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Radiation-induced cataracts (RICs) represent a significant public health challenge, particularly impacting individuals exposed to ionizing radiation (IR) through medical treatments, occupational settings, and environmental factors. Effective therapeutic strategies require a deep understanding of the mechanisms underlying RIC formation (RICF). This study investigates the roles of angiotensin II (Ang II) and oxidative stress in RIC development, with a focus on their combined effects on lens transparency and cellular function. Key mechanisms include the generation of reactive oxygen species (ROS) and oxidative damage to lens proteins and lipids, as well as the impact of Ang II on inflammatory responses and cellular apoptosis. While the generation of ROS from water radiolysis is well established, the impact of Ang II on RICs is less understood. Ang II intensifies oxidative stress by activating type 1 receptors (AT1Rs) on lens epithelial cells, resulting in increased ROS production and inflammatory responses. This oxidative damage leads to protein aggregation, lipid peroxidation, and apoptosis, ultimately compromising lens transparency and contributing to cataract formation. Recent studies highlight Ang II's dual role in promoting both oxidative stress and inflammation, which accelerates cataract development. RICs pose a substantial public health concern due to their widespread prevalence and impact on quality of life. Targeting Ang II signaling and oxidative stress simultaneously could represent a promising therapeutic approach. Continued research is necessary to validate these strategies and explore their efficacy in preventing or reversing RIC development.

Microorganisms that colonize in or on a host play significant roles in regulating the host's immunological fitness and bioenergy production, thus controlling the host's stress responses. Radiation elicits a pro-inflammatory and bioenergy-expensive state, which could influence the gut microbial compositions and, therefore, the host-microbe bidirectional relationship. To test this hypothesis, young adult mice were exposed to total body irradiation (TBI) at doses of 9.5 Gy and 11 Gy, respectively. The irradiated mice were euthanized on days 1, 3, and 9 post TBI, and their descending colon contents (DCCs) were collected. The 16S ribosomal RNAs from the DCCs were screened to find the differentially enriched bacterial taxa due to TBI. Subsequently, these data were analyzed to identify the metagenome-specific biofunctions. The bacterial community of the DCCs showed increased levels of diversity as time progressed following TBI. The abundance profile was the most divergent at day 9 post 11 Gy TBI. For instance, an anti-inflammatory and energy-harvesting bacterium, namely, Firmicutes , became highly abundant and co-expressed in the DCC with pro-inflammatory Deferribacteres at day 9 post 11 Gy TBI. A systems evaluation found a diverging trend in the regulation profiles of the functional networks that were linked to the bacteria and metabolites of the DCCs, respectively. Additionally, the network clusters associated with lipid metabolism and bioenergy synthesis were found to be activated in the DCC bacteria but inhibited in the metabolite space at day 9 post 11 Gy. Taking these results together, the present analysis indicated a disrupted mouse-bacteria symbiotic relationship as time progressed after lethal irradiation. This information can help develop precise interventions to ameliorate the symptoms triggered by TBI.

Medical procedures, such as radiation therapy, are a vital element in treating many cancers, significantly contributing to improved survival rates. However, a common long-term complication of such exposure is radiation-induced skin fibrosis (RISF), a complex condition that poses substantial physical and psychological challenges. Notably, about 50% of patients undergoing radiation therapy may achieve long-term remission, resulting in a significant number of survivors managing the aftereffects of their treatment. This article delves into the intricate relationship between RISF, reactive oxygen species (ROS), and angiotensin II (Ang II) signaling. It proposes the underlying mechanisms and examines potential treatments for mitigating skin fibrosis. The primary goal is to offer essential insights in order to better care for and improve the quality of life of cancer survivors who face the risk of developing RISF.

The purpose of this investigation was to characterize the natural history of a murine total-abdominal-irradiation exposure model to measure gastrointestinal acute radiation injury. Male CD2F1 mice at 12 to 15 weeks old received total-abdominal irradiation using 4-MV linear accelerator X-rays doses of 0, 11, 13.5, 15, 15.75 and 16.5 Gy (2.75 Gy/min). Daily cage-side (i.e., in the animal housing room) observations of clinical signs and symptoms including body weights on all animals were measured up to 10 days after exposure. Jejunum tissues from cohorts of mice were collected at 1, 3, 7 and 10 days after exposure and radiation injury was assessed by histopathological analyses. Results showed time- and dose-dependent loss of body weight [for example at 7 days: 0.66 (±0.80) % loss for 0 Gy, 6.40 (±0.76) % loss at 11 Gy, 9.43 (±2.06) % loss at 13.5 Gy, 23.53 (± 1.91) % loss at 15 Gy, 29.97 (±1.16) % loss at 15.75 Gy, and 31.79 (±0.76) % loss at 16.5 Gy]. Negligible clinical signs and symptoms, except body weight changes, of radiation injury were observed up to 10 days after irradiation with doses of 11 to 15 Gy. Progressive increases in the severity of clinical signs and symptoms were found after irradiation with doses >15 Gy. Jejunum histology showed a progressive dose-dependent increase in injury. For example, at 7 days postirradiation, the percent of crypts, compared to controls, decreased to 82.3 (±9.5), 69.2 (±12.3), 45.4 (±11.9), 18.0 (±3.4), and 11.5 (± 1.8) with increases in doses from 11 to 16.5 Gy. A mucosal injury scoring system was used that mainly focused on changes in villus morphology damage (i.e., subepithelial spaces near the tips of the villi with capillary congestion, significant epithelial lifting along the length of the villi with a few denuded villus tips). Peak levels of total-abdominal irradiation induced effects on the mucosal injury score were seen 7 days after irradiation for doses ≥15 Gy, with a trend to show a decline after 7 days. A murine multiple-parameter gastrointestinal acute-radiation syndrome severity-scoring system was established based on clinical signs and symptoms that included measures of appearance (i.e., hunched and/or fluffed fur), respiratory rate, general (i.e., decreased mobility) and provoked behavior (i.e., subdued response to stimulation), weight loss, and feces/diarrhea score combined with jejunum mucosal-injury grade score. In summary, the natural-history radio-response for murine partial-body irradiation exposures is important for establishing a well-characterized radiation model system; here we established a multiple-parameter gastrointestinal acute-radiation syndrome severity-scoring system that provides a radiation injury gastrointestinal tissue-based assessment utility., (©2024 by Radiation Research Society. All rights of reproduction in any form reserved.)

With the current volatile geopolitical climate, the threat of nuclear assault is high. Exposure to ionizing radiation from either nuclear incidents or radiological accidents often lead to major harmful consequences to human health. Depending on the absorbed dose, the symptoms of the acute radiation syndrome and delayed effects of acute radiation exposure (DEARE) can appear within hours, weeks to months. The lung is a relatively radiosensitive organ with manifestation of radiation pneumonitis as an acute effect, followed by apparent fibrosis in weeks or even months. A recently developed, first-of-its-kind murine model for partial-body irradiation (PBI) injury, which can be used to test potential countermeasures against multi-organ damage such as gastrointestinal (GI) tract and lungs was used for irradiation, with 2.5% bone marrow spared (BM2.5-PBI) from radiation exposure. Long-term damage to lungs from radiation was evaluated using µ-CT scans, pulmonary function testing, histopathological parameters and molecular biomarkers. Pulmonary fibrosis was detected by ground glass opacity observed in µ-CT scans of male and female C57BL/6J mice 6-7 months after BM2.5-PBI. Lung mechanics assessments pertaining to peripheral airways suggested fibrotic lungs with stiffer parenchymal lung tissue and reduced inspiratory capacity in irradiated animals 6-7 months after BM2.5-PBI. Histopathological evaluation of the irradiated lungs revealed presence of focal and diffuse pleural, and parenchymal inflammatory and fibrotic lesions. Fibrosis was confirmed by elevated levels of collagen when compared to lungs of age-matched naïve mice. These findings were validated by findings of elevated levels of pro-fibrotic biomarkers and reduction in anti-inflammatory proteins. In conclusion, a long-term model for radiation-induced pulmonary fibrosis was established, and countermeasures could be screened in this model for survival and protection/mitigation or recovery from radiation-induced pulmonary damage., (©2024 by Radiation Research Society. All rights of reproduction in any form reserved.)

In the current geopolitical climate there is an unmet need to identify and develop prophylactic radiation countermeasures, particularly to ensure the well-being of warfighters and first responders that may be required to perform on radiation-contaminated fields for operational or rescue missions. Currently, no countermeasures have been approved by the U.S. FDA for prophylactic administration. Here we report on the efficacious nature of FSL-1 (toll-like receptor 2/6 agonist) and the protection from acute radiation syndrome (ARS) in a murine total-body irradiation (TBI) model. A single dose of FSL-1 was administered subcutaneously in mice. The safety of the compound was assessed in non-irradiated animals, the efficacy of the compound was assessed in animals exposed to TBI in the AFRRI Co-60 facility, the dose of FSL-1 was optimized, and common hematological parameters [complete blood cell (CBC), cytokines, and bone marrow progenitor cells] were assessed. Animals were monitored up to 60 days after exposure and radiation-induced damage was evaluated. FSL-1 was shown to be non-toxic when administered to non-irradiated mice at doses up to 3 mg/kg. The window of efficacy was determined to be 24 h prior to 24 h after TBI. FSL-1 administration resulted in significantly increased survival when administered either 24 h prior to or 24 h after exposure to supralethal doses of TBI. The optimal dose of FSL-1 administration was determined to be 1.5 mg/kg when administered prior to irradiation. Finally, FSL-1 protected the hematopoietic system (recovery of CBC and bone marrow CFU). Taken together, the effects of increased survival and accelerated recovery of hematological parameters suggests that FSL-1 should be developed as a novel radiation countermeasure for soldiers and civilians, which can be used either before or after irradiation in the aftermath of a radiological or nuclear event., (©2024 by Radiation Research Society. All rights of reproduction in any form reserved.)

The detrimental effects of high-dose ionizing radiation on human health are well-known, but the influence of sex differences on the delayed effects of acute radiation exposure (DEARE) remains unclear. Here, we conducted six-month animal experiments using escalating radiation doses (7-9 Gy) on male and female C57BL/6 mice. The results show that female mice exhibited greater resistance to radiation, showing increased survival at six months post-total body irradiation. LD50/30 (lethal dose expected to cause 50% lethality in 30 days) for female mice is 8.08 Gy, while for male mice it is 7.76 Gy. DEARE causes time- and sex-dependent dysregulation of microRNA expression, processing enzymes, and the HOTAIR regulatory pathway. Differential regulation of molecular patterns associated with growth, development, apoptosis, and cancer is also observed in male and female mice. These findings shed light on the molecular basis of age and sex differences in DEARE response and emphasize the importance of personalized medicine for mitigating radiation-induced injuries and diseases., Competing Interests: The authors declare no competing interests.

The goal of this study was to establish a model of partial-body irradiation (PBI) sparing 2.5% of the bone marrow (BM2.5-PBI) that accurately recapitulates radiological/nuclear exposure scenarios. Here we have reported a model which produces gastrointestinal (GI) damage utilizing a clinical linear accelerator (LINAC) with precise dosimetry, which can be used to develop medical countermeasures (MCM) for GI acute radiation syndrome (ARS) under the FDA animal rule. The PBI model (1 hind leg spared) was developed in male and female C57BL/6 mice that received radiation doses ranging from 12-17 Gy with no supportive care. GI pathophysiology was assessed by crypt cell loss and correlated with peak lethality between days 4 and 10 after PBI. The radiation dose resulting in 50% mortality in 30 days (LD50/30) was determined by probit analysis. Differential blood cell counts in peripheral blood, colony forming units (CFU) in bone marrow, and sternal megakaryocytes were analyzed between days 1-30, to assess the extent of hematopoietic ARS (H-ARS) injury. Radiation-induced GI damage was also assessed by measuring: 1. bacterial load (16S rRNA) by RT-PCR on days 4 and 7 after PBI in liver, spleen and jejunum, 2. liposaccharide binding protein (LBP) levels in liver, and 3. fluorescein isothiocyanate (FITC)-dextran, E-selectin, sP-selectin, VEGF, FGF-2, MMP-9, citrulline, and serum amyloid A (SAA) levels in serum. The LD50/30 of male mice was 14.3 Gy (95% confidence interval 14.1-14.7 Gy) and of female mice was 14.5 Gy (95% confidence interval 14.3-14.7 Gy). Secondary endpoints included loss of viable crypts, higher bacterial loads in spleen and liver, higher LBP in liver, increased FITC-dextran and SAA levels, and decreased levels of citrulline and endothelial biomarkers in serum. The BM2.5-PBI model, developed for the first time with precise dosimetry, showed acute radiation-induced GI damage that is correlated with lethality, as well as a response to various markers of inflammation and vascular damage. Sex-specific differences were observed with respect to radiation dose response. Currently, no MCM is available as a mitigator for GI-ARS. This BM2.5-PBI mouse model can be regarded as the first high-throughput PBI model with precise dosimetry for developing MCMs for GI-ARS under the FDA animal rule., (© 2024 by Radiation Research Society.)

IL-18 has been shown to play important roles in response to total body irradiation. However, homogenous total body irradiation is not a realistic model to reflect the radiation exposure in a real nuclear event. To further study the roles of IL-18 in a real nuclear scenario, we developed a mouse partial body irradiation with 5% bone marrow sparing (PBI/BM5) model to mimic the inhomogeneous radiation exposure. We established the dose response curves of PBI/BM5 using different radiation doses ranging from 12 to 16 Gy. Using the PBI/BM5 model, we showed that IL-18 knockout mice were significantly more radiation resistant than the wild-type mice at 14.73 Gy. We further studied the hematopoietic changes using a complete blood count, bone marrow colony-forming assays, and serum cytokine assays on the mice exposed to PBI/BM5 with IL-18BP treatment and wild-type/IL-18 knockout mice. In conclusion, our data suggest that IL-18 plays important roles in mouse survival in a realistic nuclear exposure model, potentially through the IL-18/IFNγ pathway.

A library of piperonylic acid-derived hydrazones possessing variable aryl moiety was synthesized and investigated for their multifunctional properties against cholinesterases (ChEs) and monoamine oxidases (MAOs). The in vitro enzymatic assay results revealed that the tested hydrazones have exhibited excellent cholinesterase inhibition profile. Compound 4i, (E)-N'-(2,3-dichlorobenzylidene)benzo[d][1,3]dioxole-5-carbohydrazide showed promising dual inhibitory profile against AChE (0.048 ± 0.007 μM), BChE (0.89 ± 0.018 μM), and MAO-B (0.95 ± 0.12 μM) enzymes. SAR exploration revealed that the truncation of the linker connecting both the aryl binding sites of the semicarbazone scaffold, by one atom, has relatively suppressed the AChE inhibitory potential. Kinetic studies disclosed that the compound 4i reversibly inhibited AChE enzyme in a competitive manner (K i  = 8.0 ± 0.076 nM), while it displayed a non-competitive and reversible inhibition profile against MAO-B (K i  = 9.6 ± 0.021 µM). Moreover, molecular docking studies of synthesized compounds against ChEs and MAOs provided the crucial molecular features that enable their close association and interaction with the target enzymes. All atomistic simulation studies confirmed the stable association of compound 4i within the active sites of AChE and MAO-B. In addition, theoretical ADMET prediction studies demonstrated the acceptable pharmacokinetic profile of the dual inhibitors. In summary, the attempted lead simplification study afforded a potent dual ChE-MAO-B inhibitor compound that merits further investigation., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Thrombopoietin (TPO) is the primary regulator of platelet generation and a stimulator of multilineage hematopoietic recovery following exposure to total body irradiation (TBI). JNJ‑26366821, a novel PEGylated TPO mimetic peptide, stimulates platelet production without developing neutralizing antibodies or causing any adverse effects. Administration of a single dose of JNJ‑26366821 demonstrated its efficacy as a prophylactic countermeasure in various mouse strains (males CD2F1, C3H/HeN, and male and female C57BL/6J) exposed to Co-60 gamma TBI. A dose dependent survival efficacy of JNJ‑26366821 (- 24 h) was identified in male CD2F1 mice exposed to a supralethal dose of radiation. A single dose of JNJ‑26366821 administered 24, 12, or 2 h pre-radiation resulted in 100% survival from a lethal dose of TBI with a dose reduction factor of 1.36. There was significantly accelerated recovery from radiation-induced peripheral blood neutropenia and thrombocytopenia in animals pre-treated with JNJ‑26366821. The drug also increased bone marrow cellularity and megakaryocytes, accelerated multi-lineage hematopoietic recovery, and alleviated radiation-induced soluble markers of bone marrow aplasia and endothelial damage. These results indicate that JNJ‑26366821 is a promising prophylactic radiation countermeasure for hematopoietic acute radiation syndrome with a broad window for medical management in a radiological or nuclear event., (© 2023. Springer Nature Limited.)

Sarcoglycanopathy is the most frequent form of autosomal recessive limb-girdle muscular dystrophies caused by mutations in SGCB gene encoding beta-sarcoglycan proteins. In this study, we describe a shared, common haplotype co-segregating in 14 sarcoglycanopathy cases from 13 unrelated families from south Indian region with the likely pathogenic homozygous mutation c.544 T > G (p.Thr182Pro) in SGCB. Haplotype was reconstructed based on 10 polymorphic markers surrounding the c.544 T > G mutation in the cases and related family members as well as 150 unrelated controls from Indian populations using PLINK1.9. We identified haplotype H1 = G, A, G, T, G, G, A, C, T, G, T at a significantly higher frequency in cases compared to related controls and unrelated control Indian population. Upon segregation analysis within the family pedigrees, H1 is observed to co-segregate with c.544 T > G in a homozygous state in all the pedigrees of cases except one indicating a probable event of founder effect. Furthermore, Identical-by-descent and inbreeding coefficient analysis revealed relatedness among 33 new pairs of seemingly unrelated individuals from sarcoglycanopathy cohort and a higher proportion of homozygous markers, thereby indicating common ancestry. Since all these patients are from the south Indian region, we suggest this region to be a primary target of mutation screening in patients diagnosed with sarcoglycanopathy., (© 2023. Springer Nature Limited.)

The development of safe, orally available, and effective prophylactic countermeasures to protect our warfighters is an unmet need because there is no such FDA-approved countermeasure available for use. Th 1-Propanethiol, 3-(methylamino)-2-((methylamino)methyl) (PrC-210), a synthetic small molecule, is a member of a new family of aminothiols designed to reduce toxicity while scavenging reactive oxygen species (ROS). Our study investigated the protective role of a single oral administration of PrC-210 against radiation-induced hematopoietic and intestinal injury in mice. Pre-treatment with PrC-210 significantly improved the survival of mice exposed to a lethal dose of radiation. Our findings indicated that the radioprotective properties of PrC-210 are achieved by accelerating the recovery of the hematopoietic system, stimulating bone marrow progenitor cells, and ameliorating additional biomarkers of hematopoietic injury. PrC-210 pre-treatment reduced intestinal injury in mice exposed to a lethal dose of radiation by restoring jejunal crypts and villi, reducing translocation of bacteria to the spleen, maintaining citrulline levels, and reducing the sepsis marker serum amyloid A (SAA) in serum. Finally, PrC-210 pre-treatment led to a significant reduction (~10 fold) of Nos2 expression (inducible nitric oxide) in the spleen and decreased oxidative stress by enhancing the antioxidant defense system. These data support the further development of PrC-210 to receive approval from the FDA to protect warfighters and first responders from exposure to the harmful effects of ionizing radiation.

Helicobacter pylori is a Gram-negative microaerophilic gastric pathogen, responsible for the cause of peptic ulcer around half of the global population. Although several antibiotics and combination therapies have been employed for H. pylori -related gastric ulcer and cancer regiments, identifying potent inhibitors for specific targets of this bacterium will help assessing better treatment periodicity and methods to eradicate H. pylori . Herein, 1,000,000 natural compounds were virtually screened against Helicobacter pylori Peptide deformylase (HpPDF). Pharmacophore hypotheses were created using ligand and receptor-based pharmacophore modeling of GLIDE. Stringent HTVS and IFD docking protocol of GLIDE predicted leads with stable intermolecular bonds and scores. Molecular dynamics simulation of HpPDF was carried out for 100 ns using GROMACS. Hits ZINC00225109 and ZINC44896875 came up with a glide score of -9.967 kcal/mol and -12.114 kcal/mol whereas; reference compound actinonin produced a glide score of -9.730 kcal/mol. Binding energy values of these hits revealed the involvement of significant Van der Waals and Coulomb forces and the deduction of lipophilic forces that portray the deep hydrophobic residues in the S1pocket of H. pylori . The DFT analysis established the electron density-based features of the molecules and observed that the results correlate with intermolecular docking interactions. Analysis of the MD trajectories revealed the crucial residues involved in HpPDF - ligand binding and the conformational changes in the receptor. We have identified and deciphered the crucial features necessary for the potent ligand binding at catalytic site of HpPDF. The resulting ZINC natural compound hits from the study could be further employed for potent drug development.Communicated by Ramaswamy H. Sarma.

There is an increased threat of exposure to ionizing radiation; in the event of such exposure, the availability of medical countermeasures will be vital to ensure the protection of the population. Effective countermeasures should be efficacious across a varied population and most importantly amongst both males and females. Radiation research must be conducted in animal models which act as a surrogate for the human response. Here, we identify differences in survival in male and female C57BL/6 in both a total body irradiation (TBI) model using the Armed Forces Radiobiology Research Institute (AFRRI) 60Co source and a partial body irradiation (PBI) model using the AFRRI Linear Accelerator (LINAC) with 4 MV photons and 2.5% bone marrow shielding. In both models, we observed a higher degree of radioresistance in female animals and a corresponding radiosensitivity in males. One striking difference in male and female rodents is body size/weight and we investigated the role of pre-irradiation body weight on survivability for animals irradiated at the same dose of irradiation (8 Gy TBI, 14 Gy PBI). We found that weight does not influence survival in the TBI model and that heavier males but lighter females have increased survival in the PBI model. This incongruence in survival amongst the sexes should be taken into consideration in the course of developing radiation countermeasures for response to a mass casualty incident., (© 2023 S. Karger AG, Basel.)

Risks of radiation exposure necessitate the development of radioprophylactic drugs. We have reported the efficacy of CDX-301, a recombinantly developed human protein form of Fms-related tyrosine kinase 3 ligand (Flt3L), as a radioprophylactic and radiomitigatory agent. Here, we performed global microRNA profiling to further understand the mechanism of action of CDX-301. We find that CDX-301 administration 24 h prior to total body irradiation prevents radiation-induced dysregulation of microRNA biogenesis and expression in murine serum and spleen samples in a time- and tissue-dependent manner. Further analysis shows that activation of the HOTAIR regulatory pathway has a prominent function in radiation-induced injury responses, which is inhibited by pre-treatment with CDX-301. Moreover, CDX-301 attenuates radiation-induced dysregulation of several cellular functions such as inflammatory and immune responses. In corroboration, we also find that pre-treatment with CDX-301 restores the expression of bone marrow aplasia markers and inflammatory cytokines and growth factors, as well as the expression of genes associated with MAP kinase and TGF-β pathways that are altered by radiation. Our findings provide new insights into CDX-301-mediated molecular and cellular mechanisms and point to a possible novel radioprotective drug for the prevention of irradiation-induced injury and hematopoietic acute radiation syndrome., Competing Interests: L.J.T. is an employee of Celldex Therapeutics and has a financial interest in the company.

Background: Populations exhibit signatures of local adaptive traits due to spatial and environmental heterogeneity resulting in microevolution. The blue sheep is widely distributed across the high Asian mountains and are the snow leopard's principal prey species. These mountains differ in their evolutionary history due to differential glaciation and deglaciation periods, orography, and rainfall patterns, and such factors causes diversification in species., Methods and Results: Therefore, we assess the phylogeographic status of blue sheep using the mitochondrial cytochrome b gene (220 bp) across the Indian Himalayan region (IHR) and its relationship with other populations. Of the observed five haplotypes, two and three were from the western Himalayas (WH) and eastern Himalayas (EH) respectively. One of the haplotypes from WH was shared with the population of Pamir plateau, suggesting historical maternal connectivity between these areas. The phylogenetic analyses split the blue sheep into two paraphyletic clades, and western and eastern populations of IHR were within the Pamir and Tibetan plateau clades, respectively. We observed a relatively higher mean sequence divergence in the EH population than in the WH., Conclusion: We propose five 'Evolutionary Significant Units' across the blue sheep distribution range based on observed variation in the species' ecological requirements, orography, climatic conditions, and maternal lineages, viz.; Western Himalaya-Pamir plateau (WHPP); Eastern Himalaya-Tibetan plateau (EHTP); Qilian mountains; Helan mountains and Hengduan mountains population. Despite the small sample size, population divergence was observed across the IHR, therefore, we suggest a transboundary, collaborative study on comparative morphology, anatomy, ecology, behaviour, and population genetics using harmonized different genetic markers for identifying the overall taxonomic status of the blue sheep across its range for planning effective conservation strategies., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Acute Radiation Syndrome (ARS) is a syndrome involving damage to multiple organs caused by exposure to a high dose of ionizing radiation over a short period of time; even low doses of radiation damage the radiosensitive hematopoietic system and causes H-ARS. PLacenta eXpanded (PLX)-R18 is a 3D-expanded placenta-derived stromal cell product designated for the treatment of hematological disorders. These cells have been shown in vitro to secrete hematopoietic proteins, to stimulate colony formation, and to induce bone marrow migration. Previous studies in mice showed that PLX-R18 cells responded to radiation-induced hematopoietic failure by transiently secreting hematopoiesis related proteins to enhance reconstitution of the hematopoietic system. We assessed the potential effect of prophylactic PLX-R18 treatment on H-ARS. PLX-R18 cells were administered intramuscularly to C57BL/6 mice, −1 and 3 days after (LD70/30) total body irradiation. PLX R18 treatment significantly increased survival after irradiation (p < 0.0005). In addition, peripheral blood and bone marrow (BM) cellularity were monitored at several time points up to 30 days. PLX-R18 treatment significantly increased the number of colony-forming hematopoietic progenitors in the femoral BM and significantly raised peripheral blood cellularity. PLX-R18 administration attenuated biomarkers of bone marrow aplasia (EPO, FLT3L), sepsis (SAA), and systemic inflammation (sP-selectin and E-selectin) and attenuated radiation-induced inflammatory cytokines/chemokines and growth factors, including G-CSF, MIP-1a, MIP-1b, IL-2, IL-6 and MCP-1, In addition, PLX-R18 also ameliorated radiation-induced upregulation of pAKT. Taken together, prophylactic PLX-R18 administration may serve as a protection measure, mitigating bone marrow failure symptoms and systemic inflammation in the H-ARS model., Competing Interests: The following authors (V.P.K., G.P.H.-H., S.S., S.B., B.L., and S.P.G.) declare no conflict of interest. R.O. and M.S. are employees of Pluristem Ltd. and/or shareholders of Pluristem Therapeutics Inc. and stand to benefit financially from the successful development of the countermeasure.

Purpose: Symptomatic acromioclavicular joint (ACJ) osteoarthritis causes pain and limitations in activities of daily living. Open and arthroscopic distal clavicle excision techniques have been described with good outcomes. However, both techniques have their own sets of advantages and disadvantages. This study describes a novel technique of percutaneous distal clavicle excision for symptomatic ACJ osteoarthritis and our two-year results., Methods: Fifteen consecutive patients underwent percutaneous distal clavicle excision for ACJ arthritis. These patients had failed a trial of conservative treatment. The ACJ was confirmed as the pain generator with an intraarticular steroid/lignocaine injection, and shoulder MRI was used to exclude alternative pain generators in the shoulder. They had a minimum of two years of follow-up., Results: At a mean of 26.8 months postoperatively, the mean VAS pain score was 0, and the mean Constant score for the shoulder was 87.3 points (range 50-94), which corresponded to 1 good, 1 very good and 13 excellent results. The mean SF-36 score was 94.9 points (range 65-100). There were statistically significant improvements in the VAS scores, Constant shoulder scores and SF-36 scores at one year and two years of follow-up (p < 0.05). Three unique complications, namely subcutaneous emphysema, "missing" of the distal clavicle and thermal skin injury, were encountered. Our surgical technique has since been modified to circumvent these complications., Conclusion: Our novel technique of percutaneous distal clavicle excision yields a 93.3% good-to-excellent results based on the Constant shoulder score and durable pain relief based on VAS at two years., (© 2021. Istituto Ortopedico Rizzoli.)

A laccase-producing hyper performer, Schizophyllum commune, a white-rot fungus, was evaluated for its ability to selectively degrade lignin of diverse crop residues in vitro. Relative analysis of crop residue treatment using laccase obtained from immobilized cells demonstrated degradation of 30-40% in finger millet straw and sorghum stover, 27-32% in paddy straw, 21% in wheat straw, and 26% in maize straw, while 20% lignin degradation was observed when purified and recombinant laccase was used. Further investigations into in vitro dry matter digestibility studies gave promising results recording digestibility of 54-59% in finger millet straw 33-36% in paddy straw and wheat straw, 16% in maize straw for laccase obtained from cell immobilization method, whereas 14% digestibility was observed when purified and recombinant laccase was used. Sorghum stover recorded digestibility of 13-15% across all straws treated with laccase. The results obtained elucidated the positive influence of laccase treatment on lignin degradation and in vitro dry matter digestibility. The present research gave encouraging figures confirming the production of laccase using the cell immobilization method to be an efficient production method commensurate with purified and recombinant laccase under conditions of submerged cultivation, proclaiming a cost-effective, environmentally safe green technology for effectual lignin depolymerization., (© 2022. The Author(s).)

Background: Bunyumwera virus can cause 82% mortality in humans currently with no vaccine or drugs for treatment. We described an in silico multi-epitope vaccine targeting Bunyumwera virus nucleocapsid N-protein and predicted B and T cell epitopes for immunogenicity, allergenicity, toxicity, and conservancy. For creating the most potent immunological response possible, docking epitopes with HLA alleles are chosen to screen them. The 3D vaccination was docked with the Toll-like receptor-8 using molecular dynamic simulations. To ensure production efficiency, the vaccine sequence was further cloned in silico in a plasmid pIB2 vector. For efficacy and safety, results must be supported in vitro and in vivo., Results: The vaccine was cloned to enable expression and translation in a plasmid vector pIB2. It was expected to be antigenic, non-allergenic, and have a high binding affinity with TLR-8 in silico cloning. This multi-epitope vaccination may stimulate both innate and adaptive immunity., Conclusion: The vaccine developed in this work was based on the nucleocapsid N-protein of the Bunyumwera virus and was created using a reverse vaccinology method. Further experimental validation is required to assess the vaccine's therapeutic effectiveness and immunogenicity., (© 2022. The Author(s).)

The threat of a nuclear attack has increased in recent years highlighting the benefit of developing additional therapies for the treatment of victims suffering from Acute Radiation Syndrome (ARS). In this work, we evaluated the impact of a PEGylated thrombopoietin mimetic peptide, JNJ-26366821, on the mortality and hematopoietic effects associated with ARS in mice exposed to lethal doses of total body irradiation (TBI). JNJ-26366821 was efficacious as a mitigator of mortality and thrombocytopenia associated with ARS in both CD2F1 and C57BL/6 mice exposed to TBI from a cobalt-60 gamma-ray source. Single administration of doses ranging from 0.3 to 1 mg/kg, given 4, 8, 12 or 24 h post-TBI (LD70 dose) increased survival by 30-90% as compared to saline control treatment. At the conclusion of the 30-day study, significant increases in bone marrow colony forming units and megakaryocytes were observed in animals administered JNJ-26366821 compared to those administered saline. In addition, enhanced recovery of FLT3-L levels was observed in JNJ-26366821-treated animals. Probit analysis of survival in the JNJ-26366821- and saline-treated cohorts revealed a dose reduction factor of 1.113 and significant increases in survival for up to 6 months following irradiation. These results support the potential use of JNJ-26366821 as a medical countermeasure for treatment of acute TBI exposure in case of a radiological/nuclear event when administered from 4 to 24 h post-TBI., (© 2022. The Author(s).)

S-based semiconductors are attracting attention as environmentally friendly materials for energy-conversion applications because of their structural complexity and chemical flexibility. Here, we show that the delicate interplay between the chemical composition and cationic order/disorder allows one to stabilize a new sphalerite derivative phase of cubic symmetry in the Cu-Sn-S diagram: Cu 22 Sn 10 S 32 . Interestingly, its crystal structure is characterized by a semiordered cationic distribution, with the Cu-Sn disorder being localized on one crystallographic site in a long-range-ordered matrix. The origin of the partial disorder and its influence on the electronic and thermal transport properties are addressed in detail using a combination of synchrotron X-ray diffraction, Mössbauer spectroscopy, transmission electron microscopy, theoretical modeling, and transport property measurements. These measurements evidence that this compound behaves as a pseudogap, degenerate p-type material with very low lattice thermal conductivity (0.5 W m -1 K -1 at 700 K). We show that localized disorder is very effective in lowering κ L without compromising the integrity of the conductive framework. Substituting pentavalent Sb for tetravalent Sn is exploited to lower the hole concentration and doubles the thermoelectric figure of merit ZT to 0.55 at 700 K with respect to the pristine compound. The discovery of this semiordered cubic sphalerite derivative Cu 22 Sn 10 S 32 furthers the understanding of the structure-property relationships in the Cu-Sn-S system and more generally in ternary and quaternary Cu-based systems.

Background: Controversies for treatment of acromioclavicular joint injuries in particular type III injuries may be partially attributed to the lack of a standardized method of radiography and measurement technique. Previous studies looking at the Rockwood classification showed poor inter- and intraobserver reliability (Kappa value approximately 0.20-0.50). We hypothesized that the use of unilateral instead of bilateral acromioclavicular joint radiographs was the cause of this finding. In this article, we standardized the methodology to perform the radiograph and to measure the coracoclavicular distances. We designed the study to focus on the reliability of differentiating type III and type V injuries., Methods: A standardized radiographic protocol for bilateral Zanca view was established in our institution. All patients who underwent this radiographic examination over a 3-year period were reviewed. Radiographs of 55 patients with significant (type III or V) injury met the inclusion criteria. For the interobserver reliability, a retrospective radiographic review was performed by 6 orthopedic surgeons and graded as either type III or V. For intraobserver reliability, a similar process was repeated by 3 observers after a period of 6 weeks., Results: Going by the majority agreement of the 6 reviewers, there were 34 type III injuries and 19 type V injuries. The Fleiss kappa for interobserver reliability was calculated to be 0.624. The Cohen kappa for intraobserver reliability was calculated to be 0.696., Discussion: The use of a standardized radiographic protocol-taking bilateral Zanca views on the same radiographic plate-would help eliminate a significant amount of variability and improve the reliability of classifying acromioclavicular joint injuries using the Rockwood classification, which uses a relative measure to the contralateral site as its definition criteria. Other possible sources of poor reliability may include the masking of injuries by muscle spasm, resulting in a misdiagnosis of a high-grade injury as a lower-grade one and the possible need to subclassify type III injuries., Conclusion: Reliability of the Rockwood classification can be improved through the use of a standardized radiographic protocol to improve the detection of vertical instability. Similar to Rockwood dividing up Tossy grade 3 injuries when he noted the differential outcome and intervention, Rockwood type III injuries would likely require further subclassification as it remains an anomalous tool with high variability. Further studies are required to understand the pathologic basis of transition of type III into type V injury., (Copyright © 2021 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

Chartered by the U.S. Congress in 1961, the Armed Forces Radiobiology Research Institute (AFRRI) is a Joint Department of Defense (DoD) entity with the mission of carrying out the Medical Radiological Defense Research Program in support of our military forces around the globe. In the last 60 years, the investigators at AFRRI have conducted exploratory and developmental research with broad application to the field of radiation sciences. As the only DoD facility dedicated to radiation research, AFRRI's Medical Radiobiology Advisory Team provides deployable medical and radiobiological subject matter expertise, advising commanders in the response to a U.S. nuclear weapon incident and other nuclear or radiological material incidents. AFRRI received the DoD Joint Meritorious Unit Award on February 17, 2004, for its exceptionally meritorious achievements from September 11, 2001 to June 20, 2003, in response to acts of terrorism and nuclear/radiological threats at home and abroad. In August 2009, the American Nuclear Society designated the institute a nuclear historic landmark as the U.S.'s primary source of medical nuclear and radiological research, preparedness and training. Since then, research has continued, and core areas of study include prevention, assessment and treatment of radiological injuries that may occur from exposure to a wide range of doses (low to high). AFRRI collaborates with other government entities, academic institutions, civilian laboratories and other countries to research the biological effects of ionizing radiation. Notable early research contributions were the establishment of dose limits for major acute radiation syndromes in primates, applicable to human exposures, followed by the subsequent evolution of radiobiology concepts, particularly the importance of immune collapse and combined injury. In this century, the program has been essential in the development and validation of prophylactic and therapeutic drugs, such as Amifostine, Neupogen®, Neulasta®, Nplate® and Leukine®, all of which are used to prevent and treat radiation injuries. Moreover, AFRRI has helped develop rapid, high-precision, biodosimetry tools ranging from novel assays to software decision support. New drug candidates and biological dose assessment technologies are currently being developed. Such efforts are supported by unique and unmatched radiation sources and generators that allow for comprehensive analyses across the various types and qualities of radiation. These include but are not limited to both 60Co facilities, a TRIGA® reactor providing variable mixed neutron and γ-ray fields, a clinical linear accelerator, and a small animal radiation research platform with low-energy photons. There are five major research areas at AFRRI that encompass the prevention, assessment and treatment of injuries resulting from the effects of ionizing radiation: 1. biodosimetry; 2. low-level and low-dose-rate radiation; 3. internal contamination and metal toxicity; 4. radiation combined injury; and 5. radiation medical countermeasures. These research areas are bolstered by an educational component to broadcast and increase awareness of the medical effects of ionizing radiation, in the mass-casualty scenario after a nuclear detonation or radiological accidents. This work provides a description of the military medical operations as well as the radiation facilities and capabilities present at AFRRI, followed by a review and discussion of each of the research areas., (©2021 by Radiation Research Society. All rights of reproduction in any form reserved.)

Aims: Diabetes Mellitus predisposes patients to invasive fungal infections. There has been a recent surge of Mucormycosis with COVID 19 infection particularly in patients with diabetes. This study aims to study the clinical spectrum of CAM (COVID -associated Mucormycosis) with diabetes and subsequent outcomes., Material and Methods: This was a descriptive study conducted at a single COVID Care Centre in India in patients with COVID Associated Mucormycosis from April 12, 2021 to May 31, 2021., Results: Among 953 hospitalized patients with COVID 19 infection, 32 patients had CAM with an incidence of 3.36%. In patients with CAM, 87.5% had Diabetes Mellitus as the most common co-morbidity. The majority of the patients had poor glycemic control with a mean HbA1c of 9.06%. Out of the total study population, 93% had prior exposure to high dose corticosteroids. During the study period, 12.5% patients of CAM did not survive., Conclusion: Mucormycosis is an angioinvasive fungal infection with high mortality. The disease has surged in COVID 19 pandemic due to uncontrolled diabetes and improper corticosteroid use., Competing Interests: Declaration of competing interest The Authors declare there is no conflict of interest., (Copyright © 2021 Diabetes India. Published by Elsevier Ltd. All rights reserved.)

Radiation injury will result in multiorgan dysfuntion leading to multiorgan failure. In addition to many factors such as radiation dose, dose rate, the severity of the injury will also depend on organ systems which are exposed. Here, we report the protective property of gamma tocotrienol (GT3) in total as well as partial body irradiation (PBI) model in C3H/HeN male mice. We have carried out PBI by targeting thoracic region (lung-PBI) using Small Animal Radiation Research Platform, an X-ray irradiator with capabilities of an image guided irradiation with a variable collimator with minimized exposure to non-targeted tissues and organs. Precise and accurate irradiation of lungs was carried out at either 14 or 16 Gy at an approximate dose rate of 2.6 Gy/min. Though a low throughput model, it is amenable to change the field size on the spot. No damage to other non-targeted organs was observed in histopathological evaluation. There was no significant change in peripheral blood counts of irradiated mice in comparison to naïve mice. Femoral bone marrow cells had no damage in irradiated mice. As expected, damage to the targeted tissue was observed in the histopathological evaluation and non-targeted tissue was found normal. Regeneration and increase of cellularity and megakaryocytes on GT3 treatment was compared to significant loss of cellularity in saline group. Peak alveolitis was observed on day 14 post-PBI and protection from alveolitis by GT3 was noted. In irradiated lung tissue, thirty proteins were found to be differentially expressed but modulated by GT3 to reverse the effects of irradiation. We propose that possible mode of action of GT3 could be Angiopoietin 2-Tie2 pathway leading to AKT/ERK pathways resulting in disruption in cell survival/angiogenesis., (Copyright © 2020 Kumar, Ghosh, Stone, Biswas and Sharma.)

Effective therapies are lacking to treat gastrointestinal infections caused by the genus Cryptosporidium, which can be fatal in the immunocompromised. One target of interest is Cryptosporidium hominis (C. hominis) thymidylate synthase-dihydrofolate reductase (ChTS-DHFR), a bifunctional enzyme necessary for DNA biosynthesis. Targeting the TS-TS dimer interface is a novel strategy previously used to identify inhibitors against the related bifunctional enzyme in Toxoplasma gondii. In the present study, we target the ChTS dimer interface through homology modeling and high-throughput virtual screening to identifying allosteric, ChTS-specific inhibitors. Our work led to the discovery of methylenedioxyphenyl-aminophenoxypropanol analogues which inhibit ChTS activity in a manner that is both dose-dependent and influenced by the conformation of the enzyme. Preliminary results presented here include an analysis of structure activity relationships and a ChTS-apo crystal structure of ChTS-DHFR supporting the continued development of inhibitors that stabilize a novel pocket formed in the open conformation of ChTS-TS., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The threat of nuclear exposure is heightened and it is imperative to identify potential countermeasures for acute radiation syndrome. Currently no countermeasures have been approved for prophylactic administration. Effective countermeasures should function to increase survival in the short term as well as to increase the overall prognosis of an exposed individual long term. Here we describe the use of a promising radiation countermeasure, BBT-059, and the results of a long term mouse study (up to 12 months) in the male CD2F1 strain using 60 Co gamma irradiation (~0.6 Gy/min, 7.5-12.5 Gy). We report the dose reduction factor of 1.28 for BBT-059 (0.3 mg/kg) compared to control administered 24 h prior to irradiation. In the long term study animals showed accelerated recovery in peripheral blood cell counts, bone marrow colony forming units, sternal cellularity and megakaryocyte numbers in drug treated mice compared to formulation buffer. In addition, increased senescence was observed in the kidneys of animals administered control or drug and exposed to the highest doses of radiation. Decreased levels of E-cadherin, LaminB1 and increased levels of Cyc-D and p21 in spleen lysates were observed in animals administered control. Taken together the results indicate a high level of protection following BBT-059 administration in mice exposed to lethal and supralethal doses of total body gamma-radiation.

Objective: To identify coinhibitory immune pathways important in the brain, we hypothesized that comparison of T cells in lesions from patients with MS with tumor-infiltrating T cells (TILs) from patients with glioblastoma multiforme may reveal novel targets for immunotherapy., Methods: We collected fresh surgical resections and matched blood from patients with glioblastoma, blood and unmatched postmortem CNS tissue from patients with MS, and blood from healthy donors. The expression of TIGIT, CD226, and their shared ligand CD155 as well as PD-1 and PDL1 was assessed by both immunohistochemistry and flow cytometry., Results: We found that TIGIT was highly expressed on glioblastoma-infiltrating T cells, but was near-absent from MS lesions. Conversely, lymphocytic expression of PD-1/PD-L1 was comparable between the 2 diseases. Moreover, TIGIT was significantly upregulated in circulating lymphocytes of patients with glioblastoma compared with healthy controls, suggesting recirculation of TILs. Expression of CD226 was also increased in glioblastoma, but this costimulatory receptor was expressed alongside TIGIT in the majority of tumor-infiltrating T cells, suggesting functional counteraction., Conclusions: The opposite patterns of TIGIT expression in the CNS between MS and glioblastoma reflects the divergent features of the immune response in these 2 CNS diseases. These data raise the possibility that anti-TIGIT therapy may be beneficial for patients with glioblastoma., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Lethal total body irradiation (TBI) triggers multifactorial health issues in a potentially short time frame. Hence, early signatures of TBI would be of great clinical value. Our study aimed to interrogate microRNA (miRNA) and metabolites, two biomolecules available in blood serum, in order to comprehend the immediate impacts of TBI. Mice were exposed to a lethal dose (9.75 Gy) of Cobalt-60 gamma radiation and euthanized at four time points, namely, days 1, 3, 7 and 9 post-TBI. Serum miRNA libraries were sequenced using the Illumina small RNA sequencing protocol, and metabolites were screened using a mass spectrometer. The degree of early impacts of irradiation was underscored by the large number of miRNAs and metabolites that became significantly expressed during the Early phase (day 0 and 1 post-TBI). Radiation-induced inflammatory markers for bone marrow aplasia and pro-sepsis markers showed early elevation with longitudinal increment. Functional analysis integrating miRNA-protein-metabolites revealed inflammation as the overarching host response to lethal TBI. Early activation of the network linked to the synthesis of reactive oxygen species was associated with the escalated regulation of the fatty acid metabolism network. In conclusion, we assembled a list of time-informed critical markers and mechanisms of significant translational potential in the context of a radiation exposure event.

Congenital myasthenic syndromes (CMS) are a clinically and genetically heterogeneous group of disorders caused by mutations which lead to impaired neuromuscular transmission. SLC25A1 encodes a mitochondrial citrate carrier, associated mainly with the severe neurometabolic disease combined D-2- and L-2-hydroxyglutaric aciduria (D/L-2-HGA). We previously reported a single family with a homozygous missense variant in SLC25A1 with a phenotype restricted to relatively mild CMS with intellectual disability, but to date no additional cases of this CMS subtype had been reported. Here, we performed whole exome sequencing (WES) in three additional and unrelated families presenting with CMS and mild intellectual disability to identify the underlying causative gene. The WES analysis revealed the presence of a homozygous c.740G>A; p.(Arg247Gln) missense SLC25A1 variant, the same SLC25A1 variant as identified in the original family with this phenotype. Electron microscopy of muscle from two cases revealed enlarged and accumulated mitochondria. Haplotype analysis performed in two unrelated families suggested that this variant is a result of recurrent mutation and not a founder effect. This suggests that p.(Arg247Gln) is associated with a relatively mild CMS phenotype with subtle mitochondrial abnormalities, while other variants in this gene cause more severe neurometabolic disease. In conclusion, the p.(Arg247Gln) SLC25A1 variant should be considered in patients presenting with a presynaptic CMS phenotype, particularly with accompanying intellectual disability.