Protective Microbiota: From Localized to Long-Reaching Co-Immunity

Resident microbiota do not just shape host immunity, they can also contribute to host protection against pathogens and infectious diseases. Previous reviews of the protective roles of the microbiota have focused exclusively on colonization resistance localized within a microenvironment. This review shows that the protection against pathogens also involves the mitigation of pathogenic impact without eliminating the pathogens (i.e., “disease tolerance”) and the containment of microorganisms to prevent pathogenic spread. Protective microorganisms can have an impact beyond their niche, interfering with the entry, establishment, growth, and spread of pathogenic microorganisms. More fundamentally, we propose a series of conceptual clarifications in support of the idea of a “co-immunity,” where an organism is protected by both its own immune system and components of its microbiota

A3 Printed in the Islamic Republic of Iran

Abstract -A lithium borate thermoluminescence dosimeter with 0.3 wt% of manganese impurity concentration was prepared for high dose levels in the range of 1-30 kGy for gamma irradiation applications. The TLD reader was used for read out purposes from ambient temperature to about 400°C with a heating rate of 6°C/sec. The pre-and post-irradiation anneal temperature was 300°C for 1.5 and 1 hours respectively. The effects of absorbed dose, dose rate, storage time, as well as the temperature and humidity versus pre-and post-irradiation storage time have been studied. The main glow peak was found to occur at 375°C, and the dosimeter response in the range of 1-30 kGy was linear. No significant fading effect of the dosimetric peak was observed after 8 weeks of storage, and the effects of ambient temperature and humidity were less than ±5% at 95% confidence level

Working from Home: Impact on Wellbeing and Work-Life Balance

Working from home (WFH), teleworking, or telecommuting has become a new work norm since the Covid-19 pandemic. Many organisations are showing an interest in testing a hybrid work style when the pandemic is over; a mix of WFH with office-based work has the potential to improve work-life balance (WLB). Organisations across the globe quickly adopted WFH to maintain their business continuity during the pandemic. However, it co-concurred with particular occupational health and safety (OHS) concerns. Our research review shows that the frequency of WFH is significantly related to its impact on WLB. Women, specifically, are more likely to find it challenging to maintain balance between office work and domestic responsibilities. Additionally, WFH leads to personal costs for many, for example, maintaining a suitable workstation setup at home. The continuous demand for up-skilling/re-skilling due to fast improving technology and job satisfaction is another example of the risk to workers’ wellbeing. This research paper reviews the most important risk determinants of WLB due to WFH. We discuss that workplaces should align their strategies in the longer term to support employees’ wellbeing risk management. Employers, employees – women particularly – should use this rapid change as an opportunity to learn and grow

Local-scale monitoring of evapotranspiration based on downscaled GRACE observations and remotely sensed data: An application of terrestrial water balance approach

Evapotranspiration (ET), as one of the most central parameters to the climate systems, plays a predominant role in the water, energy, carbon cycles, and energy–moisture exchanges between the earth and the atmosphere. Since the in-situ estimation of ET is challenging, the remote sensing-based techniques are deemed a reliable surrogate for the traditional ET estimation methods. The Gravity Recovery And Climate Experiment (GRACE) mission turned out to perform well in detecting the variations of ET over large basins. However, the subbasin-wise variations of ET based on the GRACE mission remain challenging due to its coarse resolution. In this study, the GRACE/GRACE-FO observations were downscaled based on Random Forest Machine Learning (RFML) algorithm and were integrated with fine-resolution precipitation and runoff data within the framework of the terrestrial water balance approach to derive small-scale variations of ET over Kizilirmak Basin (KB) in Türkiye. The results were compared to the fine-resolution ET products of the Moderate Resolution Imaging Spectroradiometer (MODIS) satellite and Noah model and revealed acceptable precision of the methodology for the subbasin-wise application. The findings suggest that excluding the Lower Kizlirmak Basin (LKB), the water balance-based ET manifests a very high agreement with the MODIS- and Noah-derived ET over all the subbasins of the KB. The impacts of the main ET driving parameters such as temperature, water availability, solar radiation, surface albedo, and vegetation status were further investigated in terms of linear correlations. It is found that there is a high association between the monthly variations of ET and its conditioning factors over the KB, especially between the water availability and ET

Mouse tumor susceptibility genes identify drug combinations for multiple myeloma

Long-term genetic studies utilizing backcross and congenic strain analyses coupled with positional cloning strategies and functional studies identified Cdkn2a, Mtor, and Mndal as mouse plasmacytoma susceptibility/resistance genes. Tumor incidence data in congenic strains carrying the resistance alleles of Cdkn2a and Mtor led us to hypothesize that drug combinations affecting these pathways are likely to have an additive, if not synergistic effect in inhibiting tumor cell growth. Traditional and novel systems-level genomic approaches were used to assess combination activity, disease specificity, and clinical potential of a drug combination involving rapamycin/everolimus, an Mtor inhibitor, with entinostat, an histone deacetylase inhibitor. The combination synergistically repressed oncogenic MYC and activated the Cdkn2a tumor suppressor. The identification of MYC as a primary upstream regulator led to the identification of small molecule binders of the G-quadruplex structure that forms in the NHEIII region of the MYC promoter. These studies highlight the importance of identifying drug combinations which simultaneously upregulate tumor suppressors and downregulate oncogenes

Abstract 5850: Nrf2-mediated oxidative stress response is altered during acquired resistance to the proteasome inhibitor, oprozomib, in multiple myeloma

Abstract Multiple myeloma (MM) is a hematologic neoplasm characterized by malignant proliferation of plasma cells in the bone marrow. Proteasome inhibitors are widely used in treatment regimens for MM. Although initial responses to PI (e.g., bortezomib, carfilzomib) treatments have been promising, patients often develop resistance and become refractory to disease. Understanding molecular alterations in signaling cascades influenced by proteasome inhibitors and mechanisms underlying acquired resistance is needed. In this study, we have established a clinically relevant oproxomib-resistant subline (KMS28BMONYX) of the MM cell line KMS28BM. The KMS28BMONYX cell line is pan-resistant to PIs with a 10-fold increase in IC50 for oprozomib as compared to the parental line. To identify genes involved in modulating drug resistance, we analyzed gene expression profiles of both parental and resistant cell lines using the Affymetrix GeneChip Human Genome U133 Plus 2.0 array. Ingenuity Pathway Analysis of microarray data comparing the parental and resistant cells revealed an acute dependence on stress response proteins to maintain PI-resistance. Activation of nuclear factor-erythroid 2 (NF-E2)-related factor 2 (Nrf2; gene symbol NFE2L2) coupled with elevated levels of sequestosome 1/p62 (SQSTM1/p62) were prominent features of the KMS28BMONYX cell line. Altered levels of SQSTM1 correlated with resistance to oprozomib in several MM cell lines. Simultaneously, the KMS28BMONYX cell line showed increased expression of MYC and MCL1. Oprozomib treatment stabilized c-Myc expression in the KMS28BMONYX line. The Champion ChiP Transcription Factor Search Portal database DECODE predicted two c-Myc transcription factor binding sites in the SQSTM1 promoter. CHIP-seq data for MYC in MM1s cells also indicates strong binding in the promoter region of SQSTM1. Our data suggest that therapies targeting the SQSTM1/p62-Nrf2 pathway may help overcome proteasome inhibitor resistance in refractory MM patients. Citation Format: Snehal M. Gaikwad, Adriana Zingone, Aleksandra Michalowski, Susana Najera, Anaisa Quintanilla-Artega, Sayeh Gorjifard, John Simmons, Nick Watson, Ola Landgren, Jing Huang, Beverly Mock. Nrf2-mediated oxidative stress response is altered during acquired resistance to the proteasome inhibitor, oprozomib, in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5850

A Small Molecule Stabilizer of the MYC G4-Quadruplex Induces Endoplasmic Reticulum Stress, Senescence and Pyroptosis in Multiple Myeloma

New approaches to target MYC include the stabilization of a guanine-rich, G-quadruplex (G4) tertiary DNA structure in the NHE III region of its promoter. Recent screening of a small molecule microarray platform identified a benzofuran, D089, that can stabilize the MYC G4 and inhibit its transcription. D089 induced both dose- and time-dependent multiple myeloma cell death mediated by endoplasmic reticulum induced stress. Unexpectedly, we uncovered two mechanisms of cell death: cellular senescence, as evidenced by increased levels of p16, p21 and γ-H2AX proteins and a caspase 3-independent mechanism consistent with pyroptosis. Cells treated with D089 exhibited high levels of the cleaved form of initiator caspase 8; but failed to show cleavage of executioner caspase 3, a classical apoptotic marker. Cotreatment with the a pan-caspase inhibitor Q-VD-OPh did not affect the cytotoxic effect of D089. In contrast, cleaved caspase 1, an inflammatory caspase downstream of caspases 8/9, was increased by D089 treatment. Cells treated with D089 in addition to either a caspase 1 inhibitor or siRNA-caspase 1 showed increased IC50 values, indicating a contribution of cleaved caspase 1 to cell death. Downstream effects of caspase 1 activation after drug treatment included increases in IL1B, gasdermin D cleavage, and HMGB1 translocation from the nucleus to the cytoplasm. Drug treated cells underwent a ‘ballooning’ morphology characteristic of pyroptosis, rather than ‘blebbing’ typically associated with apoptosis. ASC specks colocalized with NLRP3 in proximity ligation assays after drug treatment, indicating inflammasome activation and further confirming pyroptosis as a contributor to cell death. Thus, the small molecule MYC G4 stabilizer, D089, provides a new tool compound for studying pyroptosis. These studies suggest that inducing both tumor senescence and pyroptosis may have therapeutic potential for cancer treatment