Competing protein-protein interactions regulate binding of Hsp27 to its client protein tau.

Small heat shock proteins (sHSPs) are a class of oligomeric molecular chaperones that limit protein aggregation. However, it is often not clear where sHSPs bind on their client proteins or how these protein-protein interactions (PPIs) are regulated. Here, we map the PPIs between human Hsp27 and the microtubule-associated protein tau (MAPT/tau). We find that Hsp27 selectively recognizes two aggregation-prone regions of tau, using the conserved β4-β8 cleft of its alpha-crystallin domain. The β4-β8 region is also the site of Hsp27-Hsp27 interactions, suggesting that competitive PPIs may be an important regulatory paradigm. Indeed, we find that each of the individual PPIs are relatively weak and that competition for shared sites seems to control both client binding and Hsp27 oligomerization. These findings highlight the importance of multiple, competitive PPIs in the function of Hsp27 and suggest that the β4-β8 groove acts as a tunable sensor for clients

Enhancing e-Infrastructures with Advanced Technical Computing: Parallel MATLAB® on the Grid

MATLAB® is widely used within the engineering and scientific fields as the language and environment for technical computing, while collaborative Grid computing on e-Infrastructures is used by scientific communities to deliver a faster time to solution. MATLAB allows users to express parallelism in their applications, and then execute code on multiprocessor environments such as large-scale e-Infrastructures. This paper demonstrates the integration of MATLAB and Grid technology with a representative implementation that uses gLite middleware to run parallel programs. Experimental results highlight the increases in productivity and performance that users obtain with MATLAB parallel computing on Grids

Competitiveness and sustainability: can ‘smart city regionalism’ square the circle?

Increasingly, the widely established, globalisation-driven agenda of economic competitiveness meets a growing concern with sustainability. Yet, the practical and conceptual co-existence—or fusion—of these two agendas is not always easy. This includes finding and operationalising the ‘right’ scale of governance, an important question for the pursuit of the distinctly transscalar nature of these two policy fields. ‘New regionalism’ has increasingly been discussed as a pragmatic way of tackling the variable spatialities associated with these policy fields and their changing articulation. This paper introduces ‘smart (new) city-regionalism’, derived from the principles of smart growth and new regionalism, as a policy-shaping mechanism and analytical framework. It brings together the rationales, agreed principles and legitimacies of publicly negotiated polity with collaborative, network-based and policy-driven spatiality. The notion of ‘smartness’, as suggested here as central feature, goes beyond the implicit meaning of ‘smart’ as in ‘smart growth’. When introduced in the later 1990s the term embraced a focus on planning and transport. Since then, the adjective ‘smart’ has become used ever more widely, advocating innovativeness, participation, collaboration and co-ordination. The resulting ‘smart city regionalism’ is circumscribed by the interface between the sectorality and territoriality of policy-making processes. Using the examples of Vancouver and Seattle, the paper looks at the effects of the resulting specific local conditions on adopting ‘smartness’ in the scalar positioning of policy-making

Dispensability of Escherichia coli's latent pathways

Gene-knockout experiments on single-cell organisms have established that expression of a substantial fraction of genes is not needed for optimal growth. This problem acquired a new dimension with the recent discovery that environmental and genetic perturbations of the bacterium Escherichia coli are followed by the temporary activation of a large number of latent metabolic pathways, which suggests the hypothesis that temporarily activated reactions impact growth and hence facilitate adaptation in the presence of perturbations. Here we test this hypothesis computationally and find, surprisingly, that the availability of latent pathways consistently offers no growth advantage, and tends in fact to inhibit growth after genetic perturbations. This is shown to be true even for latent pathways with a known function in alternate conditions, thus extending the significance of this adverse effect beyond apparently nonessential genes. These findings raise the possibility that latent pathway activation is in fact derivative of another, potentially suboptimal, adaptive response

eQuilibrator—the biochemical thermodynamics calculator

The laws of thermodynamics constrain the action of biochemical systems. However, thermodynamic data on biochemical compounds can be difficult to find and is cumbersome to perform calculations with manually. Even simple thermodynamic questions like ‘how much Gibbs energy is released by ATP hydrolysis at pH 5?’ are complicated excessively by the search for accurate data. To address this problem, eQuilibrator couples a comprehensive and accurate database of thermodynamic properties of biochemical compounds and reactions with a simple and powerful online search and calculation interface. The web interface to eQuilibrator (http://equilibrator.weizmann.ac.il) enables easy calculation of Gibbs energies of compounds and reactions given arbitrary pH, ionic strength and metabolite concentrations. The eQuilibrator code is open-source and all thermodynamic source data are freely downloadable in standard formats. Here we describe the database characteristics and implementation and demonstrate its use

Integrating genetic and oral histories of Southwest Indian populations

India is home to thousands of ethno-linguistically distinct groups, many maintaining strong self-identities that derive from oral traditions and histories. However, these traditions and histories are only partially documented and are in danger of being lost over time. More recently, genetic studies have established the existence of ancestry gradients derived from both western and eastern Eurasia as well as evidence of practices such as endogamy and consanguinity, revealing complexity in the regional population structure with consequences for the health landscape of local populations. Despite the increase in genome-wide data from India, there is still sparse sampling across finer-scale geographic regions leading to gaps in our understanding of how and when present-day genetic structure came into existence. To address the gaps in genetic and oral histories, we analyzed whole-genome sequences of 70 individuals from Southwest India identifying as Bunt, Kodava, and Nair—populations that share unique oral histories and origin narratives—and 78 recent immigrants to the United States with Kodava ancestry as part of a community-led initiative. We additionally generated genome-wide data from 10 individuals self-identifying as Kapla, a population from the same region that is socio-culturally different to the other three study populations. We supplemented existing but limited anthropological records on these populations with oral history accounts narrated by community members and non-member contacts during sampling and subsequent community engagement. Overall, we find that components of genetic ancestry are relatively homogeneous among the Bunt, Kodava, and Nair populations and comparable to neighboring populations in India, which motivates further investigation of non-local origin narratives referenced in their oral histories. A notable exception is the Kapla population, with a higher proportion of ancestry represented in the Onge from the Andaman Islands, similar to several South Indian tribal populations. Utilizing haplotype-based methods, we find latent genetic structure across South India, including the sampled populations available under aCC-BY-NC-ND 4.0 International license.was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made bioRxiv preprint doi: https://doi.org/10.1101/2022.07.06.498959; this version posted July 7, 2022. The copyright holder for this preprint (which 2 from Southwest India, suggesting more recent population structure between geographically proximal populations in the region. This study represents an attempt for community-engaged anthropological and genetic investigations in India and presents results from both sources, underscoring the need to recognize that oral and genetic histories should not be expected to overlap. Ultimately, oral traditions and unique self-identities, such as those held close by some of the study populations, warrant more community-driven anthropological investigations to better understand how they originate and their relationship to genetic histories

Mapping interactions with the chaperone network reveals factors that protect against tau aggregation.

A network of molecular chaperones is known to bind proteins ('clients') and balance their folding, function and turnover. However, it is often unclear which chaperones are critical for selective recognition of individual clients. It is also not clear why these key chaperones might fail in protein-aggregation diseases. Here, we utilized human microtubule-associated protein tau (MAPT or tau) as a model client to survey interactions between ~30 purified chaperones and ~20 disease-associated tau variants (~600 combinations). From this large-scale analysis, we identified human DnaJA2 as an unexpected, but potent, inhibitor of tau aggregation. DnaJA2 levels were correlated with tau pathology in human brains, supporting the idea that it is an important regulator of tau homeostasis. Of note, we found that some disease-associated tau variants were relatively immune to interactions with chaperones, suggesting a model in which avoiding physical recognition by chaperone networks may contribute to disease

A nurse-led model of care to improve access to contraception and abortion in rural general practice: Co-design with consumers and providers.

AIM: To describe key features of a co-designed nurse-led model of care intended to improve access to early medication abortion and long-acting reversible contraception in rural Australian general practice. DESIGN: Co-design methodology informed by the Experience-Based Co-Design Framework. METHODS: Consumers, nurses, physicians and key women's health stakeholders participated in a co-design workshop focused on the patient journey in seeking contraception or abortion care. Data generated at the workshop were analysed using Braun and Clarkes' six-step process for thematic analysis. RESULTS: Fifty-two participants took part in the co-design workshop. Key recommendations regarding setting up the model included: raising awareness of the early medication abortion and contraceptive implant services, providing flexible booking options, ensuring appointment availability, providing training for reception staff and fostering good relationships with relevant local services. Recommendations for implementing the model were also identified, including the provision of accessible information, patient-approved communication processes that ensure privacy and safety, establishing roles and responsibilities, supporting consumer autonomy and having clear pathways for referrals and complications. CONCLUSION: Our approach to experience-based co-design ensured that consumer experiences, values and priorities, together with practitioner insights, were central to the development of a nurse-led model of care. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: The co-designed nurse-led model of care for contraception and medication abortion is one strategy to increase access to these essential reproductive health services, particularly in rural areas, while providing an opportunity for nurses to work to their full scope of practice. IMPACT: Nurse-led care has gained global recognition as an effective strategy to promote equitable access to sexual and reproductive healthcare. Still, nurse-led contraception and abortion have yet to be implemented andevaluated in Australian general practice. This study will inform the model of care to be implemented and evaluated as part of the ORIENT trial to be completed in 2025. REPORTING METHOD: Reported in line with the Standards for Reporting Qualitative Research (SRQR) checklist. PATIENT OR PUBLIC CONTRIBUTION: Two consumer representatives contributed to the development of the co-design methodology as members of the ORIENT Intervention Advisory Group Governance Committee

Myopathy associated BAG3 mutations lead to protein aggregation by stalling Hsp70 networks

BAG3 is a multi-domain hub that connects two classes of chaperones, small heat shock proteins (sHSPs) via two isoleucine-proline-valine (IPV) motifs and Hsp70 via a BAG domain.\ua0Mutations in either the IPV or BAG domain of BAG3 cause a dominant form of myopathy, characterized by protein aggregation in both skeletal and cardiac muscle tissues. Surprisingly, for both disease mutants, impaired chaperone binding is not sufficient to explain disease phenotypes. Recombinant mutants are correctly folded, show unaffected Hsp70 binding but are impaired in stimulating Hsp70-dependent client processing. As a consequence, the mutant BAG3 proteins become the node for a dominant gain of function causing aggregation of itself, Hsp70, Hsp70 clients and tiered interactors within the BAG3 interactome. Importantly, genetic and pharmaceutical interference with Hsp70 binding completely reverses stress-induced protein aggregation for both BAG3 mutations. Thus, the gain of function effects of BAG3 mutants act as Achilles heel of the HSP70 machinery