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Leopard density and determinants of space use in a farming landscape in South Africa

Protected areas are traditionally the foundation of conservation strategy, but land not formally protected is of particular importance for the conservation of large carnivores because of their typically wide-ranging nature. In South Africa, leopard (Panthera pardus) population decreases are thought to be occurring in areas of human development and intense negative interactions, but research is biased towards protected areas, with quantitative information on population sizes and trends in non-protected areas severely lacking. Using Spatially Explicit Capture-Recapture and occupancy techniques including 10 environmental and anthropogenic covariates, we analysed camera trap data from commercial farmland in South Africa where negative human-wildlife interactions are reported to be high. Our findings demonstrate that leopards persist at a moderate density (2.21 /100km2) and exhibit signs of avoidance from areas where lethal control measures are implemented. This suggests leopards have the potential to navigate mixed mosaic landscapes effectively, enhancing their chances of long-term survival and coexistence with humans. Mixed mosaics of agriculture that include crops, game and livestock farming should be encouraged and, providing lethal control is not ubiquitous in the landscape, chains of safer spaces should permit vital landscape connectivity. However, continuing to promote non-lethal mitigation techniques remains vital

The SUMO deconjugating peptidase Smt4 contributes to the mechanism required for transition from sister chromatid arm cohesion to sister chromatid pericentromere separation

The pericentromere chromatin protrudes orthogonally from the sister-sister chromosome arm axis. Pericentric protrusions are organized in a series of loops with the centromere at the apex, maximizing its ability to interact with stochastically growing and shortening kinetochore microtubules. Each pericentromere loop is ∼50 kb in size and is organized further into secondary loops that are displaced from the primary spindle axis. Cohesin and condensin are integral to mechanisms of loop formation and generating resistance to outward forces from kinesin motors and anti-parallel spindle microtubules. A major unanswered question is how the boundary between chromosome arms and the pericentromere is established and maintained. We used sister chromatid separation and dynamics of LacO arrays distal to the pericentromere to address this issue. Perturbation of chromatin spring components results in 2 distinct phenotypes. In cohesin and condensin mutants sister pericentric LacO arrays separate a defined distance independent of spindle length. In the absence of Smt4, a peptidase that removes SUMO modifications from proteins, pericentric LacO arrays separate in proportion to spindle length increase. Deletion of Smt4, unlike depletion of cohesin and condensin, causes stretching of both proximal and distal pericentromere LacO arrays. The data suggest that the sumoylation state of chromatin topology adjusters, including cohesin, condensin, and topoisomerase II in the pericentromere, contribute to chromatin spring properties as well as the sister cohesion boundary

IgG light chain-independent secretion of heavy chain dimers: consequence for therapeutic antibody production and design

Rodent monoclonal antibodies with specificity towards important biological targets are developed for therapeutic use by a process of humanisation. This process involves the creation of molecules, which retain the specificity of the rodent antibody but contain predominantly human coding sequence. Here we show that some humanised heavy chains can fold, form dimers and be secreted even in the absence of light chain. Quality control of recombinant antibody assembly in vivo is thought to rely upon folding of the heavy chain CH1 domain. This domain acts as a switch for secretion, only folding upon interaction with the light chain CL domain. We show that the secreted heavy-chain dimers contain folded CH1 domains and contribute to the heterogeneity of antibody species secreted during the expression of therapeutic antibodies. This subversion of the normal quality control process is dependent upon the heavy chain variable domain, is prevalent with engineered antibodies and can occur when only the Fab fragments are expressed. This discovery will impact on the efficient production of both humanised antibodies as well as the design of novel antibody formats

Individual pericentromeres display coordinated motion and stretching in the yeast spindle

During mitosis, cohesin and condensin cross-link pericentromeres of different chromosomes to coordinate centromere attachment sites.The mitotic segregation apparatus composed of microtubules and chromatin functions to faithfully partition a duplicated genome into two daughter cells. Microtubules exert extensional pulling force on sister chromatids toward opposite poles, whereas pericentric chromatin resists with contractile springlike properties. Tension generated from these opposing forces silences the spindle checkpoint to ensure accurate chromosome segregation. It is unknown how the cell senses tension across multiple microtubule attachment sites, considering the stochastic dynamics of microtubule growth and shortening. In budding yeast, there is one microtubule attachment site per chromosome. By labeling several chromosomes, we find that pericentromeres display coordinated motion and stretching in metaphase. The pericentromeres of different chromosomes exhibit physical linkage dependent on centromere function and structural maintenance of chromosomes complexes. Coordinated motion is dependent on condensin and the kinesin motor Cin8, whereas coordinated stretching is dependent on pericentric cohesin and Cin8. Linking of pericentric chromatin through cohesin, condensin, and kinetochore microtubules functions to coordinate dynamics across multiple attachment sites

Dyskerin, tRNA genes, and condensin tether pericentric chromatin to the spindle axis in mitosis

Condensin is enriched in the pericentromere of budding yeast chromosomes where it is constrained to the spindle axis in metaphase. Pericentric condensin contributes to chromatin compaction, resistance to microtubule-based spindle forces, and spindle length and variance regulation. Condensin is clustered along the spindle axis in a heterogeneous fashion. We demonstrate that pericentric enrichment of condensin is mediated by interactions with transfer ribonucleic acid (tRNA) genes and their regulatory factors. This recruitment is important for generating axial tension on the pericentromere and coordinating movement between pericentromeres from different chromosomes. The interaction between condensin and tRNA genes in the pericentromere reveals a feature of yeast centromeres that has profound implications for the function and evolution of mitotic segregation mechanisms

Pericentric chromatin loops function as a nonlinear spring in mitotic force balance

During mitosis, cohesin- and condensin-based pericentric chromatin loops function as a spring network to balance spindle microtubule force.The mechanisms by which sister chromatids maintain biorientation on the metaphase spindle are critical to the fidelity of chromosome segregation. Active force interplay exists between predominantly extensional microtubule-based spindle forces and restoring forces from chromatin. These forces regulate tension at the kinetochore that silences the spindle assembly checkpoint to ensure faithful chromosome segregation. Depletion of pericentric cohesin or condensin has been shown to increase the mean and variance of spindle length, which have been attributed to a softening of the linear chromatin spring. Models of the spindle apparatus with linear chromatin springs that match spindle dynamics fail to predict the behavior of pericentromeric chromatin in wild-type and mutant spindles. We demonstrate that a nonlinear spring with a threshold extension to switch between spring states predicts asymmetric chromatin stretching observed in vivo. The addition of cross-links between adjacent springs recapitulates coordination between pericentromeres of neighboring chromosomes

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

A randomised controlled trial of a digital intervention (Renewed) to support symptom management, wellbeing and quality of life in cancer survivors

Background: Many cancer survivors following primary treatment have prolonged poor quality of life.Aim: To determine the effectiveness of a bespoke digital intervention to support cancer survivors.Design: Pragmatic parallel open randomised trial.Setting: UK general practices.Methods: People having finished primary treatment (&lt;= 10 years previously) for colo-rectal, breast or prostate cancers, with European-Organization-for-Research-and-Treatment-of-Cancer QLQ-C30 score &lt;85, were randomised by online software to: 1) detailed ‘generic’ digital NHS support (‘LiveWell’;n=906), 2) a bespoke complex digital intervention (‘Renewed’;n=903) addressing symptom management, physical activity, diet, weight loss, distress, or 3) ‘Renewed-with-support’ (n=903): ‘Renewed’ with additional brief email and telephone support. Results: Mixed linear regression provided estimates of the differences between each intervention group and generic advice: at 6 months (primary time point: n’s respectively 806;749;705) all groups improved, with no significant between-group differences for EORTC QLQ-C30, but global health improved more in both intervention groups. By 12 months there were: small improvements in EORTC QLQ-C30 for Renewed-with-support (versus generic advice: 1.42, 95% CIs 0.33-2.51); both groups improved global health (12 months: renewed: 3.06, 1.39-4.74; renewed-with-support: 2.78, 1.08-4.48), dyspnoea, constipation, and enablement, and lower NHS costs (generic advice £265: in comparison respectively £141 (153-128) and £77 (90-65) lower); and for Renewed-with-support improvement in several other symptom subscales. No harms were identified.Conclusion: Cancer survivors quality of life improved with detailed generic online support. Robustly developed bespoke digital support provides limited additional short term benefit, but additional longer term improvement in global healthenablement and symptom management, with substantially lower NHS costs.<br/