CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors.

Depleting regulatory T cells (Treg cells) to counteract immunosuppressive features of the tumor microenvironment (TME) is an attractive strategy for cancer treatment; however, autoimmunity due to systemic impairment of their suppressive function limits its therapeutic potential. Elucidating approaches that specifically disrupt intratumoral Treg cells is direly needed for cancer immunotherapy. We found that CD36 was selectively upregulated in intrautumoral Treg cells as a central metabolic modulator. CD36 fine-tuned mitochondrial fitness via peroxisome proliferator-activated receptor-ß signaling, programming Treg cells to adapt to a lactic acid-enriched TME. Genetic ablation of Cd36 in Treg cells suppressed tumor growth accompanied by a decrease in intratumoral Treg cells and enhancement of antitumor activity in tumor-infiltrating lymphocytes without disrupting immune homeostasis. Furthermore, CD36 targeting elicited additive antitumor responses with anti-programmed cell death protein 1 therapy. Our findings uncover the unexplored metabolic adaptation that orchestrates the survival and functions of intratumoral Treg cells, and the therapeutic potential of targeting this pathway for reprogramming the TME.

NF-κB Restricts Inflammasome Activation via Elimination of Damaged Mitochondria.

Nuclear factor κB (NF-κB), a key activator of inflammation, primes the NLRP3-inflammasome for activation by inducing pro-IL-1ß and NLRP3 expression. NF-κB, however, also prevents excessive inflammation and restrains NLRP3-inflammasome activation through a poorly defined mechanism. We now show that NF-κB exerts its anti-inflammatory activity by inducing delayed accumulation of the autophagy receptor p62/SQSTM1. External NLRP3-activating stimuli trigger a form of mitochondrial (mt) damage that is caspase-1- and NLRP3-independent and causes release of direct NLRP3-inflammasome activators, including mtDNA and mtROS. Damaged mitochondria undergo Parkin-dependent ubiquitin conjugation and are specifically recognized by p62, which induces their mitophagic clearance. Macrophage-specific p62 ablation causes pronounced accumulation of damaged mitochondria and excessive IL-1ß-dependent inflammation, enhancing macrophage death. Therefore, the "NF-κB-p62-mitophagy" pathway is a macrophage-intrinsic regulatory loop through which NF-κB restrains its own inflammation-promoting activity and orchestrates a self-limiting host response that maintains homeostasis and favors tissue repair.

Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression.

Epidemiological studies indicate that overweight and obesity are associated with increased cancer risk. To study how obesity augments cancer risk and development, we focused on hepatocellular carcinoma (HCC), the common form of liver cancer whose occurrence and progression are the most strongly affected by obesity among all cancers. We now demonstrate that either dietary or genetic obesity is a potent bona fide liver tumor promoter in mice. Obesity-promoted HCC development was dependent on enhanced production of the tumor-promoting cytokines IL-6 and TNF, which cause hepatic inflammation and activation of the oncogenic transcription factor STAT3. The chronic inflammatory response caused by obesity and enhanced production of IL-6 and TNF may also increase the risk of other cancers.

Computational Insights into Schottky Barrier Heights: Graphene and Borophene Interfaces with H- and H́-XSi2N4 (X = Mo, W) Monolayers.

The two-dimensional (2D) semiconducting family of XSi2N4 (X = Mo and W), an emergent class of air-stable monolayers, has recently gained attention due to its distinctive structural, mechanical, transport, and optical properties. However, the electrical contact between XSi2N4 and metals remains a mystery. In this study, we inspect the electronic and transport properties, specifically the Schottky barrier height (SBH) and tunneling probability, of XSi2N4-based van der Waals contacts by means of first-principles calculations. Our findings reveal that the electrical contacts of XSi2N4 with metals can serve as the foundation for nanoelectronic devices with ultralow SBHs. We further analyzed the tunneling probability of different metal contacts with XSi2N4. We found that the H-phase XSi2N4/metal contact shows superior tunneling probability compared to that of H́-based metal contacts. Our results suggest that heterostructures at interfaces can potentially enable efficient tunneling barrier modulation in metal contacts, particularly in the case of MoSi2N4/borophene compared to MoSi2N4/graphene and WSi2N4/graphene in transport-efficient electronic devices. Among the studied heterostructures, tunneling efficiency is highest at the H and H́-MoSi2N4/borophene interfaces, with barrier heights of 2.1 and 1.52 eV, respectively, and barrier widths of 1.04 and 0.8 Å. Furthermore, the tunneling probability for these interfaces was identified to be 21.3 and 36.4%, indicating a good efficiency of carrier injection. Thus, our study highlights the potential of MoSi2N4/borophene contact in designing power-efficient Ohmic devices.

Free carrier-mediated ferromagnetism in nonmagnetic ion (Bi-Li) codoped ZnO nanowires.

Non-magnetic dopants and p-type materials are attractive choices to explore the mechanism and origin of room-temperature defect-based ferromagnetism in metal oxide-based DMSs. In this study, we performed comprehensive transport, magnetic, structural, optical, and compositional as well as DFT studies of pristine, Li-doped, and Bi-Li codoped vertically aligned ZnO NW films to explore the mechanism and origin of ferromagnetism. We used a simple solution process to synthesize a wurtzite structure and vertically aligned ZnO NWs on a Si substrate. The doping, high crystallinity, and vertical alignment along the 002 planes were evidenced through HRTEM, FESEM, and XRD measurements. The XPS analysis confirmed the +1 and +3 states of Li and Bi, respectively. Moreover, Raman analysis also depicted the characteristic peaks of ZnO NWs at 98.31 cm-1 and 437.71 cm-1. The PL studies of doped NWs showed a typical NBE peak of ZnO at ∼395 nm along with a sub-gap defect-related broad peak at ∼504 nm indicating the presence of defects due to doping. The pure ZnO NW samples showed negligible saturation magnetization (Ms) at room temperature while the saturation magnetization was observed to increase with Li-doping and reduced with Bi-Li codoping. According to the Hall studies the pure ZnO NW film showed n-type conductivity, while all doped and codoped samples showed p-type conductivity. The hole concentration was observed to increase with Li-doping and decrease with Bi-Li codoping showing similar behavior to that of the Ms value, thereby suggesting a direct correlation between Ms and carrier concentration. The I-V properties showed a similar trend to that of carrier concentration and Ms. Our DFT studies showed that magnetization increased by Li doping and reduced by Li-Bi codoping in defective ZnO crystals by replacing Zn with Li and Bi atoms at the Zn site. Overall, our studies highlight the immense potential of hole-mediated Bi-Li codoped ZnO NW devices which are expected to play a pivotal role in developing spintronic devices.

The Impact of Inflammation and General Anesthesia on Memory and Executive Function in Mice.

BACKGROUND: Perioperative neurocognitive disorders (PNDs) are complex, multifactorial conditions that are associated with poor long-term outcomes. Inflammation and exposure to general anesthetic drugs are likely contributing factors; however, the relative impact of each factor alone versus the combination of these factors remains poorly understood. The goal of this study was to compare the relative impact of inflammation, general anesthesia, and the combination of both factors on memory and executive function. METHODS: To induce neuroinflammation at the time of exposure to an anesthetic drug, adult male mice were treated with lipopolysaccharide (LPS) or vehicle. One day later, they were anesthetized with etomidate (or vehicle). Levels of proinflammatory cytokines were measured in the hippocampus and cortex 24 hours after LPS treatment. Recognition memory and executive function were assessed starting 24 hours after anesthesia using the novel object recognition assay and the puzzle box, respectively. Data are expressed as mean (or median) differences (95% confidence interval). RESULTS: LPS induced neuroinflammation, as indicated by elevated levels of proinflammatory cytokines, including interleukin-1ß (LPS versus control, hippocampus: 3.49 pg/mg [2.06-4.92], P < .001; cortex: 2.60 pg/mg [0.83-4.40], P = .010) and tumor necrosis factor-α (hippocampus: 3.50 pg/mg [0.83-11.82], P = .002; cortex: 2.38 pg/mg [0.44-4.31], P = .021). Recognition memory was impaired in mice treated with LPS, as evinced by a lack of preference for the novel object (novel versus familiar: 1.03 seconds [-1.25 to 3.30], P = .689), but not in mice treated with etomidate alone (novel versus familiar: 2.38 seconds [0.15-4.60], P = .031). Mice cotreated with both LPS and etomidate also exhibited memory deficits (novel versus familiar: 1.40 seconds [-0.83 to 3.62], P = .383). In the puzzle box, mice treated with either LPS or etomidate alone showed no deficits. However, the combination of LPS and etomidate caused deficits in problem-solving tasks (door open task: -0.21 seconds [-0.40 to -0.01], P = .037; plug task: -0.30 seconds [-0.50 to -0.10], P < .001; log values versus control), indicating impaired executive function. CONCLUSIONS: Impairments in recognition memory were driven by inflammation. Deficits in executive function were only observed in mice cotreated with LPS and etomidate. Thus, an interplay between inflammation and etomidate anesthesia led to cognitive deficits that were not observed with either factor alone. These findings suggest that inflammation and anesthetic drugs may interact synergistically, or their combination may unmask covert or latent deficits induced by each factor alone, leading to PNDs.

Biological Implications of MicroRNAs as Regulators and Biomarkers of Therapeutic Toxicities in Breast Cancer.

Contemporary breast cancer management includes surgical resection combined with a multimodal approach, including chemotherapy, radiotherapy, endocrine therapy, and targeted therapies. Breast cancer treatment is now personalised in accordance with disease and host factors, which has translated to enhanced outcomes for the vast majority of patients. Unfortunately, the treatment of the disease involves patients developing treatment-induced toxicities, with cardiovascular and metabolic side effects having negative implications for long-term quality-of-life metrics. MicroRNAs (miRNAs) are a class of small non-coding ribonucleic acids that are 17 to 25 nucleotides in length, which have utility in modifying genetic expression by working at a post-transcriptional cellular level. miRNAs have involvement in modulating breast cancer development, which is well described, with these biomarkers acting as important regulators of disease, as well as potential diagnostic and therapeutic biomarkers. This review focuses on highlighting the role of miRNAs as regulators and biomarkers of disease, particularly in breast cancer management, with a specific mention of the potential value of miRNAs in predicting treatment-related cardiovascular toxicity.

A Novel Experience Of Ultrasound-Guided Erector Spinae Plane Block With Sedation In Breast Cancer Surgery: A Case Report.

We report the anaesthetic management of a breast cancer patient, at a high risk for undergoing general anaesthesia, using a single-shot ultrasound-guided Erector Spinae Plane Block (ESPB) with monitored sedation. Targetted at T4, 20 mL of 0.375% bupivacaine provided complete surgical anaesthesia in 15 minutes. Concurrent sedation was administered with target controlled infusion of propofol with entropy monitoring throughout the procedure. The surgery lasted 90 minutes and the patient remained pain free and haemodynamically stable throughout. At the end of the surgery, the patient received 1 g of paracetamol intravenously, and did not require any further analgesics other than routinely administered paracetamol until her discharge from the hospital. On top of the successful execution of our plan, this case was especially interesting as her postoperative analgesia remained completely opioid-free.

Natural history of pediatric morphine leukoencephalopathy on CT and MRI.

An increased awareness of opioids and the imaging appearance in opioid overdose-related leukoencephalopathy has rapidly become crucial with respect to its identification by emergency radiologists. It is a potentially life-threatening condition and is associated with devastating neurological outcomes. Thus, early diagnosis and management are paramount. We report a rare case of toxic leukoencephalopathy in a 20-month-old male patient secondary to morphine overdose in the outpatient setting following discharge from uncomplicated urethroplasty. Although pediatric toxic leukoencephalopathy has been reported previously in the literature, our case report is unique as it involves morphine, a less commonly used opioid in the outpatient setting. Moreover, we have provided brain computed tomography and magnetic resonance imaging and highlighted findings in the acute and chronic stages of the disease trajectory. This case report highlights the importance for radiologists, especially those involved in emergency care, to have a high index of suspicion for toxic leukoencephalopathy, a potentially devastating but treatable condition.

Assessment of National External Quality Assurance Programme of Pakistan as a tool for improving quality of lab results among participating laboratories.

OBJECTIVE: To assess the impact of the National External Quality Assessment Programme of Pakistan NEQAPP in improving the quality of laboratory results among the participating laboratories. METHODS: The cross-sectional observational study was conducted from July to December 2020 at the Department of Chemical Pathology and Endocrinology, Armed Forces Institute of Pathology, Rawalpindi, Pakistan, in association with the National Quality Assurance Programme of Pakistan. A survey questionnaire was developed and sent to the participating laboratories via email. Frequencies of their responses were calculated and data was analysed using SPSS 21. RESULTS: Of the 150 laboratories approached, 145(96.6%) responded. Among them, 140 (96.6%) laboratories were satisfied by the information provided on the programme's portal, 123(84.8%s) were pleased with the responsiveness of the programme manager, 140(96.6%) reported quality of services had improved after participation in the programme, 129(89%) indicated that the clinician's confidence had enhanced, and 122(84%) said the participation in the programme had improved the credibility of their respective of laboratories. CONCLUSIONS: The National External Quality Assessment Programme of Pakistan was found to have significantly contributed in improving the quality of laboratory results among the participating laboratories.

Establishing biotinidase reference interval: A foundation stone for newborn screening of biotinidase deficiency in Pakistan.

OBJECTIVE: To determine the reference interval of biotinidase activity in healthy neonates. METHODS: The cross-sectional study was conducted at the Department of Chemical Pathology and Endocrinology, Armed Forces Institute of Pathology, Rawalpindi, Pakistan, from May to November 2019, and comprised blood samples collected from healthy neonates aged 2-6 days. The samples were collected on filter paper and analysed on genetic screening processor based on dissociation-enhanced lanthanide flouroimmunoassay. Data was analysed using SPSS 21. RESULTS: Of the 120 dried blood spot specimens, 81(67.5%) were from male babies and 39(32.5%) from female babies. Reference interval for biotinidase activity, based on 2.5th and 97.5th percentiles, was from 3.0 to 11.0 nmol/ml/min. CONCLUSIONS: Screening of newborns for biotinidase deficiency is crucial to prevent irreversible neurological damage.

Distal arteriovenous fistula formation after percutaneous coronary intervention: An old complication of a new access site.

Dorsal or distal transradial artery access has recently gained popularity due to several perceived benefits that include favorable ergonomics, the potential for rapid hemostasis and lower rates of vascular complications. Still, no vascular access site is free of complications and reports of hematoma and pseudoaneurysm formation related to distal radial artery access have been reported in the literature. We present a case of a 71-year-old male who developed an arteriovenous fistula (AVF) involving the distal left radial artery following repeated access of the artery. This rare complication is likely avoidable with a comprehensive understanding of the surrounding anatomy and proper procedural technique, including the routine use of ultrasound for access.

Therapeutic potential of N4-substituted thiosemicarbazones as new urease inhibitors: Biochemical and in silico approach.

Urease enzyme plays a key role in pathogenesis of gastritis and peptic ulcers. Its inhibition averts our bodies from many disorders including formation of urinary calculi. In agriculture, the high urease content causes severe environmental and hence economic problems. Due to deficiency of effective and safer drugs to tackle the aforementioned disorders, the quest for new scaffolds becomes mandatory in the field of medicinal chemistry. In this regard, we herein report a new series of N4-substituted thiosemicarbazones 3a-v as potential candidates for urease inhibition. These new N4-substituted thiosemicarbazones 3a-v of distant chemical scaffolds were characterized by advanced spectroscopic techniques, such as FTIR, 1HNMR, 13CNMR, ESI-MS and in the case of compound 3g by single crystal X-ray analysis. The compounds were evaluated for their urease inhibitory potential. All newly synthesized compounds showed significant urease inhibitions with IC50 values in range of 2.7 ± 0.320-109.2 ± 3.217 µM. Molecular docking studies were used for interactions pattern and structure-activity relationship for all compounds, which demonstrated excellent binding interactions with the active site residues, such as hydrogen bonding, π-π interactions, π-H and nickel atom coordination.

Development of Coral Investigation System Based on Semantic Segmentation of Single-Channel Images.

Among aquatic biota, corals provide shelter with sufficient nutrition to a wide variety of underwater life. However, a severe decline in the coral resources can be noted in the last decades due to global environmental changes causing marine pollution. Hence, it is of paramount importance to develop and deploy swift coral monitoring system to alleviate the destruction of corals. Performing semantic segmentation on underwater images is one of the most efficient methods for automatic investigation of corals. Firstly, to design a coral investigation system, RGB and spectral images of various types of corals in natural and artificial aquatic sites are collected. Based on single-channel images, a convolutional neural network (CNN) model, named DeeperLabC, is employed for the semantic segmentation of corals, which is a concise and modified deeperlab model with encoder-decoder architecture. Using ResNet34 as a skeleton network, the proposed model extracts coral features in the images and performs semantic segmentation. DeeperLabC achieved state-of-the-art coral segmentation with an overall mean intersection over union (IoU) value of 93.90%, and maximum F1-score of 97.10% which surpassed other existing benchmark neural networks for semantic segmentation. The class activation map (CAM) module also proved the excellent performance of the DeeperLabC model in binary classification among coral and non-coral bodies.

Anthrax toxin induces macrophage death by p38 MAPK inhibition but leads to inflammasome activation via ATP leakage.

Detection of microbial constituents by membrane associated and cytoplasmic pattern recognition receptors is the essence of innate immunity, leading to activation of protective host responses. However, it is still unclear how immune cells specifically respond to pathogenic bacteria. Using virulent and nonvirulent strains of Bacillus anthracis, we have shown that secretion of ATP by infected macrophages and the sequential activation of the P2X7 purinergic receptor and nucleotide binding oligomerization domain (NOD)-like receptors are critical for IL-1-dependent host protection from virulent B. anthracis. Importantly, lethal toxin produced by virulent B. anthracis blocked activation of protein kinases, p38 MAPK and AKT, resulting in opening of a connexin ATP release channel and induction of macrophage death. Prevention of cell death or ATP release through constitutive p38 or AKT activation interfered with inflammasome activation and IL-1ß production, thereby compromising antimicrobial immunity.

Loss of CMAH during Human Evolution Primed the Monocyte-Macrophage Lineage toward a More Inflammatory and Phagocytic State.

Humans and chimpanzees are more sensitive to endotoxin than are mice or monkeys, but any underlying differences in inflammatory physiology have not been fully described or understood. We studied innate immune responses in Cmah-/- mice, emulating human loss of the gene encoding production of Neu5Gc, a major cell surface sialic acid. CMP-N-acetylneuraminic acid hydroxylase (CMAH) loss occurred ∼2-3 million years ago, after the common ancestor of humans and chimpanzees, perhaps contributing to speciation of the genus HomoCmah-/- mice manifested a decreased survival in endotoxemia following bacterial LPS injection. Macrophages from Cmah-/- mice secreted more inflammatory cytokines with LPS stimulation and showed more phagocytic activity. Macrophages and whole blood from Cmah-/- mice also killed bacteria more effectively. Metabolic reintroduction of Neu5Gc into Cmah-/- macrophages suppressed these differences. Cmah-/- mice also showed enhanced bacterial clearance during sublethal lung infection. Although monocytes and monocyte-derived macrophages from humans and chimpanzees exhibited marginal differences in LPS responses, human monocyte-derived macrophages killed Escherichia coli and ingested E. coli BioParticles better. Metabolic reintroduction of Neu5Gc into human macrophages suppressed these differences. Although multiple mechanisms are likely involved, one cause is altered expression of C/EBPß, a transcription factor affecting macrophage function. Loss of Neu5Gc in Homo likely had complex effects on immunity, providing greater capabilities to clear sublethal bacterial challenges, possibly at the cost of endotoxic shock risk. This trade-off may have provided a selective advantage when Homo transitioned to butchery using stone tools. The findings may also explain why the Cmah-/- state alters severity in mouse models of human disease.

Tamm-Horsfall glycoprotein engages human Siglec-9 to modulate neutrophil activation in the urinary tract.

Urinary tract infections are a major problem in human medicine for which better understanding of native immune defenses may reveal new pathways for therapeutic intervention. Tamm-Horsfall glycoprotein (THP), the most abundant urinary protein, interacts with bacteria including uropathogenic Escherichia coli (UPEC) as well host immune cells. In addition to its well-studied functions to antagonize bacterial colonization, we hypothesize that THP serves a critical host defense function through innate immune modulation. Using isolated human neutrophils, we found that THP binds neutrophils and that this interaction reduces reactive oxygen species generation, chemotaxis and killing of UPEC. We discovered that THP engages the inhibitory neutrophil receptor sialic acid-binding Ig-like lectin-9 (Siglec-9), and mouse functional ortholog Siglec-E, in a manner dependent on sialic acid on its N-glycan moieties. THP-null mice have significantly more neutrophils present in the urine compared with wild-type mice, both with and without the presence of inflammatory stimuli. These data support THP as an important negative regulator of neutrophil activation in the urinary tract, with dual functions to counteract bacterial colonization and suppress excessive inflammation within the urinary tract.

Evaluation of random plasma glucose for assessment of glycaemic control in type 2 diabetes mellitus.

OBJECTIVE: To evaluate the accuracy of random plasma glucose in outpatients with type 2 diabetes mellitus for assessing glycaemic control. METHODS: This comparative, cross-sectional study was conducted at the chemical pathology department of PNS Shifa Hospital, Karachi, from August 2015 to March 2016, and comprised data of subjects with type 2 diabetes mellitus who reported for evaluation of glycaemic control in non-fasting state. All blood samples were analysed for random plasma glucose and glycated haemoglobin. Random plasma glucose was compared as an index test with glycated haemoglobin considering it as reference standard at a value of less than 7% for good glycaemic control. SPSS 20 was used for data analysis. RESULTS: Of the 222 subjects, 93(42%) had good glycaemic control. Random plasma glucose showed strong positive correlation with glycated haemoglobin (p=0.000).Area under curve for random plasma glucose as determined by plotting receiver operating characteristic curve against glycated haemoglobin value of 7% was 0.89 (95% confidence interval: 0.849-0.930). Random plasma glucose at cut-off value of 150 mg/dl was most efficient for ruling out poor glycaemic control among patients with type 2 diabetes mellitus with 90.7% sensitivity and69.9% specificity and Youden's index of 0.606. CONCLUSIONS: Random plasma glucose may be used to reflect glycaemic control in adults with type 2 diabetes mellitus in areas where glycated haemoglobin is not feasible.