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Harvesting solar energy to produce value-added chemicals from carbon dioxide (CO 2 ) presents a promising route for addressing the complexities of sustainable energy systems and environmental issues. In this context, the development of metal-coordinated porous organic polymers (POPs) offers a vital avenue for improving the photocatalytic performance of organic motifs. The current study presents a metal-integrated photocatalytic system (namely, Zn@BP-POP ) developed via a one-pot Friedel-Crafts (F.C.) acylation strategy, for solid-gas phase photochemical CO 2 reduction to CO (CO 2 RR). The postsynthetic incorporation of metal (Zn) active sites on the host polymeric backbone of BP-POP significantly influences the catalytic activity. Notably, Zn@BP-POP demonstrates good photocatalytic performance in the absence of any cocatalyst and photosensitizer yielding CO while impeding the competitive hydrogen evolution reaction (HER) from water. The experimental findings collectively propose that the observed catalytic activity and selectivity arise from the synergistic interplay between the singular zinc catalytic centers and the light-harvesting capacity of the highly conjugated polymeric backbone. Further, X-ray absorption spectroscopy (XAS) analysis has significantly highlighted the prominent role played by the ZnN 2 O 4 single sites in the polymeric framework for activating the gaseous CO 2 molecules. Further, time-dependent density functional theory (DFT) analysis also reveals the thermodynamic feasibility of CO 2 RR over HER under optimized reaction conditions. This work cumulatively presents an effective strategy to demonstrate the importance of metal-active sites and effectively establish their structure-activity relationship during photocatalysis.

The Istrian (IS) and the Pag sheep (PS) are local Croatian breeds which provide significant income for the regional economy and have a cultural and traditional importance for the inhabitants. The aim of this study was to estimate some important population specific genetic parameters in IS (N = 1293) and PS (N = 2637) based on genome wide SNPs. Estimates of linkage disequilibrium effective population size (N e ) evidenced more genetic variability in PS (N e = 838) compared to IS (N e = 197), regardless of historical time (both recent and ancient genetic variability). The discrepancy in the recent genetic variability between these breeds was additionally confirmed by the estimates of genomic inbreeding (F ROH ), which was estimated to be notably higher in IS (F ROH>2 = 0.062) than in PS (F ROH>2 = 0.029). The average F ROH2-4 , F ROH4-8 , F ROH8-16 , and F ROH>16 were 0.26, 1.65, 2.14, and 3.72 for IS and 0.22, 0.61, 0.75, and 1.58 for PS, thus evidencing a high contribution of recent inbreeding in the overall inbreeding. One ROH island with > 30% of SNP incidence in ROHs was detected in IS (OAR6; 34,253,440-38,238,124 bp) while there was no ROH islands detected in PS. Seven genes (CCSER1, HERC3, LCORL, NAP1L5, PKD2, PYURF, and SPP1) involved in growth, feed intake, milk production, immune responses, and resistance were associated with the found autozygosity. The results of this study represent the first comprehensive insight into genomic variability of these two Croatian local sheep breeds and will serve as a baseline for setting up the most promising strategy of genomic Optimum Contribution Selection.

Purpose: The aim of this study was to determine how sodium hydrogen carbonate (NaHCO 3 ) ingestion during a 1-h recovery period after a 200-m front-crawl swim affects blood-gas levels, acid-base balance, and performance during a successive trial., Methods: Fourteen national-level male swimmers (age: 21 ± 3 years, body mass (BM):77 ± 10 kg, stature: 181 ± 7 cm) performed four maximal 200-m front-crawl tests. On one of the two days, the swimmers swam two 200-m tests with a 1-h recovery break, during which they drank water (WATER); on the other day, they performed the same protocol but consumed 0.3 g min -1 NaHCO 3 solution during the recovery break (NaHCO 3 )., Results: The ingestion of NaHCO 3 before the second test had no effect on swim time despite a greater [ HCO 3 - ] (19.2 ± 2.3 mmol L -1 ) than that measured during the first test (NaHCO 3 ) (14.5 ± 1.1 mmol L -1 ) and the other two tests (WATER) (12.7 ± 2.4 and 14.8 ± 1.5 mmol L -1 ; F = 18.554; p = 0.000) and a higher blood pH (7.46 ± 0.03) than that measured during the first test (NaHCO 3 ) (7.39 ± 0.02) and the other two tests (WATER) (7.16 ± 0.04 and 7.20 ± 0.05); (F = 5.255; p = 0.004). An increase in blood pCO 2 (0.2 ± 0.3 kPa) between both tests (NaHCO 3 ) compared to unchanged pCO 2 values (- 0.1 ± 0.3 kPa) between the other two tests (WATER) (t = - 2.984; p = 0.011; power = 0.741) was confirmed., Conclusions: NaHCO 3 ingestion during the recovery period between two 200-m front-crawl time trials had a strong buffering effect that did not positively affect performance. An increase in pCO 2 may have counterbalanced this impact., (© 2024. The Author(s).)

A biopolymer-based formulation for robust and active food packaging material was developed. This material consisted of a blend of three biopolymers (guar gum-sodium alginate-i-carrageenan) reinforced by cellulose nanocrystals (CNC) alongside the integration of silver nanoparticles (AgNPs) with varying sizes. The CNC utilized in this process was derived from cloth waste lint (CWL) generated from a household cloth dryer machine. This CNC synthesis underwent a series of solvent treatments to yield the CNC used in the composite. CNC and AgNPs were incorporated into the tribiopolymeric blend matrix to construct a nanocomposite film that showed excellent tensile strength (∼90 MPa). The nanocomposite film also exhibited antimicrobial activity against Escherichia coli ATCC 25922 and Bacillus cereus MTCC 1272. In this report, it was demonstrated that the zone of inhibition against E. coli and B. cereus depends on the variation of size and amount of AgNPs inside the polymeric matrix. The practical applicability of such a film was also demonstrated by applying it to sliced bread and the enhancement of the shelf life of the raped bread was compared with a control. Thus, the guar gum-sodium alginate-i-carrageenan tribiopolymer blend with a cloth waste lint extracted cellulose nanocrystal composite film is antimicrobial, hence, an excellent candidate as an active packaging film.

Ear length in sheep (Ovis aries) shows a wide range of natural variation, from the absence of an outer ear structure (anotia), to small outer ears (microtia), to regular ear length. Up until now, the underlying genetics of this phenotype has been studied in four sheep breeds from China, Jordan and Italy. These studies revealed a broad range of genes significantly associated with ear length, potentially indicating genetic heterogeneity across breeds or geographic regions. In the current study, we performed genome-wide SNP genotyping and haplotype-based mapping, in a population of 340 individuals, to identify loci influencing ear length variation in additional sheep breeds from Slovenia, Croatia, Cyprus and Greece. Additionally, two previously described candidate variants were also genotyped in our mapping population. The mapping model without candidate variant genotypes revealed only one genome-wide significant signal, which was located next to HMX1 on OAR6. This region was previously described as being associated with ear length variation in the Altay and Awassi sheep breeds. The mapping model including the candidate duplication genotype near HMX1 as a fixed effect explained the phenotypic variance on OAR6 and revealed an additional genome-wide significant locus on OAR13 associated with ear length. Our results, combined with published evidence, suggest that a duplication in the evolutionarily conserved region near HMX1 is the major regulator of ear length in sheep breeds descended from a larger region from Central Asia, to the Middle East, Cyprus, Greece and to the Alps. This distribution suggests an ancient origin of the derived allele., (© 2023 The Authors. Animal Genetics published by John Wiley & Sons Ltd on behalf of Stichting International Foundation for Animal Genetics.)

The inability of people living with HIV (PLWH) to eradicate human immunodeficiency virus (HIV) infection is due in part to the inadequate HIV-specific cellular immune response. The antiviral function of cytotoxic CD8+ T cells, which are crucial for HIV control, is impaired during chronic viral infection because of viral escape mutations, immune exhaustion, HIV antigen downregulation, inflammation, and apoptosis. In addition, some HIV-infected cells either localize to tissue sanctuaries inaccessible to CD8+ T cells or are intrinsically resistant to CD8+ T cell killing. The novel design of synthetic chimeric antigen receptors (CARs) that enable T cells to target specific antigens has led to the development of potent and effective CAR-T cell therapies. While initial clinical trials using anti-HIV CAR-T cells performed over 20 years ago showed limited anti-HIV effects, the improved CAR-T cell design, which enabled its success in treating cancer, has reinstated CAR-T cell therapy as a strategy for HIV cure with notable progress being made in the recent decade.Effective CAR-T cell therapy against HIV infection requires the generation of anti-HIV CAR-T cells with potent in vivo activity against HIV-infected cells. Preclinical evaluation of anti-HIV efficacy of CAR-T cells and their safety is fundamental for supporting the initiation of subsequent clinical trials in PLWH. For these preclinical studies, we developed a novel humanized mouse model supporting in vivo HIV infection, the development of viremia, and the evaluation of novel HIV therapeutics. Preclinical assessment of anti-HIV CAR-T cells using this mouse model involves a multistep process including peripheral blood mononuclear cells (PBMCs) harvested from human donors, T cell purification, ex vivo T cell activation, transduction with lentiviral vectors encoding an anti-HIV CAR, CAR-T cell expansion and infusion in mice intrasplenically injected with autologous PBMCs followed by the determination of CAR-T cell capacity for HIV suppression. Each of the steps described in the following protocol were optimized in the lab to maximize the quantity and quality of the final anti-HIV CAR-T cell products., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction : Central nervous system (CNS) tumours represent a significant public health issue worldwide, and their incidence and distribution vary across different populations. Although studies on CNS tumours have been conducted in various countries, there is a lack of information regarding their patterns in Macedonia. Therefore, this study is aimed at investigating the distribution, histopathological types and subtypes and demographic features of CNS tumours in our country. Materials and Methods : A cross sectional study was conducted using the electronic database of the Institute of Pathology - Medical Faculty, University "Ss. Cyril and Methodius" in Skopje which contains data from 3286 received and analysed surgical specimens, mainly from the University Clinic of Neurosurgery in Skopje, and a smaller number of surgical specimens from the University Surgical Centre "St. Naum Ohridski" in Skopje between 2012 and 2022. The collected and analysed data includes patient age, sex and histopathological types and subtypes of the tumours. Results : The majority of CNS tumours were diagnosed in adults aged between 50-70, with a male to female ratio of 1.5:1. The most common location of the tumours was the cerebrum, followed by the pituitary gland and cerebellum. The most frequent histological groups were gliomas, with glioblastoma as the most common diagnosis, followed by meningiomas. Conclusion : Following a detailed and thorough review of the CNS tumours in our study, we can conclude that the R. of Macedonia follows global statistics and trends regarding brain tumours., (© 2023 Panche Zdravkovski et al., published by Sciendo.)

Producing hydrogen peroxide (H 2 O 2 ) from H 2 O and O 2 under visible light irradiation is a promising solar-to-chemical energy conversion technology. Hydrogen peroxide has versatile applications as a green oxidant and liquid energy carrier but has been produced through energy-intensive and complex anthraquinone processes. Herein, we report the rational design of efficient and stable porous organic polymer (POP) containing redox centers, anthraquinone photocatalyst (ANQ-POP) for solar H 2 O 2 production. ANQ-POP is readily synthesized with stable dioxin-linkages via efficient one-pot, transition-metal-free nucleophilic aromatic substitution reactions between 1,2,3,4,5,6,7,8-octafluoro-9,10-anthraquinone (OFANQ) and 2,3,6,7,10,11-hexahydroxytriphenylene (HHTP). Exhibiting a fibrillar morphology, ANQ-POP boasts a high surface area of 380 m 2 ∙g -1 and demonstrates thermal stability. With 10 % ethanol, ANQ-POP yields an H 2 O 2 production rate of 320 μmol g -1 under visible light irradiation. Moreover, ANQ-POP alone can efficiently produce H 2 O 2 without any photosensitizers and cocatalysts. Density functional theory calculations reveal that the quinone groups of the anthraquinone moieties can serve as redox centers for H 2 O 2 production under light irradiation. Furthermore, unlike most conventional photocatalysts, it can produce H 2 O 2 using only water and air by catalyzing both oxygen reduction and evolution reactions under light irradiation. Our findings provide an efficient, eco-friendly pathway for photocatalytic production of H 2 O 2 under mild reaction conditions using a dioxin-derived POP-based photocatalyst., 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 Elsevier Inc. All rights reserved.)

The aim of this study was to investigate the concentrations of essential trace and toxic elements in the milk of Lacaune sheep during lactation in intensive rearing systems. This research was conducted with 30 Lacaune sheep that were monitored in the early (60 days of lactation), medium (120 days of lactation), and late (180 days of lactation) stages of lactation. The sheep were fed a pelleted feed mixture (1 kg/day), a cereal mixture (600 g/day), and alfalfa hay (ad libitum). The essential (Fe, Zn, Cu, Co, Mn, Mo, Se, Cr, and Ni) and toxic element (heavy metals: Cd, Pb, As, and Hg) concentrations in the feed and milk were determined using an inductively coupled plasma mass spectrometer. Significant variations in the main essential trace and toxic elements, except for the Mo, Se, Ni, As, and Hg concentrations, were found in the milk of Lacaune sheep during lactation. As lactation progressed, in the late stage of lactation, significantly higher concentrations of Co, Mn, Mo, Cr, and Pb were found, while Zn and Cu in the milk of Lacaune sheep decreased significantly (4.15 and 0.21 mg/kg) compared to their concentrations in the early stage of lactation (5.66 and 0.43 mg/kg). Significantly lower concentrations of Fe and higher concentrations of Cd were found in the medium stage (0.23 mg/kg and 1.08 µg/kg) of lactation compared to both the early and late stages of lactation. An analysis of the correlation coefficients between the essential trace and toxic elements in Lacaune sheep milk during lactation determined a significantly positive correlation between Fe:Cr, Fe:Mn, Fe:Co, Fe:Se, Zn:Ni, Zn:Se, Cr:Mn, Cr:Co, Cr:Se, Cr:Mo, Mn:Co, Mn:Pb, Co:Ni, Co:Se, Ni:Se, Se:Mo, Se:Pb, and Cd:Pb. A significantly negative correlation was also found between Cu:Mn, Zn:Mo, Cg:Hg, and Hg:Pb. Based on the obtained results, it is recommended that the influence of the stage of lactation, as well as the breed of sheep, should be included when designing experiments. In general, sheep milk is rich in essential trace elements, but it also contains a very low content of toxic elements, which provides justification for increasing the breeding of Lacaune sheep and indicates the convenience of consuming their milk without risking the consumer's health.

Pediatric patients with relapsed or refractory rhabdomyosarcoma (RMS) have dismal cure rates, and effective therapy is urgently needed. The oncogenic receptor tyrosine kinase fibroblast growth factor receptor 4 (FGFR4) is highly expressed in RMS and lowly expressed in healthy tissues. Here, we describe a second-generation FGFR4-targeting chimeric antigen receptor (CAR), based on an anti-human FGFR4-specific murine monoclonal antibody 3A11, as an adoptive T cell treatment for RMS. The 3A11 CAR T cells induced robust cytokine production and cytotoxicity against RMS cell lines in vitro. In contrast, a panel of healthy human primary cells failed to activate 3A11 CAR T cells, confirming the selectivity of 3A11 CAR T cells against tumors with high FGFR4 expression. Finally, we demonstrate that 3A11 CAR T cells are persistent in vivo and can effectively eliminate RMS tumors in two metastatic and two orthotopic models. Therefore, our study credentials CAR T cell therapy targeting FGFR4 to treat patients with RMS., Competing Interests: Declaration of interests J. Khan, R.J.O., D.S.D., and A.T.C. are inventors on international patent application no. PCT/US2016/052496. The 3A11 CAR sequence is in this patent application (see https://patents.justia.com/patent/11078286) filed on September 19, 2016, titled “Monoclonal antibodies specific for fibroblast growth factor receptor 4 (FGFR4) and methods of their use.”, (Published by Elsevier Inc.)

The physical properties of nanomagnetic particles are expected to be highly dependent on their size. In this study, besides the promising applications of nanocrystalline Ni-Zn spinel ferrites in the area of photocatalysis and free radical scavenging, we present a detailed study with appropriate scientific explanations on the role of size change in modifying and tuning the microstructural, optical and magnetic properties. Three nanostructured Zn 0.3 Ni 0.7 Fe 2 O 4 samples of different particle sizes were prepared via the chemical co-precipitation method. Crystallographic phase purity and formation of the spinel cubic phase for all the samples were tested by X-ray diffraction studies. The magnetic properties of the as-synthesized ferrite nanoparticles have been examined thoroughly at 5 K and 300 K. Emergence of superparamagnetic behavior has been observed for the sample with the smallest size ferrite nanoparticles (ZNF-1). The photocatalytic efficiency of all the nanocatalysts was tested on methylene blue (MB) dye and the smallest sized nanocatalyst (ZNF-1) was identified as the most efficient catalyst in degrading MB dye under light illumination. The degradation efficiency was found to decrease with increasing mean particle size of the prepared samples. The antioxidant properties of the prepared ferrite samples were also studied. Here, too, the ZNF-1 sample with the smallest sized nanoparticles exhibited maximum scavenging of free radicals compared to other samples. Hence, the present study clearly demonstrates that smaller-sized Ni-Zn spinel ferrites are efficient materials for tuning the physical properties as well as for use in photocatalytic and antioxidant applications., Competing Interests: The authors declare no competing financial interest., (This journal is © The Royal Society of Chemistry.)

The development of efficient metal-free photocatalysts for the generation of reactive oxygen species (ROS) for sulfur mustard (HD) decontamination can play a vital role against the stockpiling of chemical warfare agents (CWAs). Herein, one novel concept is conceived by smartly choosing a specific ionic monomer and a donor tritopic aldehyde, which can trigger linker-independent regioselective protonation/deprotonation in the polymeric backbone. In this context, the newly developed vinylene-linked ionic polymers (TPA/TPD-Ionic) are further explored for visible-light-assisted detoxification of HD simulants. Time-resolved-photoluminescence (TRPL) study reveals the protonation effect in the polymeric backbone by significantly enhancing the life span of photoexcited electrons. In terms of catalytic performance, TPA-Ionic outperformed TPD-Ionic because of its enhanced excitons formation and charge carrier abilities caused by the donor-acceptor (D-A) backbone and protonation effects. Moreover, the formation of singlet oxygen ( 1 O 2 ) species is confirmed via in-situ Electron Spin Resonance (ESR) spectroscopy and density functional theory (DFT) analysis, which explained the crucial role of solvents in the reaction medium to regulate the ( 1 O 2 ) formation. This study creates a new avenue for developing novel porous photocatalysts and highlights the crucial roles of sacrificial electron donors and solvents in the reaction medium to establish the structure-activity relationship., (© 2023 Wiley-VCH GmbH.)

With greater accessibility and an increased number of patients being treated with CAR T cell therapy, real-world toxicity continues to remain a significant challenge to its widespread adoption. We have previously shown that allogeneic umbilical cord blood-derived (UCB) regulatory T cells (Tregs) can resolve inflammation and treat acute and immune-mediated lung injuries. Allogeneic, cryopreserved UCB Tregs have shown a clinical benefit in patients suffering from COVID-19 acute respiratory distress syndrome. The unique properties of UCB Treg cells include a lack of plasticity under inflammatory micro-environments, no requirement for HLA matching, a long shelf life of cryopreserved cells, and immediate product availability, which makes them attractive for treating acute inflammatory syndromes. Therefore, we hypothesized that adjunct therapy with UCB Tregs may resolve the undesirable inflammation responsible for CAR T cell therapy-associated toxicity. In in vitro analysis, no interference from the addition of UCB Tregs was observed on CD19 CAR T cells' ability to kill CD19 Raji cells at different CAR T: Raji cell ratios of 8:1 (80.4% vs. 81.5%); 4:1 (62.0% vs. 66.2%); 2:1 (50.1% vs. 54.7%); and 1:1 (35.4% vs. 44.1%). In the xenogeneic B-cell lymphoma model, multiple injections of UCB Tregs were administered 3 days after CD19 CAR T cell injection, and no detrimental effect of add-on Tregs was noted on the circulating CD8 + T effector cells. The distribution of CAR T cells in multiple organs remained unaffected by the addition of the UCB Tregs. Specifically, no difference in the overall tumor burden was detected between the UCB Treg + CAR T vs. CAR T alone recipients. No tumor was detected in the liver or bone marrow in CAR T cells + UCB Tregs recipients, with a notable corresponding decrease in multiple circulating inflammatory cytokines when compared to CART alone recipients. Here we show the proof of concept for adjunct therapy with UCB Tregs to mitigate the hyper-inflammatory state induced by CAR T cells without any interference in their on-target anti-tumor activity. Administration of UCB Tregs after CAR T cells allows sufficient time for their synapse formation with tumor cells and exerts cytotoxicity, such that the UCB Tregs are diverted to interact with the antigen-presenting cells at the site of inflammation. Such a differential distribution of cells would allow for a two-pronged strategy of a UCB Treg "cooling blanket" effect and lay the groundwork for clinical study.

In recent times, a self-complementary balanced characteristic feature with the combination of both covalent bonds (structural stability) and open metal sites (single-site catalysis) introduced an advanced emerging functional nanoarchitecture termed metalated porous organic polymers (M-POPs). However, the development of M-POPs in view of the current interest in catalysis has been realized still in its infancy and remains a challenge for the years to come. In this work, we built benzothiazole-linked Fe-metalated porous organic polymer ( Fc-Bz-POP ) using ferrocene dicarboxaldehyde ( FDC ), 1,3,5-tris(4-aminophenyl) benzene ( APB ), and elemental sulfur (S 8 ) via a template-free, multicomponent, cost-effective one-pot synthetic approach. This Fc-Bz-POP is endowed with unique features including an extended network unit, isolated active sites, and catalytic pocket with a possible local structure, in which convergent binding sites are positioned in such a way that substrate molecules can be held in close proximity. Prospective catalytic application of this Fc-Bz-POP has been explored in executing catalytic allylic "C-H" bond functionalization of cyclohexene ( CHX ) in water at room temperature. Catalytic screening results identified that a superior performance with a CHX conversion of 95% and a 2-cyclohexene-1-ol selectivity ( COL ) of 80.8% at 4 h and 25 °C temperature has been achieved over Fc-Bz-POP , thereby addressing previous shortcomings of the other conventional catalytic systems. Comprehensive characterization understanding with the aid of synchrotron-based extended X-ray absorption fine structure (EXAFS) analysis manifested that the Fe atom with an oxidation state of +2 in our Fc-Bz-POP catalytic system encompasses a sandwich structural environment with the two symmetrical eclipsed cyclopentadienyl (Cp) rings, featuring nearest-neighbor (NN) Fe-C (≈2.05 Å) intramolecular bonds, as validated by the Fe L 3 -edge EXAFS fitting result. Furthermore, in situ attenuated total reflection-infrared spectroscopy (ATR-IR) analysis data for liquid-phase oxidation of cyclohexene allow for the formulation of a molecular-level reaction mechanistic pathway with the involvement of specific reaction intermediates, which is initiated by the radical functionalization of the allyl hydrogen. A deep insight investigation from density functional theory (DFT) calculations unambiguously revealed that the dominant pathway from cyclohexene to 2-cyclohexene-1-ol is initiated by an allyl-H functionalization step accompanied by the formation of 2-cyclohexene-1-hydroperoxide species as the key reaction intermediate. Electronic properties obtained from DFT simulations via the charge density difference plot, Bader charge, and density of state (DOS) demonstrate the importance of the organic polymer frame structure in altering the electronic properties of the Fe site in Fc-Bz-POP , resulting in its high activity. Our contribution has great implications for the precise design of metalated porous organic polymer-based robust catalysts, which will open a new avenue to get a clear image of surface catalysis.

The gene and cell therapy field saw its first approved treatments in Europe in 2012 and the United States in 2017 and is projected to be at least a $10B USD industry by 2025. Despite this success, a massive gap exists between the companies, clinics, and researchers developing these therapeutic approaches, and their availability to the patients who need them. The unacceptable reality is a geographic exclusion of low-and middle-income countries (LMIC) in gene therapy development and ultimately the provision of gene therapies to patients in LMIC. This is particularly relevant for gene therapies to treat human immunodeficiency virus infection and hemoglobinopathies, global health crises impacting tens of millions of people primarily located in LMIC. Bridging this divide will require research, clinical and regulatory infrastructural development, capacity-building, training, an approval pathway and community adoption for success and sustainable affordability. In 2020, the Global Gene Therapy Initiative was formed to tackle the barriers to LMIC inclusion in gene therapy development. This working group includes diverse stakeholders from all sectors and has set a goal of introducing two gene therapy Phase I clinical trials in two LMIC, Uganda and India, by 2024. Here we report on progress to date for this initiative., (© 2021. The Author(s).)

Chimeric Antigen Receptor (CAR) T cell therapy is an accepted standard of care for relapsed/refractory B cell malignancies. However, the high cost of existing industry-driven centralized production makes this therapy unaffordable in low and middle-income countries. Decentralized or point of care manufacturing has the potential to overcome some of these challenges. Here we demonstrate a decentralized manufacturing process for anti-CD19-CAR-T cells using a fully automated closed system (Miltenyi CliniMACS Prodigy®) is feasible in a developing country setting. Validation run data, as part of a pre-clinical trial safety evaluation, demonstrates the successful and robust manufacturing of anti-CD19 CAR-T cells with T cell expansion of 25 to 47-fold. The median transduction efficiency was 48.8%, with a median viability of 98% and fulfillment of all standard release criteria assays for clinical application. Evaluation of production costs in an academic, not for profit setting in India provide a benchmark for low and middle-income pricing which could greatly increase access to this therapy. Based on our analysis, the cost per product would be approximately $35,107 US dollars. Our data highlights the safety, efficacy, and reproducibility of the process for use in planned future clinical trials., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

The landscape of therapeutic options for B cell malignancies has fundamentally changed with regulatory and marketing approval of chimeric antigen receptor (CAR)-engineered T cell products. The cell types used for CAR-T production, the length of time of manufacture, the stimulation matrix, and the nature of the gene vector used to transduce human T cells all are significant variables that require adequate quality control before infusion. Having approved products available to clinicians using a centralized production paradigm has not stopped innovation in investigator-initiated trials. Moreover, the high costs of the commercial products have been a significant wake-up call to those concerned about rising costs in health care, and the ability of developing nations, and nations with managed care systems to support these costs. Place-of-care manufacturing is a clear alternative to the approved products created in a centralized manufacturing approach. It is supported by continued technological innovation and the willingness of clinicians to develop new ways to decrease costs and make these curative therapies equitably available., Competing Interests: Declaration of Competing Interest RO serves on the Scientific Advisory Board of Abound Bio, and Umoja Biopharma. MDL has consulted for Pfizer, Novartis and BMS, and serves on DSMB for AbbVie., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

We aimed to identify potential physiological and performance differences of trained cross-country skiers (V˙o 2max =60±4 ml ∙ kg -1  ∙ min -1 ) following two, 3-week long altitude modalities: 1) training at moderate altitudes (600-1700 m) and living at 1500 m (LMTM;N=8); and 2) training at moderate altitudes (600-1700 m) and living at 1500 m with additional nocturnal normobaric hypoxic exposures (FiO 2  =0.17;LHTM; N=8). All participants conducted the same training throughout the altitude training phase and underwent maximal roller ski trials and submaximal cyclo-ergometery before, during and one week after the training camps. No exercise performance or hematological differences were observed between the two modalities. The average roller ski velocities were increased one week after the training camps following both LMTM (p=0.03) and LHTM (p=0.04) with no difference between the two (p=0.68). During the submaximal test, LMTM increased the Tissue Oxygenation Index (11.5±6.5 to 1.0±8.5%; p=0.04), decreased the total hemoglobin concentration (15.1±6.5 to 1.7±12.9 a.u.;p=0.02), and increased blood pH (7.36±0.03 to 7.39±0.03;p=0.03). On the other hand, LHTM augmented minute ventilation (76±14 to 88±10 l·min -1 ;p=0.04) and systemic blood oxygen saturation by 2±1%; (p=0.02) with no such differences observed following the LMTM. Collectively, despite minor physiological differences observed between the two tested altitude training modalities both induced comparable exercise performance modulation., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

HIV-specific chimeric antigen receptor-T cell (CAR T cell) therapies are candidates to functionally cure HIV infection in people with HIV (PWH) by eliminating reactivated HIV-infected cells derived from latently infected cells within the HIV reservoir. Paramount to translating such therapeutic candidates successfully into the clinic will require anti-HIV CAR T cells to localize to lymphoid tissues in the body and eliminate reactivated HIV-infected cells such as CD4+ T cells and monocytes/macrophages. Here we show that i.v. injected anti-HIV duoCAR T cells, generated using a clinical-grade anti-HIV duoCAR lentiviral vector, localized to the site of active HIV infection in the spleen of humanized mice and eliminated HIV-infected PBMCs. CyTOF analysis of preinfusion duoCAR T cells revealed an early memory phenotype composed predominantly of CCR7+ stem cell-like/central memory T cells (TSCM/TCM) with expression of some effector-like molecules. In addition, we show that anti-HIV duoCAR T cells effectively sense and kill HIV-infected CD4+ T cells and monocytes/macrophages. Furthermore, we demonstrate efficient genetic modification of T cells from PWH on suppressive ART into anti-HIV duoCAR T cells that subsequently kill autologous PBMCs superinfected with HIV. These studies support the safety and efficacy of anti-HIV duoCAR T cell therapy in our presently open phase I/IIa clinical trial (NCT04648046).

Background: Life satisfaction (LS), a useful construct in the study of psycho-social well-being, is an important indicator of healthy aging. With a view to investigate whether the improved longevity in India is accompanied by commensurate levels of well-being and contentment among the older adults , this study aimed to examine (1) the association between LS and sleep quality among older Indian adults aged 60 years and above (2) the mediating role of depression that accounts for the association and (3) the moderating role of functional limitation in this mediation., Methods: Cross-sectional data from the Longitudinal Ageing Study in India (LASI), Wave-1 (2017-18) was used. Pearson's correlation coefficients were calculated to investigate the pair-wise relationship between sleep quality, depressive symptoms, functional limitation, and LS. Structural Equation Model was employed to analyse the moderated-mediated association between sleep quality and the level of LS., Results: Sleep quality had a direct effect (β=-0.12) as well as an indirect effect (β=-0.024) via depressive symptoms on LS, accounting for 83.6 and 16.4 per cent of the total effects, respectively. Also, the interaction term between poor seep quality and functional limitation was positive (β = 0.03, p < 0.001) in determining depressive symptoms, suggesting that higher level of functional limitation aggravated the indirect effect of poor sleep quality on LS., Conclusion: The findings of the study suggested that ensuring both the physical as well as the mental well-being of the population during the life course may confer in later life the desired level of life satisfaction., (© 2022. The Author(s).)

Chimeric antigen receptor T-cell (CAR-T cell) therapy directed at CD19 produces durable remissions in the treatment of relapsed/refractory non-Hodgkin lymphoma (NHL). Nonetheless, many patients receiving CD19 CAR-T cells fail to respond for unknown reasons. To reveal changes in 4-1BB-based CD19 CAR-T cells and identify biomarkers of response, we used single-cell RNA sequencing and protein surface marker profiling of patient CAR-T cells pre- and postinfusion into patients with NHL. At the transcriptional and protein levels, we note the evolution of CAR-T cells toward a nonproliferative, highly differentiated, and exhausted state, with an enriched exhaustion profile in CAR-T cells of patients with poor response marked by TIGIT expression. Utilizing in vitro and in vivo studies, we demonstrate that TIGIT blockade alone improves the antitumor function of CAR-T cells. Altogether, we provide evidence of CAR-T cell dysfunction marked by TIGIT expression driving a poor response in patients with NHL., Significance: This is the first study investigating the mechanisms linked to CAR-T patient responses based on the sequential analysis of manufactured and infused CAR-T cells using single-cell RNA and protein expression data. Furthermore, our findings are the first to demonstrate an improvement of CAR-T cell efficacy with TIGIT inhibition alone. This article is highlighted in the In This Issue feature, p. 1825., (©2022 American Association for Cancer Research.)

Background: Specialty training in plastic, reconstructive and aesthetic surgery is a prerequisite for safe and effective provision of care. The aim of this study was to assess and portray similarities and differences in the continuing education and specialization in plastic surgery in Europe., Material and Methods: A detailed questionnaire was designed and distributed utilizing an online survey administration software. Questions addressed core items regarding continuing education and specialization in plastic surgery in Europe. Participants were addressed directly via the European Leadership Forum (ELF) of the European Society of Plastic, Reconstructive and Aesthetic Surgery (ESPRAS). All participants had detailed knowledge of the organization and management of plastic surgical training in their respective country., Results: The survey was completed by 29 participants from 23 European countries. During specialization, plastic surgeons in Europe are trained in advanced tissue transfer and repair and aesthetic principles in all parts of the human body and within several subspecialties. Moreover, rotations in intensive as well as emergency care are compulsory in most European countries. Board certification is only provided for surgeons who have had multiple years of training regulated by a national board, who provide evidence of individually performed operative procedures in several anatomical regions and subspecialties, and who pass a final oral and/or written examination., Conclusion: Board certified plastic surgeons meet the highest degree of qualification, are trained in all parts of the body and in the management of complications. The standard of continuing education and qualification of European plastic surgeons is high, providing an excellent level of plastic surgical care throughout Europe., Hintergrund: Die Facharzt-Weiterbildung für Plastische und Ästhetische Chirurgie ist eine Grundvoraussetzung für sichere und effektive Patientenversorgung. Ziel der vorliegenden Studie war die Darstellung von Gemeinsamkeiten und Unterschieden in der Weiterbildung für Plastische Chirurgie innerhalb von Europa., Materialien Und Methoden: Ein internetbasierter Fragebogen wurde mit Hilfe eines kostenlosen Formularerstellungstools erstellt und verteilt. Die Fragen betrafen Kernpunkte der Weiterbildung für Plastische Chirurgie in Europa. Die Teilnehmer wurden direkt über das European Leadership Forum (ELF) der European Society of Plastic, Reconstructive and Aesthetic Surgery (ESPRAS) kontaktiert. Alle Teilnehmer hatten weitreichende Kenntnisse über die Organisation und Struktur der plastisch-chirurgischen Weiterbildung in ihrem jeweiligen Land., Ergebnisse: 29 Teilnehmer*innen aus 23 europäischen Ländern nahmen an der Umfrage teil. Die Weiterbildung für Plastische Chirurgie beinhaltet grundlegende Prinzipien und Techniken zur Wiederherstellung von Form und Funktion innerhalb der verschiedenen Säulen der Plastischen Chirurgie, sowie in allen Körperregionen. In den meisten europäischen Ländern ist eine Rotation in der Intensiv- und Notfallmedizin und die Behandlung kritisch kranker Patienten obligatorisch. Voraussetzung für die Facharztbezeichnung ist die mehrjährige, national organisierte Weiterbildung, der Nachweis einer festgelegten Anzahl selbstständig durchgeführter Operationen, sowie die mündliche und/oder schriftliche Abschlussprüfung., Schlussfolgerung: Fachärzte für Plastische und Ästhetische Chirurgie sind hochqualifiziert und auch im Umgang mit Komplikationen geschult. Der Standard der Weiterbildung der europäischen Plastischen Chirurgen ist hoch, so dass innerhalb Europas eine hohe Qualität plastisch-chirurgischer Versorgung gewährleistet ist., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Background: Although awareness and treatment rates of hypertension have significantly improved in recent years, the prevalence of undiagnosed and untreated hypertension remains a major public health concern for Indian policymakers. While the urban-rural variation in the prevalence, diagnosis, control, and treatment of hypertension is reasonably well-documented, the explanation behind such variation remains poorly understood given the dearth of studies conducted on exploring the determinants of the rural-urban gap in the prevalence of undiagnosed, untreated, and uncontrolled hypertension in India. In view of this research gap, our paper aims to decompose the inter-group differences between rural and urban areas in undiagnosed, untreated, and undertreated hypertension among older adults in India into the major contributing factors., Methods: Nationally representative data collected in the Longitudinal Ageing Study of India, Wave-1 (2017-18), was utilized for this study. Maximum-likelihood binary logistic-regression models were employed to capture the crude and adjusted associations between the place of residence and prevalence of undiagnosed, untreated, and undertreated hypertension. Fairlie's decomposition technique was used to decompose the inter-group differences between rural and urban residents in the prevalence of undiagnosed, untreated, and undertreated hypertension among the older population in India, into the major contributing factors, in order to explore the pathways through which these differences manifest., Results: The overall prevalence rates of undiagnosed, untreated, and undertreated hypertension among older adults were 42.3%, 6%, and 18.7%, respectively. However, the prevalence of undiagnosed and untreated hypertension was higher in rural areas, by 12.4 and 1.7 percentage-points, respectively, while undertreated hypertension was more prevalent in the urban areas (by 7.2 percentage-points). The decomposition analysis explained roughly 41% and 34% of the urban advantage over rural areas in the case of undiagnosed and untreated hypertension, while it explained 51% of the urban disadvantage in respect of undertreated hypertension. The rural-urban differentials in education and comorbidities accounted for the majority of the explained rural disadvantage in the prevalence of undiagnosed hypertension, explaining 13.51% and 13.27% of the gap, respectively. The regional factor was found to be the major driver behind urban advantage in the prevalence of untreated hypertension, contributing 37.47% to the overall gap. In the case of undertreated hypertension, education, comorbidities, and tobacco consumption were the major contributors to the urban-rural inequality, which accounted for 12.3%, 10.6%, and 9.8% of the gap, respectively., Conclusion: Socio-economic and lifestyle factors seemed to contribute significantly to the urban-rural gap in undiagnosed, untreated and undertreated hypertension in India among older adults. There is an urgent need of creating awareness programmes for the early identification of hypertensive cases and regular treatment, particularly in under-serviced rural India. Interventions should be made targeting specific population groups to tackle inequality in healthcare utilization., (© 2022. The Author(s).)

This study deals with the biomonitoring of cadmium (Cd) heavy metal in the three selected Tricholoma mushroom species collected from wild habitats of central and coastal Croatia. For this, mushroom (T. columbetta: n = 38, T. portentosum: n = 35, and T. terreum: n = 34) and surface soil samples were collected from nine forest localities of Croatia and analyzed for Cd concentration using inductively coupled plasma−optical emission spectrometry (ICP−OES) through the acid digestion method. The findings revealed that Cd was present in Tricholoma spp. and surface soil. However, the maximum mean Cd concentration (mg/kg dry weight) was recorded in T. portentosum (cap: 0.98; stipe: 0.72), followed by T. columbetta (cap: 0.96; stipe: 0.73) and T. terreum (cap: 0.81; stipe: 0.63). The bioconcentration factor (BCF) value (>1) revealed that the selected Tricholoma spp. had the potential for Cd accumulation. Moreover, the principal component (PC) and hierarchical cluster (HC) analyses were used to derive the interactions and similarities between Cd levels Tricholoma spp. and sampling localities. The multivariate analysis suggested that central sampling localities had higher Cd levels as compared to coastal localities. However, the daily intake of metals (DIM < 0.426) and health risk index (HRI < 1) showed that there was no potential health risk associated with the consumption of selected Tricholoma spp. The findings of this study are helpful to understand the Cd accumulation behavior of wild edible Tricholoma spp. collected from Croatia.

The rational synthesis of durable, earth-abundant efficient electrocatalysts for the oxygen evolution reaction (OER) from water is one of the most important routes for storing renewable energy and minimizing fossil fuel combustion. The prime hurdles for effectively utilizing commercial RuO 2 as (OER) electrocatalysts are its very low stability, catalyst deactivation, and high cost. In this work, we explored a Ru-integrated porous organic polymer (Ru@Bpy-POP) by a facile one-pot Friedel-Crafts alkylation strategy between redox-active (Ru(demob)3Cl2) and a carbazole unit, which is composed of unique features including an extended framework unit, isolated active sites, and tunable electrode kinetics. Ru@Bpy-POP can serve as a bridge between a Metal-Organic Framework (MOF) and POP-based catalytic systems with a balanced combination of covalent bonds (structural stability) and open metal sites (single site catalysis). Ru@Bpy-POP, deposited on a three-dimensional nickel foam electrode support, exhibits a promising electrocatalytic OER activity with an ultra-low ruthenium loading compared to a benchmark RuO 2 catalyst, providing an overpotential of about 270 mV to reach 10 mA cm -2 in an alkaline medium. Moreover, a high current density of 248 mA cm -2 was achieved for the Ru@Bpy-POP catalyst at only 1.6 V ( vs. RHE), which is much higher than 91 mA cm -2 for commercial RuO 2 . The robust, albeit highly conjugated, POP framework not only triggered facile electro-kinetics but also suppressed aggregation and metallic corrosion during electrolysis. In particular, the benefits of covalent integration of distinct Ru sites into the framework can modulate intermediate adsorption and charge density, which contributes to its exceptional OER activity. All of the critical steps involved in OER are complemented by Density Functional Theory (DFT) calculations, which suggest that electrocatalytic water oxidation proceeds from a closed-shell configuration to open-shell electronic configurations with high-spin states. These open-shell configurations are more stable than their closed-shell counterparts by 1 eV, improving the overall catalytic activity.