Design, Synthesis, and Antitumor Activity Evaluation of Proteolysis-Targeting Chimeras as Degraders of Extracellular Signal-Regulated Kinases 1/2.

Inhibition of the extracellular signal-regulated kinases 1/2 (ERK1/2) alone or in combination with other targets has emerged as a promising treatment strategy for a variety of human tumors. In addition to the development of inhibitors, the development of ERK1/2 degraders is an alternative approach to decrease its activity. We synthesized proteolysis-targeting chimeras (PROTACs) as effective ERK1/2 degraders, among which B1-10J showed high degradative activity, with DC50 of 102 nM and cytotoxic IC50 of 2.2 µM against HCT116 cells. Moreover, B1-10J dose-dependently inhibited tumor cell migration. Xenograft experiments in nude mice demonstrated that B1-10J inhibited HCT116 tumor cell growth and achieved significant regression of tumors at a daily dose of 25 mg/kg.

Utilizing biochar to decorate nanoscale FeS for the highly effective decontamination of Se(IV) from simulated wastewater.

Selenium (Se) as an essential nutrient for human beings at trace concentrations, the allowable concentration for the human is only 40 µg/L. Iron sulfide (FeS) nanoparticles have been applied for excessive of selenium (Se) remediation in surface water and groundwater. In this study, FeS nanoparticles were anchored onto biochar (BC) to reduce agglomeration of FeS and prepared into the composite of FeS-BC by pyrolysis to economically and efficiently remove Se(IV) from simulated wastewater based on the excellent performance of FeS and the low cost of BC. Characterizations presented the uniform anchorage of FeS on the BC surface to prevent agglomeration. The results of batch experiments revealed that the removal of Se(IV) by FeS-BC nanomaterials significantly depended on the pH value, with the maximum removal of ∼174.96 mg/g at pH 3.0. A pseudo-second-order kinetic model well reflected the kinetic removal of Se(IV) in pure Se(IV) solution with different concentration, as well as the coexistence of K+, Ca2+, Cl-, and SO42- ions. The presence of K+ ions significantly inhibited the removal of Se(IV) with the increase of K+ ion concentration compared with the effect of the other three ions. SEM-EDS and XPS analyses indicated that the removal process was achieved through adsorption by surface complexation, and reductive precipitation of Se(IV) into Se0 with the electron donor of Fe(II) and S(-II) ions. The FeS-BC nanomaterial exhibited an excellent application prospect in the remediation of Se(IV).

Discovery of novel benzimidazole derivatives as potent potassium-competitive acid blockers for the treatment of acid-related diseases.

H+, K+-ATPase, as the most critical enzyme in gastric acid secretion, has long been an attractive target for the treatment of acid-related diseases. In this study, a series of benzimidazole derivatives were designed and synthesized through conformational restriction and skeleton hopping strategies by using vonoprazan as the lead compound. Among them, compounds A12 (IC50 = 9.32 µM) and A18 (IC50 = 5.83 µM) showed better inhibition at the enzyme level. In addition, gastric acid secretion inhibition was assessed in vivo, and the results showed that A12 and A18 significantly inhibited basal gastric acid secretion, 2-deoxy-d-glucose (2DG) stimulated gastric acid secretion and histamine-stimulated gastric acid secretion. In further in vitro metabolic experiments, A12 and A18 demonstrated excellent stability and low toxicity. Pharmacokinetic studies showed that the p.o. and i.v. half-lives of A18 were 3.21 h and 8.67 ± 1.15 h, respectively. In summary, A18 might be a novel and effective potassium-competitive acid blocker, and this study provides strong support for it use in the treatment of acid-related diseases.

Negotiating Complexity: Challenges to Implementing Community-Led Nature-Based Solutions in England Pre- and Post-COVID-19.

Nature-based solutions (NbS), including green social prescribing (GSP), are sustainable ways to address health and wellbeing, especially since the COVID-19 pandemic exacerbated the strain on healthcare. NbS require national and local cross-sector coordination across complex, interrelated systems, but little is known about the specific challenges this poses for community-led NbS. We carried out a traditional literature review to establish the context and knowledge base for this study and interviewed 26 stakeholders. These came from environment, health and social care sectors at national and local levels, with local-level stakeholders from Bradford and Walsall: English cities significantly affected by the pandemic, with high levels of deprivation and health inequality. The interviews explored experiences of implementing NbS, both pre- and post-pandemic and the resulting renewed interest in the salutogenic effects of engaging with natural environments. We coded the interview transcriptions using NVivo to identify the challenges existing in the systems within which these stakeholders operate to create and manage NbS. By synthesizing what is known about the challenges from existing literature with findings from the interviews, we developed eight categories of challenges (perception and knowledge, political, financial, access to natural spaces, engagement, institutional and organisational, coordination, GSP referral and services) faced by multiple sectors in implementing community-led NbS in England. Furthermore, this study highlights the new challenges related to the pandemic. Identifying these challenges helps stakeholders in existing complex systems recognise what is needed to support and mainstream NbS in England.

Group Testing with Multiple Inhibitor Sets and Error-Tolerant and Its Decoding Algorithms.

In this article, we advance a new group testing model [Formula: see text] with multiple inhibitor sets and error-tolerant and propose decoding algorithms for it to identify all its positives by using [Formula: see text]-disjunct matrix. The decoding complexity for it is [Formula: see text], where [Formula: see text]. Moreover, we extend this new group testing to threshold group testing and give the threshold group testing model [Formula: see text] with multiple inhibitor sets and error-tolerant. By using [Formula: see text]-disjunct matrix, we propose its decoding algorithms for gap g = 0 and g > 0, respectively. Finally, we point out that the new group testing is the natural generalization for the clone model.

Exploring the role of endothelium in the tumour response to anti-angiogenic therapy.

A chronic hyperactivated angiogenic state in cancer plays an important role in tumour growth and metastasis and has been identified as one of the hallmarks of cancer. Inhibition of this process has been associated with tumour suppression in many pre-clinical contexts using different animal tumour models. Anti-angiogenic therapeutics were subsequently developed and used to treat several prevalent types of human cancer. However, recent clinical experience has revealed limitations of this approach in treating cancer as patient response varies over a wide range. Given that there are complex underlying molecular and cellular changes provoked by anti-angiogenic treatment within the tumour microenvironment (TME), it is not surprising that modest effectiveness and resistance have been observed in the clinical setting. This article discusses these issues in the context of VEGF-A-targeted anti-angiogenic treatment of cancer and provides insight into the importance of tumour endothelium for understanding the tumour response to anti-angiogenic therapy. Special consideration is also given to possible approaches for investigating how endothelium contributes to the tumour response to anti-angiogenic agents and for exploring the therapeutic and biomarker potential of targeting tumour endothelium.

Expression and purification of bioactive, low-endotoxin recombinant human vitronectin.

The secreted adhesive glycoprotein vitronectin (VTN) is a multifunctional component of plasma and the extracellular matrix. A high-yielding, inexpensive, low endotoxin source of bioactive recombinant human vitronectin (rhVTN) is highly desirable for in vitro use in diverse cell culture systems ranging from basic research settings to clinical-grade production of human cells. We describe modifications to a previously reported heparin-based affinity chromatography procedure that improve yield and achieve efficient removal of endotoxin from washed and urea-solubilized human VTN inclusion bodies following standard autoinduction of expression in Escherichia coli. This simple procedure makes accessible the low-cost expression and purification of large quantities of bioactive rhVTN using basic equipment and facilitates its use in a spectrum of endotoxin-sensitive applications.

An improved hybrid encoding cuckoo search algorithm for 0-1 knapsack problems.

Cuckoo search (CS) is a new robust swarm intelligence method that is based on the brood parasitism of some cuckoo species. In this paper, an improved hybrid encoding cuckoo search algorithm (ICS) with greedy strategy is put forward for solving 0-1 knapsack problems. First of all, for solving binary optimization problem with ICS, based on the idea of individual hybrid encoding, the cuckoo search over a continuous space is transformed into the synchronous evolution search over discrete space. Subsequently, the concept of confidence interval (CI) is introduced; hence, the new position updating is designed and genetic mutation with a small probability is introduced. The former enables the population to move towards the global best solution rapidly in every generation, and the latter can effectively prevent the ICS from trapping into the local optimum. Furthermore, the greedy transform method is used to repair the infeasible solution and optimize the feasible solution. Experiments with a large number of KP instances show the effectiveness of the proposed algorithm and its ability to achieve good quality solutions.

Nonadaptive algorithms for threshold group testing with inhibitors and error-tolerance.

A group test gives a positive (negative) outcome if it contains at least u (at most l) positive items, and an arbitrary outcome if the number of positive items is between thresholds l and u. This problem introduced by Damaschke is called threshold group testing. It is a generalization of classical group testing. Chen and Fu extended this problem to the error-tolerant version and first proposed efficient nonadaptive algorithms. In this article, we extend threshold group testing to the k-inhibitors model in which a test has a positive outcome if it contains at least u positives and at most k-1 inhibitors. By using (d + k - l, u; 2e + 1]-disjunct matrix we provide nonadaptive algorithms for the threshold group testing model with k-inhibitors and at most e-erroneous outcomes. The decoding complexity is O(n(u+k) log n) for fixed parameters (d, u, l, k, e).