating GSC properties and cellular differentiation, thus offering promising avenues for therapeutic interventions. Consequently, lncRNAs, with their ability to exert regulatory control over tumor initiation and progression, have emerged as promising targets for innovative glioblastoma therapies. This review explores notable examples of GSC-associated lncRNAs and elucidates their functional roles in driving glioblastoma progression. Additionally, we delved deeper into utilizing a 3D in vitro model for investigating GSC biology and elucidated four primary methodologies for targeting lncRNAs as potential therapeutics in managing glioblastoma., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Hazra, Debnath and Tuppad.)

Oncolytic viruses (OVs) are increasingly recognized as potent tools in cancer therapy, effectively targeting and eradicating oncogenic conditions while sparing healthy cells. They enhance antitumor immunity by triggering various immune responses throughout the cancer cycle. Genetically engineered OVs swiftly destroy cancerous tissues and activate the immune system by releasing soluble antigens like danger signals and interferons. Their ability to stimulate both innate and adaptive immunity makes them particularly attractive in cancer immunotherapy. Recent advancements involve combining OVs with other immune therapies, yielding promising results. Transgenic OVs, designed to enhance immunostimulation and specifically target cancer cells, further improve immune responses. This review highlights the intrinsic mechanisms of OVs and underscores their synergistic potential with other immunotherapies. It also proposes strategies for optimizing armed OVs to bolster immunity against tumors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

The immune system plays a pivotal role in the battle against cancer, serving as a formidable guardian in the ongoing fight against malignant cells. To combat these malignant cells, immunotherapy has emerged as a prevalent approach leveraging antibodies and peptides such as anti-PD-1, anti-PD-L1, and anti-CTLA-4 to inhibit immune checkpoints and activate T lymphocytes. The optimization of gut microbiota plays a significant role in modulating the defense system in the body. This study explores the potential of certain gut-resident bacteria to amplify the impact of immunotherapy. Contemporary antibiotic treatments, which can impair gut flora, may diminish the efficacy of immune checkpoint blockers. Conversely, probiotics or fecal microbiota transplantation can help re-establish intestinal microflora equilibrium. Additionally, the gut microbiome has been implicated in various strategies to counteract immune resistance, thereby enhancing the success of cancer immunotherapy. This paper also acknowledges cutting-edge technologies such as nanotechnology, CAR-T therapy, ACT therapy, and oncolytic viruses in modulating gut microbiota. Thus, an exhaustive review of literature was performed to uncover the elusive link that could potentiate the gut microbiome's role in augmenting the success of cancer immunotherapy., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

This article presents a coherent phenomenon called spontaneously generated coherence (SGC) under the regime of electromagnetically induced transparency (EIT) in a three-coupled multiple quantum wells. We demonstrate that the presence of SGC in these quantum wells lead to intriguing modifications in the transparency window within the absorption spectrum. At the same time, modification of the dispersive nature is also demonstrated which enables the feasibility of the system in diverse applications based on light propagation. The absorption and dispersion responses are found to be varied by the individual strength of the first and second control fields in presence as well as in absence of SGC in the EIT regime. The positional shifting of the transparency window and simultaneous modifications in the dispersive profiles by tuning the control field detunings of both the first and second control fields are also revealed. Some absorption and dispersion contours are illustrated for getting better insights into the modifications of the optical responses via SGC. Finally, by manipulating the strength of the SGC parameter, we observe the changes in the respective position of the transparency window and dispersion curve. It is expected that the current investigations will pave novel ways for innovative applications in quantum communications, and fabrication of advanced photonic devices., (© 2024. The Author(s).)

Human serum albumin (HSA) is an important biomarker that can be used for the early diagnosis of many diseases. In this work, a TICT probe bearing fused naphtho-furan scaffold (NPNF) was developed and employed in the selective turn-on sensing of HSA. The probe's selectivity towards HSA was observed using steady-state fluorescence experiments, with limit of quantitation in micromolar levels. NPNF's capability to exclusively detect HSA over BSA was further studied/rationalized using anisotropy and time-resolved studies. Molecular docking was used to shed light on the location of NPNF in the subdomain IB of HSA. The practical application of the probe was also demonstrated by the detection of HSA in urine and the HSA-assisted detection of cerium., (© 2024 Wiley-VCH GmbH.)

Traumatic brain injury (TBI) presents a significant global health challenge with no effective therapies developed to date. Regulatory T lymphocytes (Tregs) have recently emerged as a potential therapy due to their critical roles in maintaining immune homeostasis, reducing inflammation, and promoting brain repair. Following TBI, fluctuations in Treg populations and shifts in their functionality have been noted. However, the precise impact of Tregs on the pathophysiology of TBI remains unclear. In this review, we discuss recent advances in understanding the intricate roles of Tregs in TBI and other brain diseases. Increased knowledge about Tregs may facilitate their future application as an immunotherapy target for TBI treatment., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Macrophages provide a first line of defense against invading pathogens, including the leading cause of bacterial mortality, Mycobacterium tuberculosis (Mtb). A challenge for quantitative characterization of host-pathogen processes in differentially polarized primary human monocyte-derived macrophages (MDMs) is their heterogeneous morphology. Here, we describe the use of microfabricated patterns that constrain the size and shape of cells, mimicking the physiological spatial confinement cells experience in tissues, to quantitatively characterize interactions during and after phagocytosis at the single-cell level at high resolution. Comparing pro-inflammatory (M1) and anti-inflammatory (M2) MDMs, we find interferon-γ stimulation increases the phagocytic contraction, while contraction and bacterial uptake decrease following silencing of phagocytosis regulator NHLRC2 or bacterial surface lipid removal. We identify host organelle position alterations within infected MDMs and differences in Mtb subcellular localization in line with M1 and M2 cellular polarity. Our approach can be adapted to study other host-pathogen interactions and coupled with downstream automated analytical approaches., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Glioblastoma multiforme (GBM) is an aggressive, heterogeneous brain tumor in which glioblastoma stem cells (GSCs) are known culprits of therapy resistance. Long non-coding RNAs (lncRNAs) have been shown to play a critical role in both cancer and normal biology. A few studies have suggested that aberrant expression of lncRNAs is associated with GSCs. However, a comprehensive single-cell analysis of the GSC-associated lncRNA transcriptome has not been carried out. Here, we analyzed recently published single-cell RNA sequencing datasets of adult GBM tumors, GBM organoids, GSC-enriched GBM tumors, and developing human brain samples to identify lncRNAs highly expressed in GSCs. We further revealed that the GSC-specific lncRNAs GIHCG and LINC01563 promote proliferation, migration, and stemness in the GSC population. Together, this study identified a panel of uncharacterized GSC-enriched lncRNAs and set the stage for future in-depth studies to examine their role in GBM pathology and their potential as biomarkers and/or therapeutic targets in GBM., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Exploring the self and cross aggregation affinity of cholesterol (CHL) and some of its lookalikes, e.g. , cholesteryl hemisuccinate (CHM), campesterol (CAM) and arjunic acid (ARJ), provides crucial understanding towards the influence of weak forces in inducing mixed micellization through heteroaggregation. Strongly hydrophobic CHL, with a benchmark inclination towards aggregation, often forms detrimental plaques in crucial human organs that are fairly difficult to disintegrate. Traditionally known anti-dyslipidemic agents like CAM and ARJ are known to interact strongly with CHL in the gut when ingested. They further form mixed micelles along with the bile components and interfere with the CHL absorption across the epithelial cell layer of the intestine. Some invariant questions like how robust are the heteroaggregates formed between these mimetics and CHL are very important to appreciate the efficacy of such anti-dyslipidemic agents. In this work using molecular dynamics simulations and varied structural analysis, we characterize the heteroaggregates. Simulations indicate that CHL-CHM mixed assemblies are comparatively bigger and significantly stabilized by strong electrostatic and favourable vdW forces. Small and diffused CHL-ARJ aggregates are observed in our simulations with a not so favourable energetics, indicating a possible attenuation pathway of CHL aggregation in the presence of ARJ.

Background and Objective: HIV treatment options remain limited in children. Dolutegravir is a potent and well-tolerated, once-daily HIV-1 integrase inhibitor recommended for HIV-1 infection in both adults and children down to 4 weeks of age. To support pediatric dosing of dolutegravir in children, we used a population pharmacokinetic model with dolutegravir data from the P1093 and ODYSSEY clinical trials. The relationship between dolutegravir exposure and selected safety endpoints was also evaluated., Methods: A population pharmacokinetic model was developed with data from P1093 and ODYSSEY to characterize the pharmacokinetics and associated variability and to evaluate the impact of pharmacokinetic covariates. The final population pharmacokinetic model simulated exposures across weight bands, doses, and formulations that were compared with established adult reference data. Exploratory exposure-safety analyses evaluated the relationship between dolutegravir pharmacokinetic parameters and selected clinical laboratory parameters and adverse events., Results: A total of N = 239 participants were included, baseline age ranged from 0.1 to 17.5 years, weight ranged from 3.9 to 91 kg, 50% were male, and 80% were black. The final population pharmacokinetic model was a one-compartment model with first-order absorption and elimination, enabling predictions of dolutegravir concentrations in the pediatric population across weight bands and doses/formulations. The predicted geometric mean trough concentration was comparable to the adult value following a 50-mg daily dose of dolutegravir for all weight bands at recommended doses. Body weight, age, and formulation were significant predictors of dolutegravir pharmacokinetics in pediatrics. Additionally, during an exploratory exposure-safety analysis, no correlation was found between dolutegravir exposure and selected safety endpoints or adverse events., Conclusions: The dolutegravir dosing in children ≥ 4 weeks of age on an age/weight-band basis provides comparable exposures to those historically observed in adults. Observed pharmacokinetic variability was higher in this pediatric population and no additional safety concerns were observed. These results support the weight-banded dosing of dolutegravir in pediatric participants currently recommended by the World Health Organization., (© 2023. The Author(s).)

The naturally occurring yellow polyphenolic medicinal pigment curcumin shows ultrafast dynamics in the excited states. These ultrafast dynamics are strongly influenced by the rigidity of the environments of the systems. The present investigation unveils the ultrafast excited-state intramolecular hydrogen atom transfer (ESIHT) (which is involved in the antioxidant mechanism) and the solvation dynamics of curcumin inside the imidazolium surface active ionic liquid (SAIL), 1-hexadecyl-3-methylimidazolium chloride ([C 16 mim]Cl) micelle, and giant vesicles after introducing sorbitan monoesters (Span 20 and Span 80) in the aqueous medium. Interestingly, the short hydrocarbon chain containing Span 20 forms smaller, less rigid vesicles, and the long hydrocarbon chain containing Span 80 forms larger, more rigid giant vesicles after being assembled with [C 16 mim]Cl. The ESIHT and the solvation dynamics are slower in Span 80, containing rigid vesicles, than that in Span 20, comprising less rigid vesicles. Finally, we have established a three-component fluorescence resonance energy transfer (Triple-FRET) system to generate white light (WL) in the micelle and giant vesicles. Here the hydrophobic dye 1,6-diphenyl-1,3,5-hexatriene (DPH) acts as the donor, and the hydrophilic anticancer drug doxorubicin hydrochloride (DOX) serves as the acceptor along with the intermediate donor, curcumin. At a specific combination of the concentrations of these dyes in a particular self-assembled system, WL is generated due to the triple-FRET phenomena.

White-matter injury in sickle-cell disease (SCD) includes silent cerebral infarction diagnosed by diffusion tensor imaging (DTI), a complication associated with cognitive dysfunction in children with SCD. The link between white-matter injury and cognitive dysfunction has not been fully elucidated. The goal of this study was to define whether cerebrovascular lesions and cognitive function in SCD are linked to neuroaxonal damage and astrocyte activation in humanized Townes' SCD mice homozygous for human sickle hemoglobin S (SS) and control mice homozygous for human normal hemoglobin A (AA). Mice underwent MRI with DTI and cognitive testing, and histology sections from their brains were stained to assess microstructural tissue damage, neuroaxonal damage, and astrocyte activation. Fractional anisotropy, showing microstructural cerebrovascular abnormalities identified by DTI in the white matter, was significantly associated with neuronal demyelination in the SS mouse brain. SS mice had reduced learning and memory function with a significantly lower discrimination index compared with AA control mice in the novel object recognition tests. Neuroaxonal damage in the SS mice was synchronously correlated with impaired neurocognitive function and activation of astrocytes. The interplay between astrocyte function and neurons may modulate cognitive performance in SCD., (© The Author(s) 2023. Published by Oxford University Press on behalf of National Academy of Sciences.)

Unrestrained excessive inflammatory responses exacerbate ischemic brain injury and impede post-stroke brain recovery. CD4 + CD25 + Foxp3 + regulatory T (Treg) cells play important immunosuppressive roles to curtail inflammatory responses and regain immune homeostasis after stroke. Accumulating evidence confirms that Treg cells are neuroprotective at the acute stage after stroke and promote brain repair at the chronic phases. The beneficial effects of Treg cells are mediated by diverse mechanisms involving cell-cell interactions and soluble factor release. Multiple types of cells, including both immune cells and non-immune CNS cells, have been identified to be cellular targets of Treg cells. In this review, we summarize recent findings regarding the function of Treg cells in ischemic stroke and the underlying cellular and molecular mechanisms. The protective and reparative properties of Treg cells endorse them as good candidates for immune therapy. Strategies that boost the numbers and functions of Treg cells have been actively developing in the fields of transplantation and autoimmune diseases. We discuss the approaches for Treg cell expansion that have been tested in stroke models. The application of these approaches to stroke patients may bring new hope for stroke treatments., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Self-assembly of cholesterol (CHL) is infamous for its diverse deleterious effects on human health. Clinical research over several decades indicates that a diet rich in CHL typically leads to arterial plaques, cataracts and gall stones among others. Carbohydrates like the β -glucans efficiently lower serum CHL, possibly by inhibiting CHL absorption in the digestive tract. Using molecular dynamics simulations, we explore how β -D-glucose (BGLC), the building block of β -glucans, interferes with CHL aggregation. BGLC slows down CHL diffusion and disrupts the formation of the robust hydrophobic CHL assembly. Estimation of the translational entropy of the CHL molecules shows the extent of retardation induced by BGLC. Coordination numbers obtained from the adjacency matrix and collective variable analysis of the packing of the CHL molecules in presence of BGLC show the time evolution of CHL aggregation. In presence of BGLC, small isolated CHL islands form, consolidate and disintegrate over time as compared to the blank CHL system. The predominance of smaller CHL clusters is an effect of the significant retardation of the translational motion of CHL molecules induced by BGLC.Communicated by Ramaswamy H. Sarma.

Statement of Problem: Multiple classifications exist for maxillectomy defects. However, none of the existing classifications describes the defects as favorable or unfavorable from the prosthodontist's standpoint. The most common problem with prosthetic treatment in such patients is in getting adequate retention, stability, and support. The size and location of the defect usually influence the amount of impairment and difficulty in prosthetic rehabilitation., Proposed Classification: A series of cases has been studied, and a newer type of maxillary defect is seen with a better presurgical involvement of the prosthodontist. This type of defects is not present in any of the existing classification; hence, a modification is proposed, and its requisite cast partial framework design is also given. Another treatment-based classification is also proposed for easy treatment planning in these cases. A case series of maxillectomy patients with varying types of defects rehabilitated with obturators with different designs, modes of retention, and fabrication procedure in accordance to the newer classification is described., Discussion: Surgical intervention creates communication among the oral cavity, nasal cavity, and maxillary sinus. The obturator prosthesis is commonly used as an effective means for rehabilitating such cases. There is a plethora of classifications available for maxillectomy defects though none of them takes existing dentition into consideration. While remaining dentition and various other favorable and unfavorable factors decide on the final prognosis of the prosthesis. Hence, a newer classification was planned with keeping in mind newer treatment modalities., Conclusions: Prosthodontic rehabilitation with obturator prosthesis design and manufactured by various principles and techniques restores the missing structures and acts as a barrier between the communication among the various cavities and definitely improving their quality of life. Considering the complexities of maxillary anatomy, the various permutations of the maxillectomy defect, the current trends in surgical management with presurgical prosthodontic planning, and various prosthodontic treatment options available, it is imperative that a more objective modification of the current classification described in this article is warranted for and could be more operator friendly in finalizing and communicating of the treatment plan.

Wrapping of a 20-mer cholesterol nano-cluster (CHL-nanoC) by two widely different types of β-glucan polysaccharides (23-25 mers) having significantly varying glycosidic linkage patterns and side chains is studied by Well-Tempered MetaDynamics (WT-MetaD) simulations. The problem has its relevance in the faecal sterol and bile acid excretion in humans and the role of dietary fibres in aiding the process and combating dyslipidemia. Additionally, the distinctive collective variables studied here can be extended for modeling of polymer wrapped soft clusters/nano-particles in general. The wrapping ability is observed to be significantly correlated to the bending of the polysaccharide chain, an attribute of the glycosidic linkage type. By biasing two unique collective variables, the radius of gyration of the polysaccharide (R g, poly ) and the second order Legendre polynomial of the segment orientation parameter, θ, we could successfully observe the wrapping process. This work compares in detail the physical properties of the polysaccharide encapsulated CHL-nanoC by probing the radius of curvature (R curv, poly ) of the polysaccharides, their coordination number with respect to the CHL-nanoC (CN), fractional CHL-nanoC surface coverage and the electrostatic surface potentials of the complex assembly. Results indicate that the β-glucan having 1-4 glycosidic linked monomers with intermittent 1-3 linkage is able to wrap the CHL-nanoC more effectively. The 1-3 glycosidic linked β-glucan with 1-6 glycosidic bonds in side chains is significantly curled up and appears to be less efficient in wrapping the nanoC. This work provides a comparative molecular level picture of mutual interaction between two major dietary polysaccharide variants and lipid globules as indicated by numerous clinical level studies involving mice and human models., Competing Interests: Declaration of Competing Interest The authors do not have any competing interest to disclose., (Copyright © 2023 Elsevier B.V. All rights reserved.)

In utero exposure to didanosine was associated with increased risk of brain cancer in a French study. We used United States health department records to assess cancer risk among 13 617 children exposed to HIV in utero , who remained HIV-uninfected after birth (1990-2017). Risk of brain tumors was borderline elevated among these children (standardized incidence ratio 2.2, 95% confidence interval 0.8-4.8, P  = 0.12, based on six cases). Risk was not significantly increased for leukemia or other cancers., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

In the ischemic brain, hypoxia leads to mitochondrial dysfunction, insufficient energy production, and astrocyte activation. Yet, most studies investigating mitochondrial dysfunction in cerebral ischemia have focused exclusively on neurons. This review will highlight the importance of the morphological, molecular, and functional heterogeneity of astrocytes in their role in brain injuries and explore how activated astrocytes exhibit calcium imbalance, reactive oxygen species overproduction, and apoptosis. In addition, special focus will be given to the role of the mitochondrial protein frataxin in activated astrocytes during ischemia and its putative role in the pharmacological management of cerebral ischemia., (© 2022 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Occlusion of cerebral blood vessels causes acute cerebral hypoxia-an important trigger of ischemic white matter injury and stroke in sickle cell disease (SCD). While chronic hypoxia triggers compensatory neuroprotection via insulin-like growth factor-1 (IGF-1) and hypoxia inducible factor-1α (HIF-1α), severe bouts of acute hypoxia and subsequent restoration of blood flow (hypoxia/reoxygenation, H/R) overwhelm compensatory mechanisms and cause neuroaxonal damage-identified as white matter lesions-in the brain. The neuroprotective role of IGF-1 in the pathogenesis of white matter injury in SCD has not been investigated; however, it is known that systemic IGF-1 is reduced in individuals with SCD. We hypothesized that IGF-1 supplementation may prevent H/R-induced white matter injury in SCD. Transgenic sickle mice homozygous for human hemoglobin S and exposed to H/R developed white matter injury identified by elevated expression of non-phosphorylated neurofilament H (SMI32) with a concomitant decrease in myelin basic protein (MBP) resulting in an increased SMI32/MBP ratio. H/R-challenge also lowered plasma and brain IGF-1 expression. Human recombinant IGF-1 prophylaxis significantly induced HIF-1α and averted H/R-induced white matter injury in the sickle mice compared to vehicle-treated mice. The expression of the IGF-1 binding proteins IGFBP-1 and IGFBP-3 was elevated in the IGF-1-treated brain tissue indicating their potential role in mediating neuroprotective HIF-1α signaling. This study provides proof-of-concept for IGF-1-mediated neuroprotection in SCD.

The mammalian genome encodes thousands of long non-coding RNAs (lncRNAs), many of which are developmentally regulated and differentially expressed across tissues, suggesting their potential roles in cellular differentiation. Despite this expression pattern, little is known about how lncRNAs influence lineage commitment at the molecular level. Here, we demonstrate that perturbation of an embryonic stem cell/early embryonic lncRNA, pluripotency-associated transcript 4 (Platr4), directly influences the specification of cardiac-mesoderm-lineage differentiation. We show that Platr4 acts as a molecular scaffold or chaperone interacting with the Hippo-signaling pathway molecules Yap and Tead4 to regulate the expression of a downstream target gene, Ctgf, which is crucial to the cardiac-lineage program. Importantly, Platr4 knockout mice exhibit myocardial atrophy and valve mucinous degeneration, which are both associated with reduced cardiac output and sudden heart failure. Together, our findings provide evidence that Platr4 is required in cardiac-lineage specification and adult heart function in mice., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)