11.7T Diffusion Magnetic Resonance Imaging and Tractography to Probe Human Brain Organoid Microstructure.

Background: Human brain organoids are 3-dimensional cellular models that mimic architectural features of a developing brain. Generated from human induced pluripotent stem cells, these organoids offer an unparalleled physiologically relevant in vitro system for disease modeling and drug screening. In the current study, we sought to establish a foundation for a magnetic resonance imaging (MRI)-based, label-free imaging system that offers high-resolution capabilities for deep tissue imaging of whole organoids. Methods: An 11.7T Bruker/89 mm microimaging system was used to collect high-resolution multishell 3-dimensional diffusion images of 2 induced pluripotent stem cell-derived human hippocampal brain organoids. The MRI features identified in the study were interpreted on the basis of similarities with immunofluorescence microscopy. Results: MRI microscopy at ≤40 µm isotropic resolution provided a 3-dimensional view of organoid microstructure. T2-weighted contrast showed a rosette-like internal structure and a protruding spherical structure that correlated with immunofluorescence staining for the choroid plexus. Diffusion tractography methods can be used to model tissue microstructural features and possibly map neuronal organization. This approach complements traditional immunohistochemistry imaging methods without the need for tissue clearing. Conclusions: This proof-of-concept study shows, for the first time, the application of high-resolution diffusion MRI microscopy to image 2-mm diameter spherical human brain organoids. Application of ultrahigh-field MRI and diffusion tractography is a powerful modality for whole organoid imaging and has the potential to make a significant impact for probing microstructural changes in brain organoids used to model psychiatric disorders, neurodegenerative diseases, and viral infections of the human brain, as well as for assessing neurotoxicity in drug screening.

Versace et al. present a groundbreaking approach using ultrahigh-resolution MRI (11.7T) for deep tissue imaging of whole human brain organoids. These 3D miniature brains mimic the developing brain's architecture and hold promise for disease modeling and drug discovery. This label-free MRI approach offers the potential to characterize microstructural features in human brain organoids modeling psychiatric disorders, neurodegenerative diseases, viral infections, and/or drug-induced neurotoxicity.

A 5-Year Statewide Analysis of Unplanned Hospital Visits for EGD, Colonoscopy, Combined EGD/Colonoscopy, and ERCP.

Background and Aims: Conventional complication rates for gastrointestinal endoscopic procedures may underestimate the broader risk represented by postprocedure unplanned hospital visits (UHVs). We aimed to characterize UHVs for procedures in Maryland and the District of Columbia from 2014 to 2018. Methods: Data for all esophagogastroduodenoscopies (EGDs), colonoscopies, combined EGDs/colonoscopies, and endoscopic retrograde cholangiopancreatographies (ERCPs) performed between 2014 and 2018 was provided by the Maryland Health Information Exchange (Chesapeake Regional Information System for our Patients'). Patient demographics, timing of UHV within 14 days postprocedure, distance traveled, facility site ("home" vs "away" institution), and International Classification of Diseases codes for the UHV were analyzed. Only UHVs potentially attributable to the endoscopic procedures were included. Results: Among 304,786 endoscopic procedures and 3904 unplanned visits, the 14-day UHV rates were 1.7%, 0.6%, 1.3%, and 5.2% for EGD, colonoscopy, combined EGD/colonoscopy, and ERCP procedures respectively. From 2014 to 2018, the UHV rate on an annual basis remained stable for all procedure types except for ERCPs which increased. Patients who experienced UHVs were statistically different in sex, race, age, and distance traveled. UHVs most often occurred on postprocedure day 1; emergency department visits occurred most commonly. UHVs for all procedures, except ERCPs, were more likely to occur at a "home" institution. Overall, patients were more likely to be admitted postprocedure at an "away" institution. Conclusion: Postendoscopic procedure UHV rates were generally low. However, UHV rates for EGDs and colonoscopies were significantly higher than conventional complication rates. As 30%-60% of all unplanned visits occurred at an "away" institution, endoscopists should consider a broad approach to detecting postprocedure complications and not rely on a single institution for data capture.

DNA-binding factor footprints and enhancer RNAs identify functional non-coding genetic variants.

BACKGROUND: Genome-wide association studies (GWAS) have revealed a multitude of candidate genetic variants affecting the risk of developing complex traits and diseases. However, the highlighted regions are typically in the non-coding genome, and uncovering the functional causative single nucleotide variants (SNVs) is challenging. Prioritization of variants is commonly based on genomic annotation with markers of active regulatory elements, but current approaches still poorly predict functional variants. To address this, we systematically analyze six markers of active regulatory elements for their ability to identify functional variants. RESULTS: We benchmark against molecular quantitative trait loci (molQTL) from assays of regulatory element activity that identify allelic effects on DNA-binding factor occupancy, reporter assay expression, and chromatin accessibility. We identify the combination of DNase footprints and divergent enhancer RNA (eRNA) as markers for functional variants. This signature provides high precision, but with a trade-off of low recall, thus substantially reducing candidate variant sets to prioritize variants for functional validation. We present this as a framework called FINDER-Functional SNV IdeNtification using DNase footprints and eRNA. CONCLUSIONS: We demonstrate the utility to prioritize variants using leukocyte count trait and analyze variants in linkage disequilibrium with a lead variant to predict a functional variant in asthma. Our findings have implications for prioritizing variants from GWAS, in development of predictive scoring algorithms, and for functionally informed fine mapping approaches.

pH and thiosulfate dependent microbial sulfur oxidation strategies across diverse environments.

Sulfur oxidizing bacteria (SOB) play a key role in sulfur cycling in mine tailings impoundment (TI) waters, where sulfur concentrations are typically high. However, our understanding of SOB sulfur cycling via potential S oxidation pathways (sox, rdsr, and S4I) in these globally ubiquitous contexts, remains limited. Here, we identified TI water column SOB community composition, metagenomics derived metabolic repertoires, physicochemistry, and aqueous sulfur concentration and speciation in four Canadian base metal mine, circumneutral-alkaline TIs over four years (2016 - 2019). Identification and examination of genomes from nine SOB genera occurring in these TI waters revealed two pH partitioned, metabolically distinct groups, which differentially influenced acid generation and sulfur speciation. Complete sox (csox) dominant SOB (e.g., Halothiobacillus spp., Thiomonas spp.) drove acidity generation and S2O3 2- consumption via the csox pathway at lower pH (pH ~5 to ~6.5). At circumneutral pH conditions (pH ~6.5 to ~8.5), the presence of non-csox dominant SOB (hosting the incomplete sox, rdsr, and/or other S oxidation reactions; e.g. Thiobacillus spp., Sulfuriferula spp.) were associated with higher [S2O3 2-] and limited acidity generation. The S4I pathway part 1 (tsdA; S2O3 2- to S4O6 2-), was not constrained by pH, while S4I pathway part 2 (S4O6 2- disproportionation via tetH) was limited to Thiobacillus spp. and thus circumneutral pH values. Comparative analysis of low, natural (e.g., hydrothermal vents and sulfur hot springs) and high (e.g., Zn, Cu, Pb/Zn, and Ni tailings) sulfur systems literature data with these TI results, reveals a distinct TI SOB mining microbiome, characterized by elevated abundances of csox dominant SOB, likely sustained by continuous replenishment of sulfur species through tailings or mining impacted water additions. Our results indicate that under the primarily oxic conditions in these systems, S2O3 2- availability plays a key role in determining the dominant sulfur oxidation pathways and associated geochemical and physicochemical outcomes, highlighting the potential for biological management of mining impacted waters via pH and [S2O3 2-] manipulation.

MSK1 is required for the experience- and ampakine-dependent enhancement of spatial reference memory and reversal learning.

There is considerable interest in the development of nootropics, pharmacological agents that can improve cognition across a range of both cognitive modalities and cognitive disabilities. One class of cognitive enhancers, the ampakines, has attracted particular attention by virtue of improving cognition associated with animal models of neurodevelopmental, neurodegenerative, and psychiatric conditions, as well as in age-related cognitive impairment. Ampakines elevate CNS levels of BDNF, and it is through this elevation that their beneficial actions are believed to occur. However, what transduces the elevation of BDNF into long-lasting cognitive enhancement is not known. We have previously shown that MSK1, by virtue of its ability to regulate gene transcription, converts the elevation of BDNF associated with environmental enrichment into molecular, synaptic, cognitive and genomic adaptations that underlie enrichment-induced enhanced synaptic plasticity and learning and memory, a property that MSK1 retains across the lifespan. To establish whether MSK1 similarly converts ampakine-induced elevations of BDNF into cognitive enhancement we tested an ampakine (CX929) in male WT mice and in male mice in which the kinase activity of MSK1 was mutated. We found that MSK1 is required for the ampakine-dependent improvement in spatial reference memory and cognitive flexibility, and for the elevations of BDNF and the plasticity-related protein Arc associated with ampakines and experience. These observations implicate MSK1 as a key enabler of the beneficial effects of ampakines on cognitive function, and furthermore identify MSK1 as a hub for BDNF-elevating nootropic strategies.

Therapeutic Anti-Tumor Efficacy of DC-Based Vaccines Targeting TME-Associated Antigens Is Improved When Combined with a Chemokine-Modulating Regimen and/or Anti-PD-L1.

We previously reported that dendritic cell (DC)-based vaccines targeting antigens expressed by tumor-associated vascular endothelial cells (VECs) and pericytes effectively control tumor growth in translational mouse tumor models. In the current report, we examined whether the therapeutic benefits of such tumor blood vessel antigen (TBVA)-targeted vaccines could be improved by the cotargeting of tumor antigens in the s.c. B16 melanoma model. We also evaluated whether combination vaccines incorporating anti-PD-L1 checkpoint blockade and/or a chemokine-modulating (CKM; IFNα + TLR3-L [rintatolimod] + Celecoxib) regimen would improve T cell infiltration/functionality in tumors yielding enhanced treatment benefits. We report that DC-peptide or DC-tumor lysate vaccines coordinately targeting melanoma antigens and TBVAs were effective in slowing B16 growth in vivo and extending survival, with superior outcomes observed for DC-peptide-based vaccines. Peptide-based vaccines that selectively target either melanoma antigens or TBVAs elicited a CD8+ T cell repertoire recognizing both tumor cells and tumor-associated VECs and pericytes in vitro, consistent with a treatment-induced epitope spreading mechanism. Notably, combination vaccines including anti-PD-L1 + CKM yielded superior therapeutic effects on tumor growth and animal survival, in association with the potentiation of polyfunctional CD8+ T cell reactivity against both tumor cells and tumor-associated vascular cells and a pro-inflammatory TME.

Global threats of extractive industries to vertebrate biodiversity.

Mining is a key driver of land-use change and environmental degradation globally, with the variety of mineral extraction methods used impacting biodiversity across scales. We use IUCN Red List threat assessments of all vertebrates to quantify the current biodiversity threat from mineral extraction, map the global hotspots of threatened biodiversity, and investigate the links between species' habitat use and life-history traits and threat from mineral extraction. Nearly 8% (4,642) of vertebrates are assessed as threatened by mineral extraction, especially mining and quarrying, with fish at particularly high risk. The hotspots of mineral extraction-induced threat are pantropical, as well as a large proportion of regional diversity threatened in northern South America, West Africa, and the Arctic. Species using freshwater habitats are particularly at risk, while the effects of other ecological traits vary between taxa. As the industry expands, it is vital that mineral resources in vulnerable biodiversity regions are managed in accordance with sustainable development goals.

Exploring Pattern of Relapse in Pediatric Patients with Acute Lymphocytic Leukemia and Acute Myeloid Leukemia Undergoing Stem Cell Transplant Using Machine Learning Methods.

Background. Leukemic relapse remains the primary cause of treatment failure and death after allogeneic hematopoietic stem cell transplant. Changes in post-transplant donor chimerism have been identified as a predictor of relapse. A better predictive model of relapse incorporating donor chimerism has the potential to improve leukemia-free survival by allowing earlier initiation of post-transplant treatment on individual patients. We explored the use of machine learning, a suite of analytical methods focusing on pattern recognition, to improve post-transplant relapse prediction. Methods. Using a cohort of 63 pediatric patients with acute lymphocytic leukemia (ALL) and 46 patients with acute myeloid leukemia (AML) who underwent stem cell transplant at a single institution, we built predictive models of leukemic relapse with both pre-transplant and post-transplant patient variables (specifically lineage-specific chimerism) using the random forest classifier. Local Interpretable Model-Agnostic Explanations, an interpretable machine learning tool was used to confirm our random forest classification result. Results. Our analysis showed that a random forest model using these hyperparameter values achieved 85% accuracy, 85% sensitivity, 89% specificity for ALL, while for AML 81% accuracy, 75% sensitivity, and 100% specificity at predicting relapses within 24 months post-HSCT in cross validation. The Local Interpretable Model-Agnostic Explanations tool was able to confirm many variables that the random forest classifier identified as important for the relapse prediction. Conclusions. Machine learning methods can reveal the interaction of different risk factors of post-transplant leukemic relapse and robust predictions can be obtained even with a modest clinical dataset. The random forest classifier distinguished different important predictive factors between ALL and AML in our relapse models, consistent with previous knowledge, lending increased confidence to adopting machine learning prediction to clinical management.

Pericapsular Nerve Group Block Did Not Reduce Postoperative Pain or Opioid Use After Total Hip Arthroplasty.

BACKGROUND: The pericapsular nerve group (PENG) block is a newly developed regional anesthesia technique designed to manage postoperative hip pain following a fracture or surgery while also maintaining quadriceps strength and mobility. The goal of our study was to compare postoperative pain scores and opioid usage during the postoperative period before discharge following total hip arthroplasty (THA) using the posterior approach between patients who received a PENG block and those who did not. METHODS: We conducted a retrospective study on patients undergoing elective, posterior approach THA at a single tertiary-care academic center. The 2 groups included a study group (THA with PENG block in 2021; n = 66) and a control group (THA before PENG block implementation in 2019; n = 70). RESULTS: There were no significant differences in pain scores during postoperative minutes 0 to 59 (study group 6.8; control group 6.6; P = .81) or during postoperative minutes 60 to 119 (study group 6.2; control group 5.6; P = .40). There were no significant differences in total postoperative in-hospital morphine milliequivalent opioid consumption (study group 55.8 morphine milligram equivalents; control group 75.0 morphine milligram equivalents; P = .14). The study group was found to have a shorter length of stay (study group 17.0 hours; control group 32.6 hours; P < .0001) and faster mobilization (study group 3.0 hours; control group 4.9 hours; P < .0001) than the control group. CONCLUSIONS: Our results show that use of the PENG block did not result in lower postoperative pain scores or opioid consumption after THA using the posterior surgical approach. The study group had a shorter length of stay and time to mobilization than the control group, though this was likely due to standard hospital procedure shifting to same-day discharge for THA between 2019 and 2021 due to COVID-19.

Double vitrification and warming of blastocysts does not affect pregnancy, miscarriage or live birth rates.

RESEARCH QUESTION: Does double blastocyst vitrification and warming affect pregnancy, miscarriage or live birth rates, or birth outcomes, from embryos that have undergone preimplantation genetic testing for aneuploidies (PGT-A) testing? DESIGN: This retrospective observational analysis of embryo transfers was performed at a single centre between January 2017 and August 2022. The double-vitrification group included frozen blastocysts that were vitrified after 5-7 days of culture, warmed, biopsied (either once or twice) and re-vitrified. The single vitrification (SV) group included fresh blastocysts that were biopsied at 5-7 days and then vitrified. RESULTS: A comparison of the 84 double-vitrification blastocysts and 729 control single-vitrification blastocysts indicated that the double-vitrification embryos were frozen later in development and had expanded more than the single-vitrification embryos. Of the 813 embryo transfer procedures reported, 452 resulted in the successful delivery of healthy infants (56%). There were no significant differences between double-vitrification and single-vitrification embryos in the pregnancy, miscarriage or live birth rates achieved after single-embryo transfer (55% versus 56%). Logistic regression indicated that while reduced live birth rates were associated with increasing maternal age at oocyte collection, longer culture prior to freezing and lower embryo quality, double vitrification was not a significant predictor of live birth rate. CONCLUSIONS: Blastocyst double vitrification was not shown to impact pregnancy, miscarriage or live birth rates. Although caution is necessary due to the study size, no effects of double vitrification on miscarriage rates, birthweight or gestation period were noted. These data offer reassurance given the absence of the influence of double vitrification on all outcomes after PGT-A.

Blood transcriptomic signatures for symptomatic TB in an African multi-cohort study.

BACKGROUND: Multiple host blood transcriptional signatures have been developed as non-sputum triage tests for tuberculosis (TB). We aimed to compare the diagnostic performance of 20 blood transcriptomic TB signatures for differentiating between symptomatic patients who have TB versus other respiratory diseases (ORD). METHODS: As part of a nested case-control study, individuals presenting with respiratory symptoms at primary health care clinics in Ethiopia, Malawi, Namibia, Uganda, South Africa, and The Gambia were enrolled. TB was diagnosed based on clinical, microbiological, and radiological findings. Transcriptomic signatures were measured in whole blood using microfluidic RT-qPCR. Diagnostic performance was benchmarked against the WHO Target Product Profile (TPP) for a non-sputum TB triage test. RESULTS: Among 541 participants, 158 had definite, microbiologically-confirmed TB, 32 had probable TB, while 389 participants had ORD. Nine signatures differentiated between ORD and TB with equivalent performance (Satproedprai7: area under the curve 0.83 [95% CI 0.79-0.87], Jacobsen3: 0.83 [0.79-0.86]; Suliman2: 0.82 [0.78-0.86]; Roe1: 0.82 [0.78-0.86]; Kaforou22: 0.82 [0.78-0.86]; Sambarey10: 0.81 [0.77-0.85]; Duffy9: 0.81 [0.76-0.86]; Gliddon3: 0.8 [0.75-0.85]; and Suliman4 0.79 [0.75-0.84]. Benchmarked against a 90% sensitivity, these signatures achieved specificities between 44% (95% CI 38-49) and 54% (49-59), not meeting the TPP criteria. Signature scores significantly varied by HIV status and country. In country-specific analyses several signatures, such as Satproedprai7 and Penn-Nicholson6, met the minimal TPP criteria for a triage test in Ethiopia, Malawi, and South Africa. CONCLUSION: No signatures met the TPP criteria in a pooled analysis of all countries, but several signatures met the minimum criteria for a non-sputum TB triage test in some countries.

Shadows of quantum machine learning.

Quantum machine learning is often highlighted as one of the most promising practical applications for which quantum computers could provide a computational advantage. However, a major obstacle to the widespread use of quantum machine learning models in practice is that these models, even once trained, still require access to a quantum computer in order to be evaluated on new data. To solve this issue, we introduce a class of quantum models where quantum resources are only required during training, while the deployment of the trained model is classical. Specifically, the training phase of our models ends with the generation of a 'shadow model' from which the classical deployment becomes possible. We prove that: (i) this class of models is universal for classically-deployed quantum machine learning; (ii) it does have restricted learning capacities compared to 'fully quantum' models, but nonetheless (iii) it achieves a provable learning advantage over fully classical learners, contingent on widely believed assumptions in complexity theory. These results provide compelling evidence that quantum machine learning can confer learning advantages across a substantially broader range of scenarios, where quantum computers are exclusively employed during the training phase. By enabling classical deployment, our approach facilitates the implementation of quantum machine learning models in various practical contexts.

Myocardial inflammation after elective percutaneous coronary intervention.

OBJECTIVE: It is well established that inflammation plays a central role in the sequelae of percutaneous coronary intervention (PCI). Most of the studies to date have focused on the inflammatory reaction affecting the vessel wall after angioplasty. However, there are data to suggest that the main foci of inflammation are in fact in the myocardium beyond the vessel wall. The main aim of our study was to investigate the myocardial inflammation after elective, uncomplicated angioplasty with cardiovascular magnetic resonance (CMR) enhanced by ultrasmall superparamagnetic particles of iron oxide (USPIO) and also blood biomarkers. This is the first study to report such findings after elective angioplasty. METHODS: We assessed patients undergoing elective angioplasty for stable angina with USPIO-enhanced CMR two weeks after the procedure and compared the results with those of healthy volunteers who constituted the control group. We excluded patients with previous myocardial infarction, previous PCI, or any significant inflammatory condition. All patients also underwent blood biomarker testing at baseline (pre-PCI), 4 h, and two weeks later. RESULTS: A total of five patients and three controls were scanned. There was a small absolute increase, although statistically insignificant, in R2∗ values in the PCI area compared with either remote myocardium from the same patient (PCI area [left anterior descending artery (LAD)] vs remote myocardium [circumflex area]: 19.3 ± 10.8 vs 9.2 ± 7.9, p = 0.1) or healthy myocardium from healthy volunteers (PCI area [LAD] vs healthy myocardium [LAD]: 19.3 ± 10.8 vs 12.2 ± 4.0, p = 0.2). PTX3 and IL-6 were the only biomarkers that changed significantly from baseline to 4 h and 2 weeks. Both biomarkers peaked at 4 h. CONCLUSION: We used USPIO-enhanced CMR for the first time to assess myocardial inflammation after elective, uncomplicated PCI. We have demonstrated a small numerical increase in inflammation, which was not statistically significant. This study opens the way for future studies to use this method as a means to target inflammation.

Functional Articulating Antibiotic Spacers for Chronic Native Septic Knee Arthritis.

Background: Semipermanent functional spacers are now utilized for prosthetic joint infection in an attempt to avoid another surgery with 2-stage treatment. This study evaluates the results of metal-on-polyethylene articulating spacers for the treatment of chronic native septic knee arthritis. Methods: This is a retrospective review of 18 patients treated with metal-on-polyethylene articulating antibiotic spacers constructed with all-polyethylene tibial components or with polyethylene inserts (PIs) with Steinmann pins or screws for chronic native knee infection. Demographic information, spacer construct type, prior knee surgery, complications, infecting organisms, infection eradication, and functional results were analyzed. Results: Of 18, 8 (44%) spacers were all-polyethylene tibial components and 10 (56%) were PI. Of 18 patients, 5 (28%) experienced spacer complications. Of 18 patients, 12 (67%) underwent a second reimplantation surgery (mean 106 days), while 6 (33%) retained their spacer (average duration 425 days). The PI group performed better in Knee Injury and Osteoarthritis Outcome score for Joint Replacement according to minimum clinically important difference and patient acceptable symptom state (PASS) criteria. The overall reimplantation group achieved Knee Injury and Osteoarthritis Outcome score for Joint Replacement PASS criteria and minimum clinically important difference criteria, while the maintained articulating spacer group did not achieve PASS criteria; however, they did reach minimum clinically important difference. Conclusions: Functional articulating spacers are a viable treatment for chronic, native knee septic arthritis. The PI patient group had a greater improvement in Knee Injury and Osteoarthritis Outcome score for Joint Replacement scores and had no significant difference in reimplantation rate as the all-polyethylene tibial components patient group. Both planned 2-stage reimplantation and longer-term spacer retention show promising results for this difficult clinical problem.

Mapping the clinical pathway for patients undergoing vestibular schwannoma resection.

BACKGROUND: The introduction of electronic health records (EHR) has improved the collection and storage of patient information, enhancing clinical communication and academia. However, EHRs remain limited by data quality and the time-consuming task of manual data extraction. This study aims to utilise process mapping to help identify critical data entry points within the clinical pathway for VS patients, ideal for structured data entry and automated data collection, in an effort to improve patient care and research. METHODS: A two-stage methodology was conducted at a neurosurgical unit. Process maps were developed using semi-structured interviews with stakeholders in the management of VS resection. Process maps were then retrospectively validated against EHR for patients admitted between August 2019 and December 2021, establishing critical data entry points. RESULTS: Twenty stakeholders were interviewed in the process map development. Process maps were validated against the EHR of 36 patients admitted for VS resection. Operation notes, surgical inpatient reviews (including ward rounds) and discharge summaries were present for all patients, representing critical data entry points. Areas for documentation improvement were present in the preoperative clinics (30/36, 83.3%), preoperative skull base multidisciplinary team (32/36, 88.9%), postoperative follow-up clinics (32/36, 88.9%), and the postoperative skull base multidisciplinary team meeting (29/36, 80.6%). CONCLUSION: This is a first use of a two-stage methodology for process mapping the clinical pathway for patients undergoing VS resection. Our study identified critical data entry points which can be targeted for structured data entry and for automated data collection tools, positively impacting patient care and research.

Correction to: 'Unscrambling variation in avian eggshell colour and patterning in a continent-wide study' (2019), by L'Herpiniere et al.

[This corrects the article DOI: 10.1098/rsos.181269.][This corrects the article DOI: 10.1098/rsos.181269.].

Adenosine deaminase 2 regulates the activation of the toll-like receptor 9 in response to nucleic acids.

Human cells contain two types of adenosine deaminases (ADA) each with unique properties: ADA1, which is present in all cells where it modulates intracellular functions and extracellular signaling, and ADA2, which is secreted by immune cells. The exact intracellular functions of ADA2 remain undetermined and less defined than those of ADA1. ADA2 has distinct characteristics, such as low adenosine affinity, heparin-binding ability, and putative lysosomal entry. Here, we confirm that ADA2 is a lysosomal protein that binds toll-like receptor 9 (TLR9) agonists, specifically CpG oligodeoxynucleotides (CpG ODNs). We show that interferon-alpha (IFN-α) is secreted in response to TLR9 activation by CpG ODNs and natural DNA and markedly increases when ADA2 expression is downregulated in plasmacytoid dendritic cells (pDCs). Additionally, the pretreatment of pDCs with RNA further stimulates IFN-α secretion by pDCs after activation with CpG ODNs. Our findings indicate that ADA2 regulates TLR9 responses to DNA in activated pDCs. In conclusion, decreasing ADA2 expression or blocking it with specific oligonucleotides can enhance IFN-α secretion from pDCs, improving immune responses against intracellular infections and cancer.

The AKT2/SIRT5/TFEB pathway as a potential therapeutic target in non-neovascular AMD.

Non-neovascular or dry age-related macular degeneration (AMD) is a multi-factorial disease with degeneration of the aging retinal-pigmented epithelium (RPE). Lysosomes play a crucial role in RPE health via phagocytosis and autophagy, which are regulated by transcription factor EB/E3 (TFEB/E3). Here, we find that increased AKT2 inhibits PGC-1α to downregulate SIRT5, which we identify as an AKT2 binding partner. Crosstalk between SIRT5 and AKT2 facilitates TFEB-dependent lysosomal function in the RPE. AKT2/SIRT5/TFEB pathway inhibition in the RPE induced lysosome/autophagy signaling abnormalities, disrupted mitochondrial function and induced release of debris contributing to drusen. Accordingly, AKT2 overexpression in the RPE caused a dry AMD-like phenotype in aging Akt2 KI mice, as evident from decline in retinal function. Importantly, we show that induced pluripotent stem cell-derived RPE encoding the major risk variant associated with AMD (complement factor H; CFH Y402H) express increased AKT2, impairing TFEB/TFE3-dependent lysosomal function. Collectively, these findings suggest that targeting the AKT2/SIRT5/TFEB pathway may be an effective therapy to delay the progression of dry AMD.

Impact of pre-existing depression and food insecurity on the trajectory of depressive symptomatology during the COVID-19 pandemic outbreak in South Africa: A panel analysis of nationally representative South African data.

We investigated the trajectory of depressive symptoms ("depression") from the start of the COVID-19 pandemic in South Africa (March 2020) until 2021, between individuals with and without pre-pandemic depression, specifically regarding the role of food security. Our investigation used publicly available panel data (N = 6,930) from the South African National Income Dynamics Study Coronavirus Rapid Mobile Survey (SA-NIDS-CRAM from 2020-2021) on those who had also participated in the pre-pandemic South African National Income Dynamics Study (SA-NIDS, 2017) depression interview. We investigated trends in depressive symptomatology (based on a 2-item Patient Health Questionnaire) at SA-NIDS-CRAM Wave 2 (July 2020), Wave 3 (February 2021) and Wave 5 (May 2021). Generalized estimating equations (GEE) with post-estimation linear combinations of estimators were fitted to investigate the roles of pre-pandemic depression (based on 2017 SA-NIDS data) and food insecurity during the pandemic on depressive symptomatology. During the pandemic, the highest levels of depression were observed consistently among those with pre-pandemic depression and food insecurity; and were lowest among those without pre-pandemic depression and food security. Depressive symptomatology rose in nearly equal magnitude during the early phases of the pandemic in two groups: those without pre-pandemic depression but food insecure during the pandemic; as well as those with pre-pandemic depression but food secure during the pandemic. However, this dynamic changed later in the pandemic, when higher depressive symptomatology was observed in the group with both pre-pandemic depression and food insecurity, widening the gap between them from Wave 3 (adj ß = 0.63, p < 0.01) to Wave 5 (adj ß = 0.79, p < 0.01). Our results highlight the importance of addressing both population mental health and food insecurity, particularly at the early stages of a crisis/disaster. As we showed that mental health impact is linked to food insecurity during a pandemic, strengthening social protection measures, especially around food and nutrition, would help build resilience to crises in the long term.