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Content and Focus: Counselling psychologists offer their services to clients in organisational, political and economic contexts that are characterised by increasing levels of complexity, uncertainty and turbulence. Investigating the effectiveness of what we do remains critical to the future of the psychology professions, but our traditional approaches to scientific enquiry may not be adequate for the types of dilemma generated by complexity. Conclusions: This paper describes a framework, adapted from contemporary complexity theory, that can support us in thinking systematically and creatively about the range of investigative skills we might need if professional practice is to prove fit for purpose in the decades to come. It is proposed that complexity theory can assist us in responding creatively to the dilemmas of living and working in unprecedented times. [ABSTRACT FROM AUTHOR]

The c-MYC oncogene is activated in over 70% of all human cancers. The intrinsic disorder of the c-MYC transcription factor facilitates molecular interactions that regulate numerous biological pathways, but severely limits efforts to target its function for cancer therapy. Here, we use a reductionist strategy to characterize the dynamic and structural heterogeneity of the c-MYC protein. Using probe-based Molecular Dynamics (MD) simulations and machine learning, we identify a conformational switch in the c-MYC amino-terminal transactivation domain (termed coreMYC) that cycles between a closed, inactive, and an open, active conformation. Using the polyphenol epigallocatechin gallate (EGCG) to modulate the conformational landscape of coreMYC, we show through biophysical and cellular assays that the induction of a closed conformation impedes its interactions with the transformation/transcription domain-associated protein (TRRAP) and the TATA-box binding protein (TBP) which are essential for the transcriptional and oncogenic activities of c-MYC. Together, these findings provide insights into structure-activity relationships of c-MYC, which open avenues towards the development of shape-shifting compounds to target c-MYC as well as other disordered transcription factors for cancer treatment.Here, the authors identify a conformational switch in the amino-terminal transactivation domain of c-MYC, termed coreMYC, which cycles between a closed, inactive state and an open, active conformation. Polyphenol epigallocatechin gallate (EGCG) is used to modulate the conformational landscape of coreMYC, stabilizing the closed and inactive conformation. [ABSTRACT FROM AUTHOR]

Purpose: Molecular radiotherapy is a treatment modality that is highly suitable for targeting micrometastases and [177Lu]Lu-DOTATATE is currently being explored as a potential novel treatment option for high-risk neuroblastoma. p53 is a key player in the proapoptotic signalling in response to radiation-induced DNA damage and is therefore a potential target for radiosensitisation. Methods: This study investigated the use of the p53 stabilising peptide VIP116 and [177Lu]Lu-DOTATATE, either alone or in combination, for treatment of neuroblastoma tumour xenografts in mice. Initially, the uptake of [177Lu]Lu-DOTATATE in the tumours was confirmed, and the efficacy of VIP116 as a monotherapy was evaluated. Subsequently, mice with neuroblastoma tumour xenografts were treated with placebo, VIP116, [177Lu]Lu-DOTATATE or a combination of both agents. Results: The results demonstrated that monotherapy with either VIP116 or [177Lu]Lu-DOTATATE significantly prolonged median survival compared to the placebo group (90 and 96.5 days vs. 50.5 days, respectively). Notably, the combination treatment further improved median survival to over 120 days. Furthermore, the combination group exhibited the highest percentage of complete remission, corresponding to a twofold increase compared to the placebo group. Importantly, none of the treatments induced significant nephrotoxicity. Additionally, the therapies affected various molecular targets involved in critical processes such as apoptosis, hypoxia and angiogenesis. Conclusion: In conclusion, the combination of VIP116 and [177Lu]Lu-DOTATATE presents a promising novel treatment approach for neuroblastoma. These findings hold potential to advance research efforts towards a potential cure for this vulnerable patient population. [ABSTRACT FROM AUTHOR]

Although stapled α-helical peptides can address challenging targets, their advancement is impeded by poor understandings for making them cell permeable while avoiding off-target toxicities. By synthesizing >350 molecules, we present workflows for identifying stapled peptides against Mdm2(X) with in vivo activity and no off-target effects. Key insights include a clear correlation between lipophilicity and permeability, removal of positive charge to avoid off-target toxicities, judicious anionic residue placement to enhance solubility/behavior, optimization of C-terminal length/helicity to enhance potency, and optimization of staple type/number to avoid polypharmacology. Workflow application gives peptides with >292x improved cell proliferation potencies and no off-target cell proliferation effects (> 3800x on-target index). Application of these 'design rules' to a distinct Mdm2(X) peptide series improves (> 150x) cellular potencies and removes off-target toxicities. The outlined workflow should facilitate therapeutic impacts, especially for those targets such as Mdm2(X) that have hydrophobic interfaces and are targetable with a helical motif. Stapled α-helical peptides are promising for targeting challenging targets such as transcription factors, but achieving sufficient cell permeability while avoiding off-target cleavage is difficult. Here, the authors present workflows for identifying stapled peptides against Mdm2(X) with in vivo activity and no off-target effects based on comprehensive investigations of their properties. [ABSTRACT FROM AUTHOR]

Streptococcus pneumoniae (the pneumococcus) is well known for its ability to develop competence for natural DNA transformation. Competence development is regulated by an autocatalytic loop driven by variations in the basal level of transcription of the comCDE and comAB operons. These genes are part of the early gene regulon that controls expression of the late competence genes known to encode the apparatus of transformation. Several stressful conditions are known to promote competence development, although the induction pathways are remain poorly understood. Here we demonstrate that transient temperature elevation induces an immediate increase in the basal expression level of the comCDE operon and early genes that, in turn, stimulates its full induction, including that of the late competence regulon. This thermal regulation depends on the HtrA chaperone/protease and its proteolytic activity. We find that other competence induction stimulus, like norfloxacin, is not conveyed by the HtrA-dependent pathway. This finding strongly suggests that competence can be induced by at least two independent pathways and thus reinforces the view that competence is a general stress response system in the pneumococcus. Author summary: Streptococcus pneumoniae is a commensal bacterium and an opportunistic pathogen of humans. Certain environmental stimuli, such as a variety of antibiotics targeting distinct cellular functions, trigger the induction of the distinct physiological state of competence, in which cells can, among other things, import and integrate external DNA. Competence is thus considered a general stress response in this highly adaptable species. To understand the role of competence in pneumococcal interaction with its host and in pathogenicity, we have attempted to decipher the pathways that enable appropriate reactions to environmental stress, and have focused here on induction of competence by elevation of temperature to levels similar to that of a host in fever. We found that elevated temperature raises the basal expression level of the competence control operon, and thus lowers the threshold of transition to full competence induction. By genetic characterisation of the thermal induction pathway of competence, we demonstrated that the chaperone/protease HtrA is essential for relaying of the thermal signal but is not involved in transmitting other stimuli such as those arising from the presence of certain antibiotics. Our work supports the view that competence can be induced through various pathways in response to distinct stimuli, including fever-like bursts of temperature that the pneumococcus could face in its natural habitat. [ABSTRACT FROM AUTHOR]

Cyclic peptides are poised to target historically difficult to drug intracellular protein–protein interactions, however, their general cell impermeability poses a challenge for characterizing function. Recent advances in microfluidics have enabled permeabilization of the cytoplasmic membrane by physical cell deformation (i.e., mechanoporation), resulting in intracellular delivery of impermeable macromolecules in vector‐ and electrophoretic‐free approaches. However, the number of payloads (e.g., peptides) and/or concentrations delivered via microfluidic mechanoporation is limited by having to pre‐mix cells and payloads, a manually intensive process. In this work, we show that cells are momentarily permeable (t1/2 = 1.1–2.8 min) after microfluidic vortex shedding (μVS) and that lower molecular weight macromolecules can be cytosolically delivered upon immediate exposure after cells are processed/permeabilized. To increase the ability to screen peptides, we built a system, dispensing‐microfluidic vortex shedding (DμVS), that integrates a μVS chip with inline microplate‐based dispensing. To do so, we synced an electronic pressure regulator, flow sensor, on/off dispense valve, and an x‐y motion platform in a software‐driven feedback loop. Using this system, we were able to deliver low microliter‐scale volumes of transiently mechanoporated cells to hundreds of wells on microtiter plates in just several minutes (e.g., 96‐well plate filled in <2.5 min). We validated the delivery of an impermeable peptide directed at MDM2, a negative regulator of the tumor suppressor p53, using a click chemistry‐ and NanoBRET‐based cell permeability assay in 96‐well format, with robust delivery across the full plate. Furthermore, we demonstrated that DμVS could be used to identify functional, low micromolar, cellular activity of otherwise cell‐inactive MDM2‐binding peptides using a p53 reporter cell assay in 96‐ and 384‐well format. Overall, DμVS can be combined with downstream cell assays to investigate intracellular target engagement in a high‐throughput manner, both for improving structure–activity relationship efforts and for early proof‐of‐biology of non‐optimized peptide (or potentially other macromolecular) tools. [ABSTRACT FROM AUTHOR]

We have previously shown that proteasome inhibitor bortezomib stabilizes p53 in stem and progenitor cells within gastrointestinal tissues. Here, we characterize the effect of bortezomib treatment on primary and secondary lymphoid tissues in mice. We find that bortezomib stabilizes p53 in significant fractions of hematopoietic stem and progenitor cells in the bone marrow, including common lymphoid and myeloid progenitors, granulocyte-monocyte progenitors, and dendritic cell progenitors. The stabilization of p53 is also observed in multipotent progenitors and hematopoietic stem cells, albeit at lower frequencies. In the thymus, bortezomib stabilizes p53 in CD4−CD8− T cells. Although there is less p53 stabilization in secondary lymphoid organs, cells in the germinal center of the spleen and Peyer’s patch accumulate p53 in response to bortezomib. Bortezomib induces the upregulation of p53 target genes and p53 dependent/independent apoptosis in the bone marrow and thymus, suggesting that cells in these organs are robustly affected by proteasome inhibition. Comparative analysis of cell percentages in the bone marrow indicates expanded stem and multipotent progenitor pools in p53R172H mutant mice compared with p53 wild-type mice, suggesting a critical role for p53 in regulating the development and maturation of hematopoietic cells in the bone marrow. We propose that progenitors along the hematopoietic differentiation pathway express relatively high levels of p53 protein, which under steady-state conditions is constantly degraded by Mdm2 E3 ligase; however, these cells rapidly respond to stress to regulate stem cell renewal and consequently maintain the genomic integrity of hematopoietic stem/progenitor cell populations. [ABSTRACT FROM AUTHOR]

Activation of p53 by small molecule MDM2 inhibitors can induce cell cycle arrest or death in p53 wildtype cancer cells. However, cancer cells exposed to hypoxia can develop resistance to other small molecules, such as chemotherapies, that activate p53. Here, we evaluated whether hypoxia could render cancer cells insensitive to two MDM2 inhibitors with different potencies, nutlin-3a and navtemadlin. Inhibitor efficacy and potency were evaluated under short-term hypoxic conditions in human and mouse cancer cells expressing different p53 genotypes (wild-type, mutant, or null). Treatment of wild-type p53 cancer cells with MDM2 inhibitors reduced cell growth by > 75% in hypoxia through activation of the p53–p21 signaling pathway; no inhibitor-induced growth reduction was observed in hypoxic mutant or null p53 cells except at very high concentrations. The concentration of inhibitors needed to induce the maximal p53 response was not significantly different in hypoxia compared to normoxia. However, inhibitor efficacy varied by species and by cell line, with stronger effects at lower concentrations observed in human cell lines than in mouse cell lines grown as 2D and 3D cultures. Together, these results indicate that MDM2 inhibitors retain efficacy in hypoxia, suggesting they could be useful for targeting acutely hypoxic cancer cells. [ABSTRACT FROM AUTHOR]

There is substantial comorbidity between autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD), and there are well-documented executive functioning (EF) deficits in both populations. An important question concerns whether EF deficits in children with ASD are related to severity of ASD, ADHD, or both. We examined ADHD and ASD symptoms in relation to ratings of EF in the home and classroom. The sample comprised 64 children (55 males) diagnosed with ASD (mean age = 9.26 years; mean FSIQ = 92). Analyses indicated that parent and teacher ratings of EF (except Shift and Emotional Control) were consistently related to ADHD symptom severity, but not to ASD severity. Thus, functioning in the domains of Shift and Emotional control appear relatively spared, whereas performance in all other EF was impaired in relation to ADHD symptoms. [ABSTRACT FROM AUTHOR]

This article is based on a relatively small-scale qualitative research study for the Greater Cambridgeshire Social Work Teaching Partnership (GCSWTP) and Anglia Ruskin University (ARU), the aim of which was to identify the core quality components of social work practice learning in order to achieve excellence, in preparation for frontline professional social work practice. The research took a broadly phenomenological approach to describe and interpret the participants' lived experiences of social work practice learning. A purposive sample of 35 participants, which included: practice educators (local authority, voluntary and independent), service users (adults only, via ARU's social work service user group), frontline social work practitioners, both experienced and newly qualified (adult and children's services), frontline team managers (adult and children's services), children's guardians, final and second year social work students (ARU's BA and MA) and ARU social work academics. The findings therefore represent the perspectives of a wide range of professionals involved, both directly and indirectly, in practice learning. Data was obtained using semi-structured, open-ended one-to-one interviews, which were audio-recorded. The research highlighted a gap between academic input and the realities and challenges of current social work practice, particularly in terms of depth and complexity of the knowledge and skills needed for frontline practice. [ABSTRACT FROM AUTHOR]

Increased Integrated Pest Management (IPM) adoption hinges not only on the future of innovative research, but also on the willingness of growers to adopt new IPM technologies. Adoption and diffusion of innovations can encounter many different challenges. By better understanding the drivers of and barriers to IPM adoption, future research, extension, and education can better target behavior change. This study sought to better understand the IPM adoption drivers and barriers, along with the impacts of IPM, from the perspective of state IPM coordinators via an online Qualtrics survey. These professionals have a statewide perspective on IPM adoption. There were 37 completed surveys out of 56 email survey invitations, a 66% response rate. Overall, the participants ranked 'high cost of practice' as the most critical barrier to IPM adoption. 'Difficulty of implementation' and 'lack of awareness' were also highly ranked as critical barriers to adoption. When asked about ways to increase IPM adoption, participants ranked 'improved cost-benefit analysis' as the most critically important. Overall, these findings demonstrate the importance of providing improved IPM economic cost-benefit analyses to accompany the promotion of new and existing IPM innovations. Furthermore, even though the results of this study suggest that the impact of the Regional IPM Centers has been increasing regional IPM coordination, communication, collaboration, and cooperation. These findings also suggest a need for more comprehensive extension and education programs to specifically address the perceived 'high cost of practice,' 'difficulty of implementation', and 'lack of awareness' by communicating improved IPM cost-benefit analyses. [ABSTRACT FROM AUTHOR]

This article describes an encounter between servomechanism innovator, digital computing pioneer and creator of system dynamics, Jay Forrester, and Isaac Asimov, renowned author of science fiction (including "The Foundation Trilogy" and its fictional discipline of psychohistory) and works of popular science. Their lengthy exchange took place at a workshop in 1975 and four descriptions of it are extant. What emerges in passing is a possible link between Asimov's thinking and Forrester's work on "World Dynamics". Most notable, however, is that the encounter saw the two exchanging ideas on how to think about the future, how to bring about a desirable future, and quite what that desirable future should look like. The two had fundamental differences on key points. The paper explores the unusual interaction, drawing out the points of disagreement and agreement in the views of the two and how they applied these to thinking about the future. © 2022 The Authors. System Dynamics Review published by John Wiley & Sons Ltd on behalf of System Dynamics Society. [ABSTRACT FROM AUTHOR]

The OER Universitas (OERu) is a consortium of more than 30 higher education institutions on five continents. It was founded in 2011 to provide learners everywhere with learning opportunities and pathways to official recognition or credit. The OERu maintains a very economical base with very low expenses. It supports a sustainable learning environment with incremental increases in infrastructural capacity as and when it is needed. The OERu's global digital infrastructure has been created to facilitate learner access to micro-courses on the internet from any geographical location. This Next Generation Digital Learning Environment (NGDLE) is based entirely on free and open source software (FOSS). The OERu has established a working model for transnational micro-credentialling for approved university qualifications. To date it has supported more than 200,000 learners in over 100 countries. The OERu is based on a scalable, FOSS NGDLE which has dramatically reduced the cost of providing learning opportunities to anyone, anywhere, on the web. [ABSTRACT FROM AUTHOR]

The RON receptor tyrosine kinase is an exceptionally interesting target in oncology and immunology. It is not only overexpressed in a wide variety of tumors but also has been shown to be expressed on myeloid cells associated with tumor infiltration, where it serves to dampen tumour immune responses and reduce the efficacy of anti-CTLA4 therapy. Potent and selective inhibitory antibodies to RON might therefore both inhibit tumor cell growth and stimulate immune rejection of tumors. We derived cloned and sequenced a new panel of exceptionally avid anti-RON antibodies with picomolar binding affinities that inhibit MSP-induced RON signaling and show remarkable potency in antibody dependent cellular cytotoxicity. Antibody specificity was validated by cloning the antibody genes and creating recombinant antibodies and by the use of RON knock out cell lines. When radiolabeled with 89-Zirconium, the new antibodies 3F8 and 10G1 allow effective immuno-positron emission tomography (immunoPET) imaging of RON-expressing tumors and recognize universally exposed RON epitopes at the cell surface. The 10G1 was further developed into a novel bispecific T cell engager with a 15 pM EC50 in cytotoxic T cell killing assays. [ABSTRACT FROM AUTHOR]

Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD) are associated with adaptive function impairments. This study measured adaptive functioning in a sample of 92 children with ASD, including 80 children with co-occurring ADHD. Regression models examined whether ASD and ADHD symptom severity were associated with adaptive functioning level relative to same-age peers (standard scores). ASD severity predicted weaker overall adaptive functioning, relative to peers; ASD and ADHD severity each independently predicted weaker adaptive function in Socialization. Thus, severity of ADHD in children with ASD is associated with greater adaptive deficits than what would be expected on the basis of ASD severity alone. In contrast, ADHD was not significantly related to greater deficits in other adaptive domains, above and beyond that associated with ASD. Clinicians should be aware that ADHD confers additional developmental risk in the area of socialization in children with ASD, and that treatment plans should be designed accordingly. [ABSTRACT FROM AUTHOR]

The article describes a study of the foodborne transmission mechanisms for norovirus. It was undertaken for the U.K. Food Standards Agency and received the System Dynamics Society's 2020 "System Dynamics Applications Award". The article opens with descriptions of norovirus, the organisational context and the aims of the study. The first phase involved the construction of a large, fully formulated SD simulation model which included person‐to‐person mechanisms and, newly built, food‐related mechanisms for norovirus transmission. The group modelling process and the model structure are described. The model's existence demonstrated that enough was known about foodborne mechanisms to create an explicit and carefully documented representation that specialists recognised, understood, and accepted. Additionally, a framework for analysing the model's parameters—some currently unknown—helped organise FSA thinking on future research and potential policy levers. A second phase used mathematical analysis of a simplified SD model to assess the relative scale of the foodborne effects. In terms of contributions, this generated insights into possible sources of seasonality and insights into whether the most effective leverage points in the system lay solely within the remit of the FSA or were also within the remits of other government departments. The article closes by summarising the findings and then exploring their policy implications and recording the client's reactions to them. © 2022 The Authors. System Dynamics Review published by John Wiley & Sons Ltd on behalf of System Dynamics Society. [ABSTRACT FROM AUTHOR]

An attractive approach to target intracellular macromolecular interfaces and to model putative drug interactions is to design small high-affinity proteins. Variable domains of the immunoglobulin heavy chain (VH domains) are ideal miniproteins, but their development has been restricted by poor intracellular stability and expression. Here we show that an autonomous and disufhide-free VH domain is suitable for intracellular studies and use it to construct a high-diversity phage display library. Using this library and affinity maturation techniques we identify VH domains with picomolar affinity against eIF4E, a protein commonly hyper-activated in cancer. We demonstrate that these molecules interact with eIF4E at the eIF4G binding site via a distinct structural pose. Intracellular overexpression of these miniproteins reduce cellular proliferation and expression of malignancy-related proteins in cancer cell lines. The linkage of high-diversity in vitro libraries with an intracellularly expressible miniprotein scaffold will facilitate the discovery of VH domains suitable for intracellular applications. Approaches have been devised to increase the discovery rate of intrabodies but often these yield results that aren't functional in cells. Here the authors engineer and optimise an autonomous and disulphide-free human VH domain for intracellular expression, and they identify several VH domain binders against eIF4E. [ABSTRACT FROM AUTHOR]

Background: The incidence of cutaneous malignant melanoma continues to increase worldwide and in Canada. It is unclear whether the increase in incidence and clinical characteristic trends of cutaneous malignant melanoma are similar in the province of Newfoundland and Labrador. Objective: The objective of this study is to examine the incidence and trends of cutaneous malignant melanoma in Eastern Newfoundland and Labrador. Methods: Patients aged 18 years or older diagnosed with cutaneous malignant melanoma were identified from the Eastern Health Authority's Cancer Registry. The diagnosis was confirmed by a pathologist via histological subtype. Patients were excluded if the diagnosis was unspecified, a nonmelanoma skin cancer or if there was a recurrence in the same lesion location. In total 298 patients diagnosed with cutaneous malignant melanoma from 2007 to 2015 were included in the analysis. Results: The total incidence increased from 4.1 to 15.6 cases/100,000 person-years, which represents a 283.0% increase from 2007 to 2015. The largest increases in incidence were seen in males and patients aged from 60 to 79 years. The most common lesion anatomical locations were the trunk in males and the lower extremity in females. The majority of cases had a Breslow thickness below 1.0 mm. Conclusion: The incidence of cutaneous malignant melanoma in Eastern Newfoundland and Labrador is increasing at a faster rate than in any other region in Canada. Health care providers should work to be aware of the clinical trends and risk factors associated with this disease to facilitate early detection and prevent morbidity. [ABSTRACT FROM AUTHOR]

The process of sprouting angiogenesis can be measured in vitro using endothelial cells in sprouting assays such as the fibrin bead assay and the spheroid-based assay. While the technical aspects of these sprouting assays have been well-optimized, the analysis aspects have been limited to manual methods, which can be time-consuming and difficult to reproduce. Here, we developed an automated analysis tool called AQuTAS to quantify sprouting parameters from the spheroid-based sprouting assay. We trained and validated the algorithm on two subsets of data, and tested its sensitivity by measuring changes in sprouting parameters over a range of concentrations of pro- and antiangiogenic compounds. Our results demonstrate that the algorithm detects known differences in sprouting parameters in endothelial spheroids treated with pro- and antiangiogenic compounds. Moreover, it is sensitive to biological changes that are ≥40%. Among the five quantified parameters, cumulative sprout length is likely the most discriminative parameter for measuring differences in sprouting behavior because it had the highest effect size (>1.5 Cohen's d). In summary, we have generated an automated tool that quantifies sprouting parameters from the spheroid-based assay in a reproducible and sensitive manner. [ABSTRACT FROM AUTHOR]

p53 is primarily known as a downstream transcriptional effector in the DNA damage-response cascade. We report that endogenous p53 rapidly accumulates at DNA damage sites within 2 s of UVA microirradiation. The kinetics of p53 recruitment mimics those of known DNA damage-response proteins, such as Ku70 and poly(- ADP-ribose) polymerase (PARP), and precedes recruitment of Nbs1, 53BP1, and DDB1. Mutations in the DNA-binding and C-terminal domains significantly suppress this rapid recruitment. The C-terminal domain of p53 contains key residues for PARP interac- tion that are required for rapid recruitment of p53 to DNA damage sites, as is PARP-dependent modification. The presence of p53 at damage sites influences the recruitment kinetics of 53BP1 and DDB1 and directs the choice of nonhomologous end joining repair (NHEJ) and nucleotide excision repair. Mutations that suppressed rapid recruitment of p53 promoted error-prone alternative end- joining (alt-NHEJ) and inhibited nucleotide excision repair. Our finding that p53 is a critical early responder to DNA damage stands in contrast with its extensively studied role as a downstream transcriptional regulator in DNA damage repair. We highlight an unrecognized role of p53 in directing DNA repair dynamics and integrity and suggest a parallel mode of p53 tumor suppression apart from its function as a transcription factor. [ABSTRACT FROM AUTHOR]

Background: In humans, multiple researchers have not only determined that there is a relationship between urinary incontinence (UI) and lower back pain (LBP), but that by treating the LBP, clinicians are able to improve or resolve the UI. Up until now, no equivalent canine research has investigated whether treatment of LBP can improve the clinical signs of acquired, non-neurologic UI in dogs. Aim: To determine if a relationship exists between LBP and urethral sphincter mechanism incompetence (USMI) in dogs. Methods: Review of medical records of all patients that presented to Points East West Veterinary Services with a history of naturally occurring acquired UI from May 2013 to December 2019. Thirty-nine patients treated for LBP using combined acupuncture and manual therapy, and 33/39 patients that also received concurrent photobiomodulation (PBM) therapy, qualified for this study. Results: Treated patients showed a statistically significant reduction in both the frequency (p < 0.01) and volume (p < 0.01) of UI episodes. Treatment responses ranged from no improvement, to complete resolution of the USMI clinical signs. Conclusion: The reduction of USMI clinical signs following LBP treatment suggests a relationship between these two conditions. Combined acupuncture, manual therapy, with or without PBM was shown to be an effective treatment for USMI. By corollary, USMI incontinence should be considered a potential pain symptom. [ABSTRACT FROM AUTHOR]

Lenin's theories and tactics are specific to the early twentieth century and cannot be repeated. His project should be considered in terms of its methodology, its understanding of capitalism, the political agency of the working class and the geo-political structures of economic and political power. Lenin combined political economy, geo-politics, political organisation and a sociology of social structure to form an innovative revolutionary praxis. He was correct in his appraisal of the social forces in support of revolutions in Russia. But he provided an over-optimistic prediction for the disintegration of monopoly capitalism and a partial analysis of the working classes in the advanced capitalist countries. His political approach requires a redefinition of countervailing forces and class alliances and a shift of focus away from the semi-periphery to the "strongest links" in the capitalist chain. His proposals for a "party of a new type" and the "dictatorship of the proletariat" require revision. A "renewal" of Lenin has to consider the contradictions of global capitalism and the re-territorialisation of classes. The author considers that a "return to Lenin" is not to adopt his policies but a prompt to reinvent a socialist political and economic vision derived from Marx's analysis of capitalism. [ABSTRACT FROM AUTHOR]

Scavenger receptors are pattern recognition receptors that recognize both foreign and self-ligands, and initiate different mechanisms of cellular activation, often as co-receptors. The function of scavenger receptor CD36 in the immune system has mostly been studied in macrophages but it is also highly expressed by innate type B cells where its function is less explored. Here we report that CD36 is involved in macro-autophagy/autophagy in B cells, and in its absence, the humoral immune response is impaired. We found that CD36-deficient B cells exhibit a significantly reduced plasma cell formation, proliferation, mitochondrial mobilization and oxidative phosphorylation. These changes were accompanied by impaired initiation of autophagy, and we found that CD36 regulated autophagy and colocalized with autophagosome membrane protein MAP1LC3/LC3 (microtubule-associated protein 1 light chain 3). When we investigated T-cell-dependent immune responses, we found that mice with CD36 deficiency, specifically in B cells, exhibited attenuated germinal center responses, class switching, and antibody production as well as autophagosome formation. These findings establish a critical role for CD36 in B cell responses and may also contribute to our understanding of CD36-mediated autophagy in other cells as well as in B cell lymphomas that have been shown to express the receptor. Abbreviations: AICDA/AID: activation-induced cytidine deaminase; ATG5: autophagy related 5; ATP: adenosine triphosphate; BCR: B-cell receptor; CPG: unmethylated cytosine-guanosine; CQ: chloroquine; DC: dendritic cells; FOB: follicular B cells; GC: germinal center; Ig: immunoglobulin; LPS: lipopolysaccharide; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MFI: mean fluorescence intensity; MZB: marginal zone B cells; NP-CGG: 4-hydroxy-3-nitrophenylacetyl-chicken gamma globulin; OCR: oxygen consumption rate; oxLDL: oxidized low-density lipoprotein; PC: plasma cells; Rapa: rapamycin; SQSTM1/p62: sequestosome 1; SRBC: sheep red blood cells; Tfh: follicular helper T cells; TLR: toll-like receptor. [ABSTRACT FROM AUTHOR]

Phishing emails pose a serious threat to individuals and organizations. Users' ability to identify phishing emails is critical to avoid becoming victims of these attacks. The current study examined the effectiveness of a short online phishing training program designed to help users identify phishing emails. Half of the participants were in the training group and the other half worked on a control filler task. The training group's sensitivity (d′) at correctly classifying emails as legitimate or phishing increased by 1.14 whereas the control group's sensitivity increased by only 0.48. This difference in d' changes was significant, t (38) = 2.05, p =.048. This improvement in performance was likely due to users learning how to check reliable cues and interpret them. Despite a sizeable improvement in detecting phishing emails, the training group correctly classified only about two-thirds of phishing emails. Accordingly, a short training program appears beneficial, but a more comprehensive training program would be needed to reduce vulnerability to an acceptable level. [ABSTRACT FROM AUTHOR]

This paper empirically examines the relations between homicide rates by age (adults 18 to 24 and adults 25 or older), the tattoo shop density, on-site and off-site alcohol outlets, and disadvantage. It offers an additional explanation for the relation between alcohol outlets and homicide besides alcohol availability and consumption being facilitators of such lethal violence, suggesting that these businesses are a proxy for attracting those most prone to violent behavior. The analysis estimated linear pooled cross-sectional time series models to test the relations between age-specific homicide rates and tattoo shop density, on-site alcohol density, off-site alcohol density, and a multidimensional measure of disadvantage. These relations were examined among 88 of the largest cities in the United States for the years 1998 to 2006 (city-years = 792). The findings showed positive relations between homicides rates involving young adults 18 to 24 years of age, off-site alcohol outlets, tattoo shops, controlling for disadvantage. Findings suggest business establishments that attract young adults increase the likelihood of lethal violence not solely because of the availability and consumption of alcohol, but by increasing the convergence in space and time of motivated offenders and suitable targets, with limited or absent capable guardianship. [ABSTRACT FROM AUTHOR]

In vitro protein folding is a complex process which often results in protein aggregation, low yields and low specific activity. Here we report the use of nanoscale exoshells (tES) to provide complementary nanoenvironments for the folding and release of 12 highly diverse protein substrates ranging from small protein toxins to human albumin, a dimeric protein (alkaline phosphatase), a trimeric ion channel (Omp2a) and the tetrameric tumor suppressor, p53. These proteins represent a unique diversity in size, volume, disulfide linkages, isoelectric point and multi versus monomeric nature of their functional units. Protein encapsulation within tES increased crude soluble yield (3-fold to >100-fold), functional yield (2-fold to >100-fold) and specific activity (3-fold to >100-fold) for all the proteins tested. The average soluble yield was 6.5 mg/100 mg of tES with charge complementation between the tES internal cavity and the protein substrate being the primary determinant of functional folding. Our results confirm the importance of nanoscale electrostatic effects and provide a solution for folding proteins in vitro. In vitro protein folding can often result in aggregation and low yields. Here the authors use nanoscale exoshells to improve soluble yield, functional yield and specific activity of folded proteins. [ABSTRACT FROM AUTHOR]

Lenin transposed Marx's analysis of capitalism from the advanced capitalist economies to the dependent colonial countries. He combined political economy, geopolitics, political organisation and a sociology of social structure to form an innovative revolutionary praxis. The expansion of Western capitalism shifted the social and political contradictions to countries moving from feudalism to capitalism. Lenin was correct in his appraisal of the social forces in support of a bourgeois revolution. But he provided an over-optimistic prediction for the disintegration of monopoly capitalism and only a partial analysis of the working classes in the advanced capitalist countries. His political approach requires a redefinition of countervailing forces and class alliances and a shift of focus from the semi-periphery to the 'strongest links' in the capitalist chain. A 'return to Lenin' is not to adopt his policies but a prompt to reinvent a socialist sociological vision derived from the expectations of the Enlightenment and Marx's analysis of capitalism. [ABSTRACT FROM AUTHOR]

Purpose: To develop a novel, target agnostic liposome click membrane permeability assay (LCMPA) using liposome encapsulating copper free click reagent dibenzo cyclooctyne biotin (DBCO-Biotin) to conjugate azido modified peptides that may effectively translocate from extravesicular space into the liposome lumen. Method: DBCO-Biotin liposomes were prepared with egg phosphatidylcholine and cholesterol by lipid film rehydration, freeze/thaw followed by extrusion. Size of DBCO-Biotin liposomes were characterized with dynamic light scattering. Results: The permeable peptides representing energy independent mechanism of permeability showed higher biotinylation in LCMPA. Individual peptide permeability results from LCMPA correlated well with shifts in potency in cellular versus biochemical assays (i.e., cellular/ biochemical ratio) demonstrating quantitative correlation to intracellular barrier in intact cells. Conclusion: The study provides a novel membrane permeability assay that has potential to evaluate energy independent transport of diverse peptides. [ABSTRACT FROM AUTHOR]

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Tumor-associated macrophages (TAMs) can have protumor properties, including suppressing immune responses, promoting vascularization and, consequently, augmenting tumor progression. To stop TAM-mediated immunosuppression, we use a novel treatment by injecting antibodies specific for scavenger receptor MARCO, which is expressed on a specific subpopulation of TAMs in the tumor. We now report the location of this TAM as well as the pleiotropic mechanism of action of anti-MARCO antibody treatment on tumor progression and further show that this is potentially relevant to humans. Using specific targeting, we observed decreased tumor vascularization, a switch in the metabolic program of MARCO-expressing macrophages, and activation of natural killer (NK) cell killing through TNF-related apoptosis-inducing ligand (TRAIL). This latter activity reverses the effect of melanoma cell-conditioned macrophages in blocking NK activation and synergizes with T cell-directed immunotherapy, such as antibodies to PD-1 or PD-L1, to enhance tumor killing. Our study thus reveals an approach to targeting the immunosuppressive tumor microenvironment with monoclonal antibodies to enhance NK cell activation and NK cell-mediated killing. This can complement existing T cell-directed immunotherapy, providing a promising approach to combinatorial immunotherapy for cancer. [ABSTRACT FROM AUTHOR]

An introduction to the journal's special issue is presented in which the guest editors discuss the use of the system dynamics approach (SD).

Rational: cMet is abnormally regulated in gastrointestinal cancer, and is associated with increased invasiveness of the disease and poor overall survival. There are indications that targeted therapy against cMet, alone or in combination with additional cancer therapies, can help improve treatment outcome. Thus, in the present study we investigated the therapeutic efficacy of a novel cMet-targeting antibody therapy in gastrointestinal cancer models, and assessed potential augmenting effects in combination with tyrosine kinase inhibitor (TKI) targeted therapy or radiotherapy. Methods: Three different cMet-targeting antibodies were first characterized with respect to antigen binding and effects on cell viability in vitro. The best performing candidate seeMet 12 was then further assessed for effects on colorectal cancer cell growth, proliferation and migration. Combinations with the TKI-inhibitor sorafenib or external beam radiotherapy were then evaluated for potential additive or synergistic effects in vitro using monolayer- and multicellular tumor spheroid assays. Finally, the combination of seeMet 12 and radiotherapy was evaluated in vivo in a proof-of-concept colorectal cancer xenograft study. Results: Dose-dependent therapeutic effects were demonstrated for all three cMet-targeting antibodies. Monotherapy using seeMet 12 resulted in impaired cellular migration/proliferation and reduced tumor spheroid growth. Moreover, seeMet 12 was able to potentiate therapeutic effects in vitro for both sorafenib and radiotherapy treatments. Finally, the in vivo therapy study demonstrated promising results, where a combination of seeMet 12 and fractionated radiotherapy increased median survival by 79% compared to radiotherapy alone, and tripled maximum survival. Conclusion: The novel anti-cMet antibody seeMet 12 demonstrated therapeutic effects in cMet positive gastrointestinal cancer cells in vitro. Moreover, the addition of seeMet 12 augmented the effects of sorafenib and radiotherapy. An in vivo proof-of-concept study of seeMet 12 and radiotherapy further validated the results. Thus, cMet-targeted therapy should be further explored as a promising approach to increase therapeutic effects, circumvent treatment resistance, and reduce side effects. [ABSTRACT FROM AUTHOR]

Historical materialism envisages law-like tendencies ('scientific' Marxism) promoting the development of productive forces and, concurrently, a political praxis ('active' Marxism) requiring human intervention. These positions give rise to conflicting interpretations of Marxism: first to understand society, second to change it – to abolish economic exploitation. The twentieth century witnessed a shift in the locus of the contradictions of capitalism to the economically dependent territories of the imperial powers. Socialist parties, when in power and adopting a Leninist political praxis, furthered modernisation and were successful in reducing economic exploitation. The paper addresses the relationship between the scientific and praxis components of Marxism in contemporary global capitalism. It considers post-Marxist interpretations of the changing class structure, the rise of identity politics and the evolving nature of capital. Forms of domination, oppression and discrimination (bureaucracy, patriarchy, racism, militarism and credentialism) give rise to their own distinctive forms of power relations. It is contended that they should not be equated with Marx's crucial insight into the nature of economic exploitation. Many current Marxist (and 'post-Marxist') writers adopt a 'scientific' position emphasising the inherent contradictions of capitalism. The author claims that without appropriate political praxis, the resolution of such contradictions is unlikely to transcend capitalism. [ABSTRACT FROM AUTHOR]

Disaster victim identification following a mass fatality incident is focussed on identifying the deceased and returning them to their families as quickly as possible, while gathering as much information as practical to aid investigators in establishing the cause of the incident. Ante-mortem data is gathered and compared with the post-mortem data obtained in order to positively identify the deceased. This paper presents results from a study concerned with the first part of the process of identifying the deceased—the triage or Primary Survey and how this can be done without access to hospital facilities such as conventional X-ray imaging or computed tomography. In particular, this study focuses on the imaging undertaken prior to the opening of the body bag by a multidisciplinary team, and how this imaging can assist particularly when forensic anthropologists are involved in the identification process. There are several advantages to imaging the body bags before they are opened and one of the most important is safety. Thus, this paper examines the viability of using a baggage scanner as a practical resource for X-ray imaging, as many regions worldwide may not be able to access conventional imaging equipment. Baggage scanners are readily available and found in airports and various government buildings. The baggage scanner is particularly suited to this task and produces images that can be used by forensic anthropologists to distinguish between human and non-human remains, identify items of evidence and personal effects, and even perform a preliminary or partial biological profile. When considering their response plans, emergency responders should consider including baggage scanners as a contingency for screening body bags if no other imaging system is available. [ABSTRACT FROM AUTHOR]

Proteins require an optimal balance of conformational flexibility and stability in their native environment to ensure their biological functions. A striking example is spidroins, spider silk proteins, which are stored at extremely high concentrations in soluble form, yet undergo amyloid‐like aggregation during spinning. Here, we elucidate the stability of the highly soluble N‐terminal domain (NT) of major ampullate spidroin 1 in the Escherichia coli cytosol as well as in inclusion bodies containing fibrillar aggregates. Surprisingly, we find that NT, despite being largely composed of amyloidogenic sequences, showed no signs of concentration‐dependent aggregation. Using a novel intracellular hydrogen/deuterium exchange mass spectrometry (HDX‐MS) approach, we reveal that NT adopts a tight fold in the E. coli cytosol and in this manner conceals its aggregation‐prone regions by maintaining a tight fold under crowded conditions. Fusion of NT to the unstructured amyloid‐forming Aβ40 peptide, on the other hand, results in the formation of fibrillar aggregates. However, HDX‐MS indicates that the NT domain is only partially incorporated into these aggregates in vivo. We conclude that NT is able to control its aggregation to remain functional under the extreme conditions in the spider silk gland. [ABSTRACT FROM AUTHOR]

Family business coaching is characterised by a blended approach in coaching. There are growing concerns about which comes first, family or business (Shams & Lane, 2016) and this leads to the critical question - if a team approach in family business can address both a family and their business simultaneously? Team coaching refers to the capacity building of a team, team effectiveness, team values and shared behavioural norms (Britton, 2015). Team coaching explores issues related to individuals in a team as well as a team collectively, as such, team coaching is the most effective intervention for improving family functions and the business functions in a family business. This article aims to highlight the need to explore the positive influence of team coaching to enhance the growth of a family business, and to help improving and maintaining a cohesive family business unit. We have used an example and an integrated team coaching model to justify that team coaching can provide the means to optimise collective talent of a family in a business context. The discussion supports the positive influence of team coaching on a family team's performance, and that this coaching approach enables a family to increase their collective effort to achieve successful business outcomes. [ABSTRACT FROM AUTHOR]

The ParB-parS partition complexes that bacterial replicons use to ensure their faithful inheritance also find employment in visualization of DNA loci, as less intrusive alternatives to fluorescent repressor-operator systems. The ability of ParB molecules to interact via their N-terminal domains and to bind to non-specific DNA enables expansion of the initial complex to a size both functional in partition and, via fusion to fluorescent peptides, visible by light microscopy. We have investigated whether it is possible to dispense with the need to insert parS in the genomic locus of interest, by determining whether ParB fused to proteins that bind specifically to natural DNA sequences can still assemble visible complexes. In yeast cells, coproduction of fusions of ParB to a fluorescent peptide and to a TALE protein targeting an endogenous sequence did not yield visible foci; nor did any of several variants of these components. In E.coli, coproduction of fusions of SopB (F plasmid ParB) to fluorescent peptide, and to dCas9 together with specific guide RNAs, likewise yielded no foci. The result of coproducing analogous fusions of SopB proteins with distinct binding specificities was also negative. Our observations imply that in order to assemble higher order partition complexes, ParB proteins need specific activation through binding to their cognate parS sites. [ABSTRACT FROM AUTHOR]

Gain of function (GOF) DNA binding domain (DBD) mutations of TP53 upregulate chromatin regulatory genes that promote genome-wide histone methylation and acetylation. Here, we therapeutically exploit the oncogenic GOF mechanisms of p53 codon 158 (Arg158) mutation, a DBD mutant found to be prevalent in lung carcinomas. Using high throughput compound screening and combination analyses, we uncover that acetylating mutp53R158G could render cancers susceptible to cisplatin-induced DNA stress. Acetylation of mutp53R158G alters DNA binding motifs and upregulates TRAIP, a RING domain-containing E3 ubiquitin ligase which dephosphorylates IĸB and impedes nuclear translocation of RelA (p65), thus repressing oncogenic nuclear factor kappa-B (NF-ĸB) signaling and inducing apoptosis. Given that this mechanism of cytotoxic vulnerability appears inapt in p53 wild-type (WT) or other hotspot GOF mutp53 cells, our work provides a therapeutic opportunity specific to Arg158-mutp53 tumors utilizing a regimen consisting of DNA-damaging agents and mutp53 acetylators, which is currently being pursued clinically. Codon 158 gain-of-function mutant p53 (158-mutp53) promotes tumourigenesis in lung cancer. Here, the authors show that 158-mutp53 render cancers sensitive to cisplatin and p53 acetylation agents through a mechanism where acetylated mutant p53 upregulates TRAIP and inhibits NF-ĸB signaling. [ABSTRACT FROM AUTHOR]

Invariant natural killer T (iNKT) cells serve as early rapid responders in the innate immune response to self-derived autoantigens and pathogen-derived danger signals and antigens. iNKT cells can serve both as helpers for effector B cells and negatively regulate autoreactive B cells. Specifically, iNKT cells drive B cell proliferation, class switch, and antibody production to induce primary antigen-specific immune responses. On the other hand, inflammasome-mediated activation drives accumulation of neutrophils, which license iNKT cells to negatively regulate autoreactive B cells via Fas ligand (FasL). This positions iNKT cells at an apex to support or inhibit B cell responses in inflammation. However, it is unknown which effector mechanism dominates in the face of cognate glycolipid activation during chronic inflammation, as might result from glycolipid vaccination or infection during chronic autoimmune disease. We stimulated iNKT cells by cognate glycolipid antigen α-galactosylceramide (αGalCer) and measured B cell activation during interleukin 18 (IL-18)-induced chronic inflammation. Moreover, glycolipid-activated iNKT cells increased the serum concentration of autoantibodies, frequency of germinal center (GC) B cells, and antigen-specific plasma cells induced during chronic IL-18-mediated inflammation, as compared with IL-18 alone. Further, activation of iNKT cells via cognate glycolipid during IL-18-mediated inflammation overrides the licensing function of neutrophils, instead inducing iNKT follicular helper (iNKTfh) cells that in turn promote autoimmunity. Thus, our data demonstrate that glycolipids which engage iNKT cells support antigen-specific B cell help during inflammasome-mediated inflammation. [ABSTRACT FROM AUTHOR]

Background: Precision therapeutics continuously make advances in cancer therapy, and a field of growing interest is the combination of targeted radionuclide therapy (TRNT) with potential radiosensitizing agents. This study evaluated whether the effects of in vitro TRNT, using the 177Lu-labeled anti-CD44v6 antibody AbN44v6, were potentiated by the novel stapled MDM2/X-p53 antagonist PM2. Materials and methods: Two wt p53 cell lines, HCT116 (colorectal carcinoma) and UM-SCC-74B (head and neck squamous cell carcinoma), expressing different levels of the target antigen, CD44v6, were used. Antigen-specific binding of 177Lu-AbN44v6 was initially verified in a 2D cell assay, after which the potential effects of unlabeled AbN44v6 on downstream phosphorylation of Erk1/2 were evaluated by western blotting. Further, the therapeutic effects of unlabeled AbN44v6, 177Lu-AbN44v6, PM2, or a combination (labeled/unlabeled AbN44v6 +/− PM2) were assessed in 3D multicellular tumor spheroid assays. Results: Radiolabeled antibody bound specifically to CD44v6 on both cell lines. Unlabeled AbN44v6 binding did not induce downstream phosphorylation of Erk1/2 at any of the concentrations tested, and repeated treatments with the unlabeled antibody did not result in any spheroid growth inhibition. 177Lu-AbN44v6 impaired spheroid growth in a dose-dependent and antigen-dependent manner. A single modality treatment with 20 μM of PM2 significantly impaired spheroid growth in both spheroid models. Furthermore, the combination of TRNT and PM2-based therapy proved significantly more potent than either monotherapy. In HCT116 spheroids, this resulted in a two- and threefold spheroid growth rate decrease for the combination of PM2 and 100 kBq 177Lu-AbN44v6 compared to monotherapies 14-day post treatment. In UM-SCC-74B spheroids, the combination therapy resulted in a reduction in spheroid size compared to the initial spheroid size 10-day post treatment. Conclusion: TRNT using 177Lu-AbN44v6 proved efficient in stalling spheroid growth in a dose-dependent and antigen-dependent manner, and PM2 treatment demonstrated a growth inhibitory effect as a monotherapy. Moreover, by combining TRNT with PM2-based therapy, therapeutic effects of TRNT were potentiated in a 3D multicellular tumor spheroid model. This proof-of-concept study exemplifies the strength and possibility of combining TRNT targeting CD44v6 with PM2-based therapy. [ABSTRACT FROM AUTHOR]

This special issue is focusing on the 'extraordinary ordinary' of everyday life in residential care. This is appropriate as daily life is not only the bread and butter but also the meat of the work. It is its main strength but also its main weakness. The residential care profession does not have its own distinct body of knowledge, and its status in the UK, unlike much of continental Europe, is low. The key to successful care lies primarily with the values and motivation of the workers. [ABSTRACT FROM AUTHOR]

Targeted degradation approaches such as proteolysis targeting chimeras (PROTACs) offer new ways to address disease through tackling challenging targets and with greater potency, efficacy, and specificity over traditional approaches. However, identification of high-affinity ligands to serve as PROTAC starting points remains challenging. As a complementary approach, we describe a class of molecules termed biological PROTACs (bioPROTACs)- engineered intracellular proteins consisting of a target-binding domain directly fused to an E3 ubiquitin ligase. Using GFP-tagged proteins as model substrates, we show that there is considerable flexibility in both the choice of substrate binders (binding positions, scaffold-class) and the E3 ligases. We then identified a highly effective bioPROTAC against an oncology target, proliferating cell nuclear antigen (PCNA) to elicit rapid and robust PCNA degradation and associated effects on DNA synthesis and cell cycle progression. Overall, bioPROTACs are powerful tools for interrogating degradation approaches, target biology, and potentially for making therapeutic impacts. [ABSTRACT FROM AUTHOR]

Membrane proteins engage in a variety of contacts with their surrounding lipids, but distinguishing between specifically bound lipids, and non‐specific, annular interactions is a challenging problem. Applying native mass spectrometry to three membrane protein complexes with different lipid‐binding properties, we explore the ability of detergents to compete with lipids bound in different environments. We show that lipids in annular positions on the presenilin homologue protease are subject to constant exchange with detergent. By contrast, detergent‐resistant lipids bound at the dimer interface in the leucine transporter show decreased koff rates in molecular dynamics simulations. Turning to the lipid flippase MurJ, we find that addition of the natural substrate lipid‐II results in the formation of a 1:1 protein–lipid complex, where the lipid cannot be displaced by detergent from the highly protected active site. In summary, we distinguish annular from non‐annular lipids based on their exchange rates in solution. [ABSTRACT FROM AUTHOR]