Experiments in becoming: corporeality, attunement and doing research

Human geography has become deeply interested in a range of research methods that focus on researchers’ corporeal engagement with their research sites. This interest has opened up an exciting set of research horizons, energising the discipline in a whole range of ways. Welcoming this engagement, this paper presents a series of meditations on the process of using the researcher’s corporeal learning as a research tool. Exploring two research projects, as well as the work of the photographer Nikki S Lee, it examines how the process of becoming corporeally capable might productively be framed as sets of ongoing experiments. Framing such engagements as experiments is a useful heuristic through which to think rigorously about what such research can claim as knowledge. More controversially, the paper argues that the heuristic of the experiment helps us to attend to the varying durations of becoming in ways that much existing work has discounted. Developing corporeal capacities – gaining a skill, becoming capable of doing a particular activity – involves becoming attuned to a range of thresholds, the crossing of which open up novel and frequently unexpected perspectives. Attunement to these thresholds does not arise simply through the process of mixing in and participating in a research site. It requires careful attention to the parameters of transformation involved in being able to participate. The paper explores how such parameters might be decided upon and calibrated as part of an ongoing engagement with a research site or event. Our aim is not to artificially restrict or constrain how human geographers approach their research design. Rather it is to encourage human geographers to show more courage in their use of corporeal based research methodologies

Historical Legacies in World Amphibian Diversity Revealed by the Turnover and Nestedness Components of Beta Diversity

Historic processes are expected to influence present diversity patterns in combination with contemporary environmental factors. We hypothesise that the joint use of beta diversity partitioning methods and a threshold-based approach may help reveal the effect of large-scale historic processes on present biodiversity. We partitioned intra-regional beta diversity into its turnover (differences in composition caused by species replacements) and nestedness-resultant (differences in species composition caused by species losses) components. We used piecewise regressions to show that, for amphibian beta diversity, two different world regions can be distinguished. Below parallel 37, beta diversity is dominated by turnover, while above parallel 37, beta diversity is dominated by nestedness. Notably, these regions are revealed when the piecewise regression method is applied to the relationship between latitude and the difference between the Last Glacial Maximum (LGM) and the present temperature but not when present energy-water factors are analysed. When this threshold effect of historic climatic change is partialled out, current energy-water variables become more relevant to the nestedness-resultant dissimilarity patterns, while mountainous areas are associated with higher spatial turnover. This result suggests that nested patterns are caused by species losses that are determined by physiological constraints, whereas turnover is associated with speciation and/or Pleistocene refugia. Thus, the new threshold-based view may help reveal the role of historic factors in shaping present amphibian beta diversity patterns

A whey protein-based multi-ingredient nutritional supplement stimulates gains in lean body mass and strength in healthy older men: A randomized controlled trial

Protein and other compounds can exert anabolic effects on skeletal muscle, particularly in conjunction with exercise. The objective of this study was to evaluate the efficacy of twice daily consumption of a protein-based, multi-ingredient nutritional supplement to increase strength and lean mass independent of, and in combination with, exercise in healthy older men. Forty-nine healthy older men (age: 73 ± 1 years [mean ± SEM]; BMI: 28.5 ± 1.5 kg/m2) were randomly allocated to 20 weeks of twice daily consumption of either a nutritional supplement (SUPP; n = 25; 30 g whey protein, 2.5 g creatine, 500 IU vitamin D, 400 mg calcium, and 1500 mg n-3 PUFA with 700 mg as eicosapentanoic acid and 445 mg as docosahexanoic acid); or a control (n = 24; CON; 22 g of maltodextrin). The study had two phases. Phase 1 was 6 weeks of SUPP or CON alone. Phase 2 was a 12 week continuation of the SUPP/CON but in combination with exercise: SUPP + EX or CON + EX. Isotonic strength (one repetition maximum [1RM]) and lean body mass (LBM) were the primary outcomes. In Phase 1 only the SUPP group gained strength (Σ1RM, SUPP: +14 ± 4 kg, CON: +3 ± 2 kg, P < 0.001) and lean mass (LBM, +1.2 ± 0.3 kg, CON: -0.1 ± 0.2 kg, P < 0.001). Although both groups gained strength during Phase 2, upon completion of the study upper body strength was greater in the SUPP group compared to the CON group (Σ upper body 1RM: 119 ± 4 vs. 109 ± 5 kg, P = 0.039). We conclude that twice daily consumption of a multi-ingredient nutritional supplement increased muscle strength and lean mass in older men. Increases in strength were enhanced further with exercise training

Clamp loader ATPases and the evolution of DNA replication machinery

Clamp loaders are pentameric ATPases of the AAA+ family that operate to ensure processive DNA replication. They do so by loading onto DNA the ring-shaped sliding clamps that tether the polymerase to the DNA. Structural and biochemical analysis of clamp loaders has shown how, despite differences in composition across different branches of life, all clamp loaders undergo the same concerted conformational transformations, which generate a binding surface for the open clamp and an internal spiral chamber into which the DNA at the replication fork can slide, triggering ATP hydrolysis, release of the clamp loader, and closure of the clamp round the DNA. We review here the current understanding of the clamp loader mechanism and discuss the implications of the differences between clamp loaders from the different branches of life

Polo kinase recruitment via the constitutive centromere-associated network at the kinetochore elevates centromeric RNA

The kinetochore, a multi-protein complex assembled on centromeres, is essential to segregate chromosomes during cell division. Deficiencies in kinetochore function can lead to chromosomal instability and aneuploidy-a hallmark of cancer cells. Kinetochore function is controlled by recruitment of regulatory proteins, many of which have been documented, however their function often remains uncharacterized and many are yet to be identified. To identify candidates of kinetochore regulation we used a proteome-wide protein association strategy in budding yeast and detected many proteins that are involved in post-translational modifications such as kinases, phosphatases and histone modifiers. We focused on the Polo-like kinase, Cdc5, and interrogated which cellular components were sensitive to constitutive Cdc5 localization. The kinetochore is particularly sensitive to constitutive Cdc5 kinase activity. Targeting Cdc5 to different kinetochore subcomplexes produced diverse phenotypes, consistent with multiple distinct functions at the kinetochore. We show that targeting Cdc5 to the inner kinetochore, the constitutive centromere-associated network (CCAN), increases the levels of centromeric RNA via an SPT4 dependent mechanism

Global histone modification fingerprinting in human cells using epigenetic reverse phase protein array

The balance between acetylation and deacetylation of histone proteins plays a critical role in the regulation of genomic functions. Aberrations in global levels of histone modifications are linked to carcinogenesis and are currently the focus of intense scrutiny and translational research investments to develop new therapies, which can modify complex disease pathophysiology through epigenetic control. However, despite significant progress in our understanding of the molecular mechanisms of epigenetic machinery in various genomic contexts and cell types, the links between epigenetic modifications and cellular phenotypes are far from being clear. For example, enzymes controlling histone modifications utilize key cellular metabolites associated with intra- and extracellular feedback loops, adding a further layer of complexity to this process. Meanwhile, it has become increasingly evident that new assay technologies which provide robust and precise measurement of global histone modifications are required, for at least two pressing reasons: firstly, many approved drugs are known to influence histone modifications and new cancer therapies are increasingly being developed towards targeting histone deacetylases (HDACs) and other epigenetic readers and writers. Therefore, robust assays for fingerprinting the global effects of such drugs on preclinical cell, organoid and in vivo models is required; and secondly, robust histone-fingerprinting assays applicable to patient samples may afford the development of next-generation diagnostic and prognostic tools. In our study, we have used a panel of monoclonal antibodies to determine the relative changes in the global abundance of post-translational modifications on histones purified from cancer cell lines treated with HDAC inhibitors using a novel technique, called epigenetic reverse phase protein array. We observed a robust increase in acetylation levels within 2–24 h after inhibition of HDACs in different cancer cell lines. Moreover, when these cells were treated with N-acetylated amino acids in addition to HDACs, we detected a further increase in histone acetylation, demonstrating that these molecules could be utilized as donors of the acetyl moiety for protein acetylation. Consequently, this study not only offers a novel assay for diagnostics and drug screening but also warrants further research of the novel class of inexpensive, non-toxic natural compounds that could potentiate the effects of HDAC inhibitors and is therefore of interest for cancer therapeutics

An intergenerational approach in the promotion of balance and strength for fall prevention: a mini-review

The risk of sustaining a fall is particularly high in children and seniors. Deficits in postural control and muscle strength either due to maturation, secular declines or biologic aging are two important intrinsic risk factors for falls. During life span, performance in variables of static postural control follows a U-shaped curve with children and seniors showing larger postural sway than healthy adults. Measures of dynamic postural control (i.e. gait speed) as well as isometric (i.e. maximal strength) and dynamic muscle strength (i.e. muscular power) follow an inverted U-shaped curve during life span, again with children and seniors showing deficits compared to adults. There is evidence that particularly balance and resistance training are effective in counteracting these neuromuscular constraints in both children and seniors. Further, these training regimens are able to reduce the rate of sustaining injuries and falls in these age groups. An intergenerational intervention approach is suggested to enhance the effectiveness of these training programs by improving compliance and increasing motivation of children and seniors exercising together. Thus, the objectives of this mini-review are: (1) to describe the epidemiology and etiology of falls in children and seniors; (2) to discuss training programs that counteract intrinsic fall risk factors by reducing the rate of falling, and (3) to present an intergenerational approach that has the potential to make training programs even more effective by including children and seniors together in one exercise group

Protocol for serious fall injury adjudication in the Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE) study.

BackgroundThis paper describes a protocol for determining the incidence of serious fall injuries for Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE), a large, multicenter pragmatic clinical trial with limited resources for event adjudication. We describe how administrative data (from participating health systems and Medicare claims) can be used to confirm participant-reported events, with more time- and resource-intensive full-text medical record data used only on an "as-needed" basis.MethodsSTRIDE is a pragmatic cluster-randomized controlled trial involving 5451 participants age ≥ 70 and at increased risk for falls, served by 86 primary care practices in 10 US health systems. The STRIDE intervention involves a nurse falls care manager who assesses a participant's underlying risks for falls, suggests interventions using motivational interviewing, and then creates, implements and longitudinally follows up on an individualized care plan with the participant (and caregiver when appropriate), in partnership with the participant's primary care provider. STRIDE's primary outcome is serious fall injuries, defined as a fall resulting in: (1) medical attention billable according to Medicare guidelines with a) fracture (excluding isolated thoracic vertebral and/or lumbar vertebral fracture), b) joint dislocation, or c) cut requiring closure; OR (2) overnight hospitalization with a) head injury, b) sprain or strain, c) bruising or swelling, or d) other injury determined to be "serious" (i.e., burn, rhabdomyolysis, or internal injury). Two sources of data are required to confirm a serious fall injury. The primary data source is the participant's self-report of a fall leading to medical attention, identified during telephone interview every 4 months, with the confirmatory source being (1) administrative data capturing encounters at the participating health systems or Medicare claims and/or (2) the full text of medical records requested only as needed.DiscussionAdjudication is ongoing, with over 1000 potentially qualifying events adjudicated to date. Administrative data can be successfully used for adjudication, as part of a hybrid approach that retrieves full-text medical records only when needed. With the continued refinement and availability of administrative data sources, future studies may be able to use administrative data completely in lieu of medical record review to maximize the quality of adjudication with finite resources.Trial registrationClinicalTrials.gov (NCT02475850)