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Agriculture faces a significant problem as a result of the decline in per capita freshwater supply that has been observed over the past couple of decades. Better water management strategies are required in order to make agriculture water secure, environmentally sustainable, and economically attractive. The goal of this study was to develop water productivity scenarios for rice and wheat crops in India's Indo-Gangetic Plain (IGP) by analysing agricultural production from the perspective of water consumption. To pinpoint the areas that are hydrologically suitable for growing rice and wheat crops under RCP4.5 and RCP8.5 climate change scenarios, water footprints and water productivity have been mapped. The study found that changes in temperature trends under future climate scenarios are probably going to increase crop water requirements, leading to greater water footprints for IGP regions. Water risk hotspots have been identified in the IGP for the rice- and wheat-growing states of Uttar Pradesh, Punjab, and Haryana. In order to achieve food security in a sustainable way, attention should be given to increase the water productivity of both crops., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

CD73 is a cell surface 5'nucleotidase (NT5E) and key node in the catabolic process generating immunosuppressive adenosine in cancer. Using a murine monoclonal antibody surrogate of Oleclumab, we investigated the effect of CD73 inhibition in concert with cytotoxic therapies (chemotherapies as well as fractionated radiotherapy) and PD-L1 blockade. Our results highlight improved survival in syngeneic tumor models of colorectal cancer (CT26 and MC38) and sarcoma (MCA205). This therapeutic outcome was in part driven by cytotoxic CD8 T-cells, as evidenced by the detrimental effect of CD8 depleting antibody treatment of MCA205 tumor bearing mice treated with anti-CD73, anti-PD-L1 and 5-Fluorouracil+Oxaliplatin (5FU+OHP). We hypothesize that the improved responses are tumor microenvironment (TME)-driven, as suggested by the lack of anti-CD73 enhanced cytopathic effects mediated by 5FU+OHP on cell lines in vitro . Pharmacodynamic analysis, using imaging mass cytometry and RNA-sequencing, revealed noteworthy changes in specific cell populations like cytotoxic T cells, B cells and NK cells in the CT26 TME. Transcriptomic analysis highlighted treatment-related modulation of gene profiles associated with an immune response, NK and T-cell activation, T cell receptor signaling and interferon (types 1 & 2) pathways. Inclusion of comparator groups representing the various components of the combination allowed deconvolution of contribution of the individual therapeutic elements; highlighting specific effects mediated by the anti-CD73 antibody with respect to immune-cell representation, chemotaxis and myeloid biology. These pre-clinical data reflect complementarity of adenosine blockade with cytotoxic therapy, and T-cell checkpoint inhibition, and provides new mechanistic insights in support of combination therapy.

Many physical systems exhibit translational invariance, meaning that the underlying physical laws are independent of the position in space. Data driven approximations of the infinite dimensional but linear Koopman operator of non-linear dynamical systems need to be physically informed in order to respect such physical symmetries. In the current work, we introduce a translation invariant extended dynamic mode decomposition (tieDMD) for coupled non-linear systems on periodic domains. This is achieved by exploiting a block-diagonal structure of the Koopman operator in Fourier space. Variants of tieDMD are applied to data obtained on one-dimensional periodic domains from the non-linear phase-diffusion equation, the Burgers equation, the Korteweg-de Vries equation, and a coupled FitzHugh-Nagumo system of partial differential equations. The reconstruction capability of tieDMD is compared to existing linear and non-linear variants of the dynamic mode decomposition applied to the same data. For the regarded data, tieDMD consistently shows superior capabilities in data reconstruction., (© 2024 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International (CC BY-NC-ND) license (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Quantum nonlocality, pioneered in Bell's seminal work and subsequently verified through a series of experiments, has drawn substantial attention due to its practical applications in various protocols. Evaluating and comparing the extent of nonlocality within distinct quantum correlations holds significant practical relevance. Within the resource theoretic framework this can be achieved by assessing the interconversion rate among different nonlocal correlations under free local operations and shared randomness. In this study we, however, present instances of quantum nonlocal correlations that are incomparable in the strongest sense. Specifically, when starting with an arbitrary many copies of one nonlocal correlation, it becomes impossible to obtain even a single copy of the other correlation, and this incomparability holds in both directions. Such incomparable quantum correlations can be obtained even in the simplest Bell scenario, which involves two parties, each having two dichotomic measurements setups. Notably, there exist an uncountable number of such incomparable correlations. Our result challenges the notion of a "unique gold coin," often referred to as the "maximally resourceful state," within the framework of the resource theory of quantum nonlocality. To this end, we provide examples of isotropic quantum correlations that cannot be distilled up to the Tsirelson point, and thus partially answer a long-standing open question in nonlocality distillation.

The extraction of bast fibres such as jute from plant stems involves the removal of pectin, hemicellulose, and other noncellulosic materials through a complex microbial community. A consortium of pectinolytic bacterial strains has been developed and commercialized to reduce the retting time and enhance fibre quality. However, there are currently no studies on jute that describe the structural changes and sequential microbial colonization and pectin loss that occur during microbe-assisted water retting. This study investigated the stages of microbial colonization, microbial interactions, and sequential degradation of pectic substances from jute bark under controlled and conventional water retting. The primary occurrence during water retting of bast fibres is the bacterially induced sequential breakdown of pectin surrounding the fibre bundles. The study also revealed that the pectin content of the jute stem significantly decreases during the retting process. These findings provide a strong foundation for improving microbial strains for improved pectinolysis with immense industrial significance, leading to a sustainable jute-based "green" economy., (© 2024. The Author(s).)

The Ataxia telangiectasia and Rad3-related (ATR) inhibitor ceralasertib in combination with the PD-L1 antibody durvalumab demonstrated encouraging clinical benefit in melanoma and lung cancer patients who progressed on immunotherapy. Here we show that modelling of intermittent ceralasertib treatment in mouse tumor models reveals CD8 + T-cell dependent antitumor activity, which is separate from the effects on tumor cells. Ceralasertib suppresses proliferating CD8 + T-cells on treatment which is rapidly reversed off-treatment. Ceralasertib causes up-regulation of type I interferon (IFNI) pathway in cancer patients and in tumor-bearing mice. IFNI is experimentally found to be a major mediator of antitumor activity of ceralasertib in combination with PD-L1 antibody. Improvement of T-cell function after ceralasertib treatment is linked to changes in myeloid cells in the tumor microenvironment. IFNI also promotes anti-proliferative effects of ceralasertib on tumor cells. Here, we report that broad immunomodulatory changes following intermittent ATR inhibition underpins the clinical therapeutic benefit and indicates its wider impact on antitumor immunity., (© 2024. The Author(s).)

Agriculture in the 21st century faces grave challenges to meet the unprecedented food demand of the burgeoning population as well as reduce the ecological footprint for achieving sustainable development goals. The extensive use of harsh synthetic surfactants in pesticides and the agrochemical industry has substantial adverse impacts on the soil and environment due to their toxic and non-biodegradable nature. Biosurfactants derived from plant, animal, and microbial sources can be an eco-friendly alternative to chemical surfactants. Microbes producing biosurfactants play a noteworthy role in biofilm formation, plant pathogen elimination, biodegradation, bioremediation, improving nutrient bioavailability, and can thrive well under stressful environments. Microbial biosurfactants are well suited for heavy metal and organic contaminants remediation in agricultural soil due to their low toxicity, high activity at fluctuating temperatures, biodegradability, and stability over a wide array of environmental conditions. This green technology will improve the agricultural soil quality by increasing the soil flushing efficiency, mobilization, and solubilization of nutrients by forming metal-biosurfactant complexes, and through the dissemination of complex nutrients. Such characteristics help it to play a pivotal role in environmental sustainability in the foreseeable future, which is required to increase the viability of biosurfactants for extensive commercial uses, making them accessible, affordable, and economically sustainable., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Neoadjuvant chemoimmunotherapy improves pathologic complete response rate and event-free survival in patients with resectable non-small cell lung cancer (NSCLC) versus chemotherapy alone. NeoCOAST was the first randomized, multidrug platform trial to examine novel neoadjuvant immuno-oncology combinations for patients with resectable NSCLC, using major pathologic response (MPR) rate as the primary endpoint. Eighty-three patients received a single cycle of treatment: 26 received durvalumab (anti-PD-L1) monotherapy, 21 received durvalumab plus oleclumab (anti-CD73), 20 received durvalumab plus monalizumab (anti-NKG2A), and 16 received durvalumab plus danvatirsen (anti-STAT3 antisense oligonucleotide). MPR rates were higher for patients in the combination arms versus durvalumab alone. Safety profiles for the combinations were similar to those of durvalumab alone. Multiplatform immune profiling suggested that improved MPR rates in the durvalumab plus oleclumab and durvalumab plus monalizumab arms were associated with enhanced effector immune infiltration of tumors, interferon responses and markers of tertiary lymphoid structure formation, and systemic functional immune cell activation., Significance: A neoadjuvant platform trial can rapidly generate clinical and translational data using candidate surrogate endpoints like MPR. In NeoCOAST, patients with resectable NSCLC had improved MPR rates after durvalumab plus oleclumab or monalizumab versus durvalumab alone and tumoral transcriptomic signatures indicative of augmented immune cell activation and function. See related commentary by Cooper and Yu, p. 2306. This article is featured in Selected Articles from This Issue, p. 2293., (©2023 The Authors; Published by the American Association for Cancer Research.)

Increasing demand for shopping and packaging carrier bags has given rise to various issues relating to its disposal as well as to the overall environmental footprint and sustainability of the packaging materials. This study assesses the carbon footprint and life cycle environmental impacts of the production, usage, and disposal of low density polyethylene (LDPE) and two natural fibre carrier bags (jute and kenaf). Life cycle assessment study was conducted of all inputs and outputs, aggregated in the form of resources used and environmental emissions, extending from the production of raw materials to the final disposal of the product. The carbon footprint and GHG emissions of jute and kenaf carrier bags were estimated using the CO 2 , N 2 O, and CH 4 emissions coefficients of inputs. Research literature from life cycle impact assessment (LCIA) results was used to determine the effects of LDPE polyethylene packaging material. It was observed that the global warming potential (GWP) for the production of 1 kg of LDPE (100 micron) carrier bag (39.4 kg CO 2 eq) is more than 490 times higher than jute and kenaf carrier bags. In general, LDPE materials have the greatest impact on the carbon footprint and resource depletion. The LDPE material also has the highest impacts on indicators of terrestrial ecotoxicity, photochemical oxidation, acidification, and eutrophication as compared to jute and kenaf fibres. Since jute and kenaf are natural fibres, they sequester a substantial quantity of carbon during their agricultural stages. As a result, greenhouse gas (GHG) emission emissions of jute and kenaf were found to be negative. Popularising the use of jute and kenaf products as alternatives to plastic in industrialised countries would benefit the reduction of plastic waste and its negative environmental effects. Additional production of jute and kenaf fibre, which are already available in major bast fibre producing countries like India and Bangladesh, could meet the demand for fibre-based carrier bags., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: CD73 is overexpressed in EGFR-mutated NSCLC and may promote immune evasion, suggesting potential for combining CD73 blockers with EGFR tyrosine kinase inhibitors (TKIs). This phase 1b-2 study (NCT03381274) evaluated the anti-CD73 antibody oleclumab plus the third-generation EGFR TKI osimertinib in advanced EGFR-mutated NSCLC., Methods: Patients had tissue T790M-negative NSCLC with TKI-sensitive EGFR mutations after progression on a first- or second-generation EGFR TKI and were osimertinib naive. They received osimertinib 80 mg orally once daily plus oleclumab 1500 mg (dose level 1 [DL1]) or 3000 mg (DL2) intravenously every 2 weeks. Primary end points included safety and objective response rate by Response Evaluation Criteria in Solid Tumors version 1.1., Results: By July 9, 2021, five patients received DL1 and 21 received DL2. Of these patients, 60.0% and 85.7% had any-grade treatment-related adverse events (TRAEs) and 20.0% and 14.3% had grade 3 TRAEs, respectively. No dose-limiting toxicities, serious TRAEs, or deaths occurred. Four patients were T790M positive on retrospective circulating tumor DNA (ctDNA) testing; three had objective partial responses. In patients who were T790M negative in tumor and ctDNA, objective response rate was 25.0% at DL1 and 11.8% at DL2 (all partial responses); response durations at DL2 were 14.8 and 16.6 months. In patients receiving DL2, excluding those who were T790M positive by ctDNA, median progression-free survival was 7.4 months, and median overall survival was 24.8 months. DL2 was the recommended phase 2 dose., Conclusions: Oleclumab plus osimertinib was found to have moderate activity with acceptable tolerability in previously treated patients with advanced EGFR-mutated NSCLC., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Reduction of inherent structural recalcitrance and improved saccharification efficiency are two important facets to enhance fermentable sugar yield for bioethanol production from lignocellulosic biomass. This study optimized alkaline pretreatment and saccharification conditions employing response surface methodology to improve saccharification yield of jute (Corchorus olitorius cv. JROB-2) biomass. The biomass is composed of cellulose (66.6 %), lignin (19.4 %) and hemicellulose (13.1 %). NaOH concentration exhibited significant effect on delignification during pretreatment. The highest delignification (80.42 %) was obtained by pretreatment with 2.47 % NaOH at 55.8 °C for 5.9 h removing 79.8 % lignin and 34.2 % hemicellulose from biomass, thereby increasing cell wall porosity and allowing better accessibility to saccharification enzyme. During saccharification optimization, significant effect was observed for biomass loading, enzyme concentration and temperature. Optimized saccharification condition yielded maximum saccharification (76.48 %) when hydrolysis was performed at 6.9 % biomass loading with enzyme concentration of 49.52 FPU/g substrate at 51.05 °C for 74.46 h., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Laxmi Sharma reports financial support was provided by Department of Higher Education, Science and Technology & Biotechnology, Government of West Bengal, India. Laxmi Sharma reports financial support was provided by ICAR-National Innovations in Climate Resilient Agriculture, Ministry of Agriculture, Government of India., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Ferroptosis is a non-apoptotic form of regulated cell death that is triggered by the discoordination of regulatory redox mechanisms culminating in massive peroxidation of polyunsaturated phospholipids. Ferroptosis inducers have shown considerable effectiveness in killing tumour cells in vitro, yet there has been no obvious success in experimental animal models, with the notable exception of immunodeficient mice 1,2 . This suggests that the effect of ferroptosis on immune cells remains poorly understood. Pathologically activated neutrophils (PMNs), termed myeloid-derived suppressor cells (PMN-MDSCs), are major negative regulators of anti-tumour immunity 3-5 . Here we found that PMN-MDSCs in the tumour microenvironment spontaneously die by ferroptosis. Although decreasing the presence of PMN-MDSCs, ferroptosis induces the release of oxygenated lipids and limits the activity of human and mouse T cells. In immunocompetent mice, genetic and pharmacological inhibition of ferroptosis abrogates suppressive activity of PMN-MDSCs, reduces tumour progression and synergizes with immune checkpoint blockade to suppress the tumour growth. By contrast, induction of ferroptosis in immunocompetent mice promotes tumour growth. Thus, ferroptosis is a unique and targetable immunosuppressive mechanism of PMN-MDSCs in the tumour microenvironment that can be pharmacologically modulated to limit tumour progression., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

A massive carbon footprint is associated with the ubiquitous use of plastics and their afterlife. Greenhouse gas (GHG) emissions from plastics are rising and increasingly consuming the global "carbon budget". It is, hence, paramount to implement an effective strategy to reclaim postconsumer plastic as feedstock for technologically innovative materials. Credible opportunity is offered by advances in materials chemistry and catalysis. Here, we demonstrate that by dynamically crosslinking thermoplastic polyolefins, commodity plastics can be upcycled into technically superior and economically competitive materials. A broadly applicable crosslinking strategy has been applied to polymers containing solely carbon-carbon and carbon-hydrogen bonds, initially by maleic anhydride functionalization, followed by epoxy-anhydride curing. These dynamic networks show a distinct rubber modulus above the melting transition. We demonstrate that sustainability and performance do not have to be mutually exclusive. The dynamic network can be extruded into a continuous filament to be in three-dimensional (3D) printing of complex objects, which retain the mechanical integrity of vitrimers. Being covalently crosslinked, these networks show a thermally triggered shape-memory response, with 90% recovery of a programmed shape. This study opens up the possibility of reclaiming recycled thermoplastics by imparting performance, sustainability, and technological advances to the reprocessed plastic., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Climate change influences the current tropospheric ozone (O 3 ) budget due to industrialization and urbanization processes. In recent years, the impact of elevated O 3 on crop development and yield loss has emerged as one of the most important environmental issues, particularly in rural and suburban areas of the lower Indo-Gangetic Plains of India. The impact of the current tropospheric ozone (O 3 ) on the crop yield, photosynthetic yield, and enzymatic antioxidants of six rice (Oryza sativa L.) cultivars (IR 36, MTU 1010, GB 3, Khitish, IET 4786, and Ganga Kaveri) was investigated with and without the application of ethylenediurea (EDU). The results revealed that O 3 stress significantly affected crop yield, photosynthetic yield, and antioxidant enzymes. The findings showed that O 3 toxicity induces oxidative stress biomarkers, i.e., malondialdehyde (MDA) content, and was manifested by increasing the enzymatic antioxidants, i.e., superoxidase dismutase (SOD) and catalase (CAT) in four rice cultivars (IR 36, GB 3, IET 4786, and Ganga Kaveri). At the same time, the results also illustrated that the rice cultivars MTU 1010 and Khitish are more tolerant to O 3 stress as they had less oxidative damage, greater photosynthetic SPAD value, SOD and CAT activities, and lower MDA activity. The results also elucidated that the application of EDU decreased O 3 toxicity in sensitive cultivars of rice by increasing antioxidant defense systems. The current O 3 level is likely to show an additional increase in the near future, and the use of tolerant genotypes of rice may reduce the negative impacts of O 3 on rice production., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Heat stress has a significant impact on the climatic adaptation of flax, a cool-season economic crop. Genome-wide DNA methylation patterns are crucial for understanding how flax cultivars respond to heat adversities. It is worth noting that the DNA methylome in flax has yet to be investigated at the nucleotide level. Although heat stress above 40°C caused oxidative damage in flax leaves, 5-azacytidine, a hypomethylating agent, reduced this effect by 15%-24%. Differences in the expression of the LuMET1 (DNA methyltransferase) gene suggested that DNA methylation/demethylation may play a major role in the flax heat stress response. Thus, whole-genome bisulfite sequencing-derived DNA methylation profiles in flax, with or without heat stress and 5-azaC, were developed and analyzed here. In response to heat stress, a high percentage of significant differentially methylated regions (DMRs), particularly hypomethylated DMRs, were identified in the CHH nucleotide sequence context (H = A/T/C). Some of these DMRs overlapped with transposable element insertions. The majority of DMRs were discovered in intergenic regions, but several DMR loci were also found near genes relevant to heat stress response and epigenetic processes. These DMRs, in particular, are linked to CpG islands, implying a possible role in promoter methylation and gene silencing. The DMRs discovered in this study are crucial for understanding and identifying the key players in heat stress response in flax, which will help in developing climate-smart flax varieties., (© 2022 Scandinavian Plant Physiology Society.)

Background: The Regulatory T cell (Treg) lineage is defined by the transcription factor FOXP3, which controls immune-suppressive gene expression profiles. Tregs are often recruited in high frequencies to the tumor microenvironment where they can suppress antitumor immunity. We hypothesized that pharmacological inhibition of FOXP3 by systemically delivered, unformulated constrained ethyl-modified antisense oligonucleotides could modulate the activity of Tregs and augment antitumor immunity providing therapeutic benefit in cancer models and potentially in man., Methods: We have identified murine Foxp3 antisense oligonucleotides (ASOs) and clinical candidate human FOXP3 ASO AZD8701. Pharmacology and biological effects of FOXP3 inhibitors on Treg function and antitumor immunity were tested in cultured Tregs and mouse syngeneic tumor models. Experiments were controlled by vehicle and non-targeting control ASO groups as well as by use of multiple independent FOXP3 ASOs. Statistical significance of biological effects was evaluated by one or two-way analysis of variance with multiple comparisons., Results: AZD8701 demonstrated a dose-dependent knockdown of FOXP3 in primary Tregs, reduction of suppressive function and efficient target downregulation in humanized mice at clinically relevant doses. Surrogate murine FOXP3 ASO, which efficiently downregulated Foxp3 messenger RNA and protein levels in primary Tregs, reduced Treg suppressive function in immune suppression assays in vitro. FOXP3 ASO promoted more than 70% reduction in FOXP3 levels in Tregs in vitro and in vivo, strongly modulated Treg effector molecules (eg, ICOS, CTLA-4, CD25 and 4-1BB), and augmented CD8 + T cell activation and produced antitumor activity in syngeneic tumor models. The combination of FOXP3 ASOs with immune checkpoint blockade further enhanced antitumor efficacy., Conclusions: Antisense inhibitors of FOXP3 offer a promising novel cancer immunotherapy approach. AZD8701 is being developed clinically as a first-in-class FOXP3 inhibitor for the treatment of cancer currently in Ph1a/b clinical trial (NCT04504669)., Competing Interests: Competing interests: The authors are paid employees of AstraZeneca or Ionis Pharmaceuticals, as indicated by their affiliations., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Present study is a maiden attempt to assess net ecosystem exchange (NEE) of carbon dioxide (CO 2 ) flux from jute crop (Corchorus olitorius L.) in the Indo-Gangetic plain by using open-path eddy covariance (EC) technique. Diurnal variations of NEE were strongly influenced by growth stages of jute crop. Daytime peak NEE varied from - 5 µmol m -2  s -1 (in germination stage) to - 23 µmol m -2  s -1 (in fibre development stage). The ecosystem was net CO 2 source during nighttime with an average NEE value of 5-8 μmol m -2  s -1 . Combining both daytime and nighttime CO 2 fluxes, jute ecosystem was found to be a net CO 2 sink on a daily basis except the initial 9 days from date of sowing. Seasonal and growth stage-wise NEEs were computed, and the seasonal total NEE over the jute season was found to be - 268.5 gC m -2  (i.e. 10.3 t CO 2 ha -1 ). In different jute growth stages, diurnal variations of NEE were strongly correlated (R 2  > 0.9) with photosynthetic photon flux density (PPFD). Ecosystem level photosynthetic efficiency parameters were estimated at each growth stage of jute crop using the Michaelis-Menten equation. The maximum values of photosynthetic capacity (P max , 63.3 ± 1.15 µmol CO 2 m -2  s -1 ) and apparent quantum yield (α, 0.072 ± 0.0045 µmol CO 2 µmol photon -1 ) were observed during the active vegetative stage, and the fibre development stage, respectively. Results of the present study would significantly contribute to understanding of the carbon flux from the Indian agro-ecosystems, which otherwise are very sparse., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

In recent years, research into blockchain technology and the Internet of Things (IoT) has grown rapidly due to an increase in media coverage. Many different blockchain applications and platforms have been developed for different purposes, such as food safety monitoring, cryptocurrency exchange, and secure medical data sharing. However, blockchain platforms cannot store all the generated data. Therefore, they are supported with data warehouses, which in turn is called a hybrid blockchain platform. While several systems have been developed based on this idea, a current state-of-the-art systematic overview on the use of hybrid blockchain platforms is lacking. Therefore, a systematic literature review (SLR) study has been carried out by us to investigate the motivations for adopting them, the domains at which they were used, the adopted technologies that made this integration effective, and, finally, the challenges and possible solutions. This study shows that security, transparency, and efficiency are the top three motivations for adopting these platforms. The energy, agriculture, health, construction, manufacturing, and supply chain domains are the top domains. The most adopted technologies are cloud computing, fog computing, telecommunications, and edge computing. While there are several benefits of using hybrid blockchains, there are also several challenges reported in this study.

Little is known of the quality of life (QoL) of cancer patients in the Northern Territory (NT) of Australia, where healthcare delivery is geographically challenged. This exploratory study describes QoL among Aboriginal and non-Aboriginal cancer patients in the NT, in the first year of diagnosis. Participants were recruited from the only cancer care centre in the NT and completed the Assessment of Quality-of-Life questionnaire (AQoL-4D). The results were descriptively analysed. The participants' (n = 63; mean age 58.8 years) mean AQoL utility score was 0.72 (SD 0.26); patients scored lowest in the relationships and mental health dimensions of the questionnaire (mean 0.89, SD 0.19, and 0.89, SD 0.17, respectively). Participants living in remote and very remote areas (46%) reported higher QoL scores, compared with participants in the outer regional capital city of the NT in the overall (mean 0.76, SD 0.22 and 0.78, SD 0.20 vs. 0.67, SD 0.29, respectively), and mental health dimensions (mean 0.92, SD 0.09 and mean 0.94, SD 0.06 vs. 0.85, SD 0.22, respectively). The findings were suggestive of clinically meaningful differences across socioeconomic groups, cancer and treatment types, and comorbidity status. Mean QoL scores were consistent with previous reports in other Australian cancer cohorts. The findings suggest a need to support cancer patients' mental health and relationships during the diagnosis and treatment phase of their cancer journey.

Myeloid-derived suppressor cells (MDSCs) are major negative regulators of immune responses in cancer and chronic infections. It remains unclear if regulation of MDSC activity in different conditions is controlled by similar mechanisms. We compared MDSCs in mice with cancer and lymphocytic choriomeningitis virus (LCMV) infection. Chronic LCMV infection caused the development of monocytic MDSCs (M-MDSCs) but did not induce polymorphonuclear MDSCs (PMN-MDSCs). In contrast, both MDSC populations were present in cancer models. An acquisition of immune-suppressive activity by PMN-MDSCs in cancer was controlled by IRE1α and ATF6 pathways of the endoplasmic reticulum (ER) stress response. Abrogation of PMN-MDSC activity by blockade of the ER stress response resulted in an increase in tumor-specific immune response and reduced tumor progression. In contrast, the ER stress response was dispensable for suppressive activity of M-MDSCs in cancer and LCMV infection. Acquisition of immune-suppressive activity by M-MDSCs in spleens was mediated by IFN-γ signaling. However, it was dispensable for suppressive activity of M-MDSCs in tumor tissues. Suppressive activity of M-MDSCs in tumors was retained due to the effect of IL-6 present at high concentrations in the tumor site. These results demonstrate disease- and population-specific mechanisms of MDSC accumulation and the need for targeting different pathways to achieve inactivation of these cells.

Introduction: Cancer patients in Australia's Northern Territory (NT) face unique challenges to accessing cancer-related community and allied health services (referred here as 'health services'). This is in part due to the NT's unique geographic, socioeconomic and demographic profile. This paper describes the use of health services by cancer patients in the NT., Methods: Adult cancer patients attending appointments at a cancer centre in Darwin, NT and who were diagnosed within the past five years were invited to participate in face-to-face interviews about their use of allied and community health services. A descriptive analysis of health services utilization was conducted., Results: Of the 76 participants interviewed, 63% identified as non-Indigenous, 53% female and 45% lived in very remote areas. Mean age at interview was 58.7 years (SD 13.2). Overall, 82% of participants utilized at least one health service since their cancer diagnosis. All Indigenous participants used at least one service, while 28% of non-Indigenous participants did not use any health service. The services most frequently used by participants were community services (42%) and information sources (40%)., Conclusion: The findings from this study suggest there is variation in the type of community and allied health services used by NT cancer patients across clinical and demographic groups (including Indigenous status). Further qualitative enquiry is needed to better understand this variation, which may reflect differences in service preference, accessibility, health literacy of patients or patient engagement. Such knowledge may inform service delivery improvements to better support cancer patients through their cancer care pathway.

Ensembles of composite quantum states can exhibit nonlocal behavior in the sense that their optimal discrimination may require global operations. Such an ensemble containing N pairwise orthogonal pure states, however, can always be perfectly distinguished under an adaptive local scheme if (N-1) copies of the state are available. In this Letter, we provide examples of orthonormal bases in two-qubit Hilbert space whose adaptive discrimination require three copies of the state. For this composite system, we analyze multicopy adaptive local distinguishability of orthogonal ensembles in full generality which, in turn, assigns varying nonlocal strength to different such ensembles. We also come up with ensembles whose discrimination under an adaptive separable scheme require less numbers of copies than adaptive local schemes. Our construction finds important application in multipartite secret sharing tasks and indicates toward an intriguing superadditivity phenomenon for locally accessible information.

The transcription factor Rora has been shown to be important for the development of ILC2 and the regulation of ILC3, macrophages and Treg cells. Here we investigate the role of Rora across CD4+ T cells in general, but with an emphasis on Th2 cells, both in vitro as well as in the context of several in vivo type 2 infection models. We dissect the function of Rora using overexpression and a CD4-conditional Rora-knockout mouse, as well as a RORA-reporter mouse. We establish the importance of Rora in CD4+ T cells for controlling lung inflammation induced by Nippostrongylus brasiliensis infection, and have measured the effect on downstream genes using RNA-seq. Using a systematic stimulation screen of CD4+ T cells, coupled with RNA-seq, we identify upstream regulators of Rora, most importantly IL-33 and CCL7. Our data suggest that Rora is a negative regulator of the immune system, possibly through several downstream pathways, and is under control of the local microenvironment., Competing Interests: The authors have read the journal’s policy and have the following competing interests: JF was an employee of Microsoft Research Cambridge at the time the study was conducted, but is no longer an employee of the company. EN is an employee of Aleph Labs, but was not employed by the company at the time the study was conducted. GK is an employee of AstraZeneca, but was not employed by the company at the time the study was conducted. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare.

Objective: Compare musculoskeletal discomfort, productivity, postural risks, and perceived fatigue for a sit-stand-walk intervention between two workstation configurations - one, individually customized for office workers according to ergonomic guidelines (Ergo-Fit); another, self-adjusted by office workers according to their preference (Self-Adjusted)., Methods: 36 participants performed a 60-min computer typing task in both configurations using a within-participants, counterbalanced design. Musculoskeletal discomfort and perceived fatigue were reported through surveys; productivity was operationalized by typing speed and typing error; postural risks were assessed by RULA for seated work, and REBA for standing work., Results: Musculoskeletal discomfort and perceived fatigue did not vary significantly between configurations. Postural risks for seated and standing work were significantly lower for Ergo-Fit configuration; productivity was significantly higher for Self-Adjusted configuration., Conclusion: Use of Ergo-Fit configuration for a sit-stand-walk intervention can facilitate postural transitions and increase physical activity, while enabling neutral postures in seated and standing work to minimize postural risks., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Tumors subvert immune cell function to evade immune responses, yet the complex mechanisms driving immune evasion remain poorly understood. Here we show that tumors induce de novo steroidogenesis in T lymphocytes to evade anti-tumor immunity. Using a transgenic steroidogenesis-reporter mouse line we identify and characterize de novo steroidogenic immune cells, defining the global gene expression identity of these steroid-producing immune cells and gene regulatory networks by using single-cell transcriptomics. Genetic ablation of T cell steroidogenesis restricts primary tumor growth and metastatic dissemination in mouse models. Steroidogenic T cells dysregulate anti-tumor immunity, and inhibition of the steroidogenesis pathway is sufficient to restore anti-tumor immunity. This study demonstrates T cell de novo steroidogenesis as a mechanism of anti-tumor immunosuppression and a potential druggable target.

Here, using single-cell RNA sequencing, we examine the stromal compartment in murine melanoma and draining lymph nodes (LNs) at points across tumor development, providing data at http://www.teichlab.org/data/. Naive lymphocytes from LNs undergo activation and clonal expansion within the tumor, before PD1 and Lag3 expression, while tumor-associated myeloid cells promote the formation of a suppressive niche. We identify three temporally distinct stromal populations displaying unique functional signatures, conserved across mouse and human tumors. Whereas "immune" stromal cells are observed in early tumors, "contractile" cells become more prevalent at later time points. Complement component C3 is specifically expressed in the immune population. Its cleavage product C3a supports the recruitment of C3aR + macrophages, and perturbation of C3a and C3aR disrupts immune infiltration, slowing tumor growth. Our results highlight the power of scRNA-seq to identify complex interplays and increase stromal diversity as a tumor develops, revealing that stromal cells acquire the capacity to modulate immune landscapes from early disease., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Current-induced spin-transfer torques (STT) and spin-orbit torques (SOT) enable the electrical switching of magnetic tunnel junctions (MTJs) in non-volatile magnetic random access memories. To develop faster memory devices, an improvement in the timescales that underlie the current-driven magnetization dynamics is required. Here we report all-electrical time-resolved measurements of magnetization reversal driven by SOT in a three-terminal MTJ device. Single-shot measurements of the MTJ resistance during current injection reveal that SOT switching involves a stochastic two-step process that consists of a domain nucleation time and propagation time, which have different genesis, timescales and statistical distributions compared to STT switching. We further show that the combination of SOT, STT and the voltage control of magnetic anisotropy leads to reproducible subnanosecond switching with the spread of the cumulative switching time smaller than 0.2 ns. Our measurements unravel the combined impact of SOT, STT and the voltage control of magnetic anisotropy in determining the switching speed and efficiency of MTJ devices.

The liver parenchyma is composed of hepatocytes and bile duct epithelial cells (BECs). Controversy exists regarding the cellular origin of human liver parenchymal tissue generation during embryonic development, homeostasis or repair. Here we report the existence of a hepatobiliary hybrid progenitor (HHyP) population in human foetal liver using single-cell RNA sequencing. HHyPs are anatomically restricted to the ductal plate of foetal liver and maintain a transcriptional profile distinct from foetal hepatocytes, mature hepatocytes and mature BECs. In addition, molecular heterogeneity within the EpCAM + population of freshly isolated foetal and adult human liver identifies diverse gene expression signatures of hepatic and biliary lineage potential. Finally, we FACS isolate foetal HHyPs and confirm their hybrid progenitor phenotype in vivo. Our study suggests that hepatobiliary progenitor cells previously identified in mice also exist in humans, and can be distinguished from other parenchymal populations, including mature BECs, by distinct gene expression profiles.

Human lungs enable efficient gas exchange and form an interface with the environment, which depends on mucosal immunity for protection against infectious agents. Tightly controlled interactions between structural and immune cells are required to maintain lung homeostasis. Here, we use single-cell transcriptomics to chart the cellular landscape of upper and lower airways and lung parenchyma in healthy lungs, and lower airways in asthmatic lungs. We report location-dependent airway epithelial cell states and a novel subset of tissue-resident memory T cells. In the lower airways of patients with asthma, mucous cell hyperplasia is shown to stem from a novel mucous ciliated cell state, as well as goblet cell hyperplasia. We report the presence of pathogenic effector type 2 helper T cells (T H 2) in asthmatic lungs and find evidence for type 2 cytokines in maintaining the altered epithelial cell states. Unbiased analysis of cell-cell interactions identifies a shift from airway structural cell communication in healthy lungs to a T H 2-dominated interactome in asthmatic lungs.

Background: The IRE1a-XBP1 pathway is a conserved adaptive mediator of the unfolded protein response. The pathway is indispensable for the development of secretory cells by facilitating protein folding and enhancing secretory capacity. In the immune system, it is known to function in dendritic cells, plasma cells, and eosinophil development and differentiation, while its role in T helper cell is unexplored. Here, we investigated the role of the IRE1a-XBP1 pathway in regulating activation and differentiation of type-2 T helper cell (Th2), a major T helper cell type involved in allergy, asthma, helminth infection, pregnancy, and tumor immunosuppression., Methods: We perturbed the IRE1a-XBP1 pathway and interrogated its role in Th2 cell differentiation. We performed genome-wide transcriptomic analysis of differential gene expression to reveal IRE1a-XBP1 pathway-regulated genes and predict their biological role. To identify direct target genes of XBP1 and define XBP1's regulatory network, we performed XBP1 ChIPmentation (ChIP-seq). We validated our predictions by flow cytometry, ELISA, and qPCR. We also used a fluorescent ubiquitin cell cycle indicator mouse to demonstrate the role of XBP1 in the cell cycle., Results: We show that Th2 lymphocytes induce the IRE1a-XBP1 pathway during in vitro and in vivo activation. Genome-wide transcriptomic analysis of differential gene expression by perturbing the IRE1a-XBP1 pathway reveals XBP1-controlled genes and biological pathways. Performing XBP1 ChIPmentation (ChIP-seq) and integrating with transcriptomic data, we identify XBP1-controlled direct target genes and its transcriptional regulatory network. We observed that the IRE1a-XBP1 pathway controls cytokine secretion and the expression of two Th2 signature cytokines, IL13 and IL5. We also discovered that the IRE1a-XBP1 pathway facilitates activation-dependent Th2 cell proliferation by facilitating cell cycle progression through S and G2/M phase., Conclusions: We confirm and detail the critical role of the IRE1a-XBP1 pathway during Th2 lymphocyte activation in regulating cytokine expression, secretion, and cell proliferation. Our high-quality genome-wide XBP1 ChIP and gene expression data provide a rich resource for investigating XBP1-regulated genes. We provide a browsable online database available at http://data.teichlab.org .

Modafinil is generally known as a drug with low addiction potential. There are few case reports in the literature demonstrating that Modafinil, stated being capable of diminishing symptoms of attention deficit/hyperactivity disorder (ADHD), causes addiction. In the present article a Modafinil addicted ADHD case, consuming usurious doses (5,000 mg/per day) of Modafinil is presented. The case presented to our psychiatry outpatient clinic due to: requirement of in taking high dose Modafinil in order to achieve the initial effects, difficulty in obtaining the drug, irritability, anxiousness, sleep irregularities, fatigue and unpleasant vivid dreams when he did not use the drug. It was realized that the patient, himself increased doses of Modafinil incrementally, in order to keep its effects on attention symptoms at the same level. It has to be kept in mind that ADHD patients can develop Modafinil addiction. It is necessary to carry out systemic studies on this subject.

Phosphorus ore extraction for soil fertilization supports the demand of modern agriculture, but extractable resource limitations, due to scarcity, impose a P reuse and recycling research agenda. Here we propose to integrate biochar production (pyrogenic carbon) with municipal and agricultural waste management systems, to recover and reuse phosphorous that would otherwise be lost from the ecological food web. A meta-analysis and available data on total P in biochar indicated that P-enriched feedstocks include animal manure, human excreta, and plant-biomass collected from P-polluted sites. Phosphorus in biochar could participate in P equilibriums in soils and is expected to supply P. The release, sorption and desorption of P by biochar will codetermine the potential of P replenishment by biochar and P loss from biochar-amended soils. Abiotic and biotic factors are expected to affect sorption/desorption of P between biochar and soil aggregates, and P acquisition by plants. Chemical extraction, using acid or alkaline solutions, is considered as a means for P retrieval from high P biochar, especially for biochar with high heavy metal contents. To bridge the gap between academia and practice, this paper proposes future development for phosphorus acclamation by pyrolysis: 1) identification of high-P bio-waste for pyrolysis; 2) retrieval of P by using biochar as soil amendment or by chemical leaching; 3) biochar modification by inorganic nutrients, P solubilizing microorganisms and other organic matter; and 4) compatible pyrolysis equipment fit to the current waste management context, such as households, and waste water treatment plants., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Sequential chemical extraction and synchrotron-based XANES spectroscopy techniques were used to identify P species in two ashes before and after addition to a prairie soil. The used ashes were: meat and bone meal ash (MBMA) and dried distillers grains ash (DDGA) plus mineral P fertilizer (MP) for comparison. Soil treated with MP contained higher content of resin-Pi and NaHCO 3 -Pi followed by DDGA and MBMA. The MBMA amended soil had the highest (47%) proportion of the soil P contained in recalcitrant HCl extractable fraction, reflecting more Ca-bound P present and being formed in soil after application. Analysis of both ashes with XANES spectroscopy before application to soil revealed that MBMA had strong spectral features consistent with hydroxyapatite (Ca 5 (PO 4 ) 3 (OH)). DDGA exhibited spectral features consistent with a mixture of several Mg and K phosphate salts rather than a single mineral species. The distinctive features in the XANES spectra of both ashes largely disappeared after amendment to the soil, suggesting transformation to different P forms in the soil after application. It is also possible that the added amount of P to the studied soil via DDGS or MBMA was small enough so that P speciation is not different from the background P level.

The crucial capability of T cells for discrimination between self and non-self peptides is based on negative selection of developing thymocytes by medullary thymic epithelial cells (mTECs). The mTECs purge autoreactive T cells by expression of cell-type specific genes referred to as tissue-restricted antigens (TRAs). Although the autoimmune regulator (AIRE) protein is known to promote the expression of a subset of TRAs, its mechanism of action is still not fully understood. The expression of TRAs that are not under the control of AIRE also needs further characterization. Furthermore, expression patterns of TRA genes have been suggested to change over the course of mTEC development. Herein we have used single-cell RNA-sequencing to resolve patterns of TRA expression during mTEC development. Our data indicated that mTEC development consists of three distinct stages, correlating with previously described jTEC, mTEChi and mTEClo phenotypes. For each subpopulation, we have identified marker genes useful in future studies. Aire-induced TRAs were switched on during jTEC-mTEC transition and were expressed in genomic clusters, while otherwise the subsets expressed largely overlapping sets of TRAs. Moreover, population-level analysis of TRA expression frequencies suggested that such differences might not be necessary to achieve efficient thymocyte selection.

We obtain vibro-acoustic (VA) spectral signatures of a remotely palpated region in tissue or tissue-like objects through diffusing-wave spectroscopy (DWS) measurements. Remote application of force is through focused ultrasound, and the spectral signatures correspond to vibrational modes of the focal volume (also called the ROI) excited through ultrasound forcing. In DWS, one recovers the time evolution of mean-square displacement (MSD) of Brownian particles from the measured decay of intensity autocorrelation of light, adapted also to local particles pertaining only to the ROI. We observe that the plateau of the MSD-versus-time curve has noisy fluctuations when ultrasound is applied, which disappear when forcing is removed. It is shown that the spectrum of fluctuations contains peaks corresponding to some of the modes of vibration of the ROI. This enables us to measure the vibrational modes carried by VA waves. We also show recovery of components of the orthotropic elastic tensor pertaining to the material of the ROI from the measured vibrational modes. We first recover the elastic constants for agar slabs, which are verified to be isotropic. Thereafter, we repeat the exercise on fat recovered from pork back tissue, which, from these measurements, is seen to be orthotropic. We validate some of our present measurements through independent runs in a rheometer. The present work is the first step taken, to the best of our knowledge, to characterize biological tissue on the basis of the anisotropic elasticity property, which may potentially aid in the diagnosis and tracking of the progress of cancer in soft-tissue organs.

The recent developments in high-throughput single-cell RNA sequencing technology (scRNA-seq) have enabled the generation of vast amounts of transcriptomic data at cellular resolution. With these advances come new modes of data analysis, building on high-dimensional data mining techniques. Here, we consider biological questions for which scRNA-seq data is used, both at a cell and gene level, and describe tools available for these types of analyses. This is an exciting and rapidly evolving field, where clustering, pseudotime inference, branching inference and gene-level analyses are particularly informative areas of computational analysis., (© 2017 The Authors. FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Polycomb repressive complexes (PRCs) are important histone modifiers, which silence gene expression; yet, there exists a subset of PRC-bound genes actively transcribed by RNA polymerase II (RNAPII). It is likely that the role of Polycomb repressive complex is to dampen expression of these PRC-active genes. However, it is unclear how this flipping between chromatin states alters the kinetics of transcription. Here, we integrate histone modifications and RNAPII states derived from bulk ChIP-seq data with single-cell RNA-sequencing data. We find that Polycomb repressive complex-active genes have greater cell-to-cell variation in expression than active genes, and these results are validated by knockout experiments. We also show that PRC-active genes are clustered on chromosomes in both two and three dimensions, and interactions with active enhancers promote a stabilization of gene expression noise. These findings provide new insights into how chromatin regulation modulates stochastic gene expression and transcriptional bursting, with implications for regulation of pluripotency and development.Polycomb repressive complexes modify histones but it is unclear how changes in chromatin states alter kinetics of transcription. Here, the authors use single-cell RNAseq and ChIPseq to find that actively transcribed genes with Polycomb marks have greater cell-to-cell variation in expression.

The epidermis is maintained by multiple stem cell populations whose progeny differentiate along diverse, and spatially distinct, lineages. Here we show that the transcription factor Gata6 controls the identity of the previously uncharacterized sebaceous duct (SD) lineage and identify the Gata6 downstream transcription factor network that specifies a lineage switch between sebocytes and SD cells. During wound healing differentiated Gata6 + cells migrate from the SD into the interfollicular epidermis and dedifferentiate, acquiring the ability to undergo long-term self-renewal and differentiate into a much wider range of epidermal lineages than in undamaged tissue. Our data not only demonstrate that the structural and functional complexity of the junctional zone is regulated by Gata6, but also reveal that dedifferentiation is a previously unrecognized property of post-mitotic, terminally differentiated cells that have lost contact with the basement membrane. This resolves the long-standing debate about the contribution of terminally differentiated cells to epidermal wound repair.

Introduction: Globally, Chronic Kidney Disease (CKD) is a critical and rapidly growing health problem and also a major cause of mortality and morbidity. Neurological complications occur in all levels of the nervous system. Central nervous system complications include cerebrovascular accidents, posterior reversible encephalopathy syndrome, osmotic demyelization syndrome, cerebral infection and sinus vein thrombosis. Peripheral nervous system complications include polyneuropathy, mononeuropathy and carpal tunnel syndrome. Haemodialysis (HD) related neurological complications include dialysis disequilibrium syndrome, dementia and cerebrovascular accidents., Aim: To assess the neurological complications of CKD and to compare the various neurological complications in patients on HD with those not on HD., Materials and Methods: Hundred patients with CKD were included in the study. They were categorized into two groups according to the stage of CKD and those with stage 3 or more were considered as cases and stage 2 or less as controls. The cases and controls were followed up during subsequent visits for neurological complications., Results: This study comprised of 50 cases and 50 controls. Among 50 cases, males were 62% and females were 38% with male: female ratio was 1.6:1 and in controls, male: female ratio was 1.08:1. The maximum patients were in the age group of 51-60 years. The incidence of neurological complications was significantly higher in cases compared to controls and among people who underwent dialysis compared to those who were not. Headache was the most common complication both among cases and controls and as well as in people who were on HD. Stroke, seizures and altered sensorium were significantly associated with later stage of CKD. Cases underwent HD had significant association with headache, altered sensorium and stroke than those without HD but peripheral neuropathy and seizure did not show such association., Conclusion: The chances of development of neurological complications were significantly higher in late stages of CKD compared to early stages of CKD. Those neurological complications were more among people who underwent dialysis when compared to those not on maintenance HD.

Background: Differentiation of lymphocytes is frequently accompanied by cell cycle changes, interplay that is of central importance for immunity but is still incompletely understood. Here, we interrogate and quantitatively model how proliferation is linked to differentiation in CD4+ T cells., Results: We perform ex vivo single-cell RNA-sequencing of CD4+ T cells during a mouse model of infection that elicits a type 2 immune response and infer that the differentiated, cytokine-producing cells cycle faster than early activated precursor cells. To dissect this phenomenon quantitatively, we determine expression profiles across consecutive generations of differentiated and undifferentiated cells during Th2 polarization in vitro. We predict three discrete cell states, which we verify by single-cell quantitative PCR. Based on these three states, we extract rates of death, division and differentiation with a branching state Markov model to describe the cell population dynamics. From this multi-scale modelling, we infer a significant acceleration in proliferation from the intermediate activated cell state to the mature cytokine-secreting effector state. We confirm this acceleration both by live imaging of single Th2 cells and in an ex vivo Th1 malaria model by single-cell RNA-sequencing., Conclusion: The link between cytokine secretion and proliferation rate holds both in Th1 and Th2 cells in vivo and in vitro, indicating that this is likely a general phenomenon in adaptive immunity.

Three new ortho-metallated palladium complexes, [Pd(O,O'-hfacac)(κ(2)-2-C6F4PPh2)] (), [Pd2(O,O'-hfacac)2(μ-2-C6F4PPh2)2] () and [Pd(O,O'-hfacac)(κC-2-C6F4PPh2)(PPh3)] () (hfacac = hexafluoroacetylacetonate), have been prepared and fully characterised. The electrochemical reductions of complexes , together with those of other cyclopalladated complexes containing 2-C6R4PPh2 ligands (R = H, F) were studied by cyclic, rotating disk and microelectrode voltammetry. Evidence for the one-electron reduction of [PdI(κ(2)-2-C6F4PPh2)(PPh2Fc)] () was obtained from coulometric analysis, although the product is unstable and undergoes further chemical processes. Preparative electro-reduction of [Pd2(μ-Br)2(κ(2)-2-C6F4PPh2)2] () in CH2Cl2 causes reductive cleavage of its Pd-C σ-bonds and formation of the complex [PdBr2{PPh2(2-C6F4H)}2] (); possible mechanisms are discussed.

The ubiquitin-proteosome system (UPS) regulates a wide range of cellular processes including protein degradation, DNA repair, transcription regulation, and cell signaling. Alterations and mutations in UPS components give rise to various human diseases, most prominently cancer and neurodegenerative disorders. Here, we review recent advances in UPS-based drug discovery highlighting the emerging relationships between the UPS and disease and discuss potential future therapeutic interventions. In particular, we focus on recent structural approaches in UPS and explain how the knowledge of protein structural details can guide the design of specifically targeted inhibitors.

Ubiquitination is crucial for many cellular processes such as protein degradation, DNA repair, transcription regulation, and cell signaling. Ubiquitin attachment takes place via a sequential enzymatic cascade involving ubiquitin activation (by E1 enzymes), ubiquitin conjugation (by E2 enzymes), and ubiquitin substrate tagging (by E3 enzymes). E3 ligases mediate ubiquitin transfer from E2s to substrates and as such confer substrate specificity. Although E3s can interact and function with numerous E2s, it is still unclear how they choose which E2 to use. Identifying all E2 partners of an E3 is essential for inferring the principles guiding E2 selection by an E3. Here we model the interactions of E3 and E2 proteins in a large, proteome-scale strategy based on interface structural motifs, which allows elucidation of (1) which E3s interact with which E2s in the human ubiquitination pathway and (2) how they interact with each other. Interface analysis of E2-E3 complexes reveals that loop L1 of E2s is critical for binding; the residue in the sixth position in loop L1 is widely utilized as an interface hot spot and appears indispensible for E2 interactions. Other loop L1 residues also confer specificity on the E2-E3 interactions: HECT E3s are in contact with the residue in the second position in loop L1 of E2s, but this is not the case for the RING finger type E3s. Our modeled E2-E3 complexes illuminate how slight sequence variations in E2 residues may contribute to specificity in E3 binding. These findings may be important for discovering drug candidates targeting E3s, which have been implicated in many diseases.

The growing perception that diseases are often consequences of multiple molecular abnormalities rather than being the result of a single defect highlights the importance of network-centric view in therapeutic approaches. Protein interaction networks may contribute to understanding of disease, assist in drug design and discovery. Here, we review some recent advances in disease-associated protein interaction networks taking a structural approach. We first describe structural aspects of protein-protein interactions and properties of protein interfaces as related to drug design; we address protein interactions in a network perspective; in particular, we illustrate how integrating protein interfaces onto interaction networks can guide the identification of selective drug targets or drugs targeting multiple proteins in a network.

Proteins can exist in a large number of conformations around their native states that can be characterized by an energy landscape. The landscape illustrates individual valleys, which are the conformational substates. From the functional standpoint, there are two key points: first, all functionally relevant substates pre-exist; and second, the landscape is dynamic and the relative populations of the substates will change following allosteric events. Allosteric events perturb the structure, and the energetic strain propagates and shifts the population. This can lead to changes in the shapes and properties of target binding sites. Here we present an overview of dynamic conformational ensembles focusing on allosteric events in signaling. We propose that combining equilibrium fluctuation concepts with genomic screens could help drug discovery., (Copyright © 2010 Elsevier Ltd. All rights reserved.)