Targeting the absence: Homozygous DNA deletions as immutable signposts for cancer therapy

Many cancers harbor homozygous DNA deletions (HDs). In contrast to other attributes of cancer cells, their HDs are immutable features that cannot change during tumor progression or therapy. I describe an approach, termed deletion-specific targeting (DST), that employs HDs (not their effects on RNA/protein circuits, but deletions themselves) as the targets of cancer therapy. The DST strategy brings together both existing and new methodologies, including the ubiquitin fusion technique, the split-ubiquitin assay, zinc-finger DNA-recognizing proteins and split restriction nucleases. The DST strategy also employs a feedback mechanism that receives input from a circuit operating as a Boolean OR gate and involves the activation of split nucleases, which destroy DST vector in normal (nontarget) cells. The logic of DST makes possible an incremental and essentially unlimited increase in the selectivity of therapy. If DST strategy can be implemented in a clinical setting, it may prove to be curative and substantially free of side effects

High rates of bodychecking, head conatcts, and suspected injuries found in youth ringette through video analysis.

Objective: Ringette is a popular team ice sport in Canada, primarily played by females. Bodychecking is prohibited at all levels of play. This study used video-analysis to evaluate physical contact (PC), head contact (HC), and suspected injury and concussion incidence rates (IR) in youth ringette. Study Design: Cross-sectional. Subjects: Youth ringette players from the 2021-2022 season playing in the U16 (ages 14-15) or U19 (ages 16-18) age groups (A or AA levels). Games were filmed from regular season, provincials, and nationals (AA only). Observation Technique: Game video-recordings were analyzed using Dartfish video-analysis software. Validated criteria were used to assess trunk PC intensity (levels 1-3=lower-intensity PC, levels 4-5=higher-intensity bodychecking), HC type (HC1=direct player-to-player, HC2=indirect), suspected injury (concussion, non-concussion), and penalty enforcement. Outcome Measures: Multivariable Poisson regression analyses (adjusted for cluster by teamgame, offset by game-minutes) were used to estimate PC, HC, and suspected injury and concussion IRs. Incidence rate ratios (IRR) were used to compare IR across age groups, levels of play, and game types. Proportions of bodychecks and HC1s penalized were reported. Results: Seventy-eight team-games were included (U16 n=40, U19 n=38; A n=30, AA n=48; regular season n=30, provincials n=32, nationals n=16). The overall bodychecking IR was 17.34/100 team-minutes (95% CI:14.80-20.33), HC 19.09/100 team-minutes (95% CI:16.7421.78), suspected injury 1.53/100 team-minutes (95% CI:1.13-2.09), and suspected concussion 0.74/100 team-minutes (95% CI:0.48-1.13). Only 29% (95% CI:24.97-32.59) of bodychecks and 7% (95% CI:4.76-9.70) of HC1s were penalized. No differences were found in bodychecking, HCs, or suspected injury and concussion IRs between age groups or levels of play. Bodychecking IRs were 64% (IRR=1.64; 95% CI:1.13-2.39) higher in provincials and 24% (IRR=1.24; 95% CI:1.02-1.50) higher in nationals than regular season games. A 31% (IRR=0.69; 95% CI:0.49-0.97) lower rate of HCs was reported in national games compared to provincial games. Bodychecking was the most common mechanism for concussion (70%) and nonconcussion injuries (67%), with concussions most often associated with HC2s (62.5%). Conclusions: Bodychecking and HC1 IRs were high among youth ringette players, despite rules prohibiting them. Future research should target prevention strategies aimed to reduce HC1s and bodychecking to reduce injury and concussion IRs in youth ringette

Patellofemoral joint geometry and osteoarthritis features 3–10 years after knee injury compared with uninjured knees

In this cross-sectional study, we compared patellofemoral geometry in individuals with a youth-sport-related intra-articular knee injury to uninjured individuals, and the association between patellofemoral geometry and magnetic resonance imaging (MRI)-defined osteoarthritis (OA) features. In the Youth Prevention of Early OA (PrE-OA) cohort, we assessed 10 patellofemoral geometry measures in individuals 3–10 years following injury compared with uninjured individuals of similar age, sex, and sport, using mixed effects linear regression. We also dichotomized geometry to identify extreme (&gt;1.96 standard deviations) features and assessed likelihood of having extreme values using Poisson regression. Finally, we evaluated the associations between patellofemoral geometry with MRI-defined OA features using restricted cubic spline regression. Mean patellofemoral geometry did not differ substantially between groups. However, compared with uninjured individuals, injured individuals were more likely to have extremely large sulcus angle (prevalence ratio [PR] 3.9 [95% confidence interval, CI: 2.3, 6.6]), and shallow lateral trochlear inclination (PR 4.3 (1.1, 17.9)) and trochlear depth (PR 5.3 (1.6, 17.4)). In both groups, high bisect offset (PR 1.7 [1.3, 2.1]) and sulcus angle (PR 4.0 [2.3, 7.0]) were associated with cartilage lesion, and most geometry measures were associated with at least one structural feature, especially cartilage lesions and osteophytes. We observed no interaction between geometry and injury. Certain patellofemoral geometry features are correlated with higher prevalence of structural lesions compared with injury alone, 3–10 years following knee injury. Hypotheses generated in this study, once further evaluated, could contribute to identifying higher-risk individuals who may benefit from targeted treatment aimed at preventing posttraumatic OA.</p

Silica SHB chiral Pc-L* copper complexes for halogen-free solvent cyclopropanation reactions

The grafting of the preformed Pc-L* (pyridine containing macrocyclic ligands) copper(I) complexes on different ordered and non-ordered silicas, and their use, under heterogeneous batch conditions, as catalysts for the olefin cyclopropanation are reported. High yields (up to 99%), good recyclability in halogen-free solvent reactions were obtained, together with negligible copper leaching (0.1% of total copper)

ES&T Guest Comment: Celebrating Bidleman’s 1988 “Atmospheric Processes”

Since its 1988 appearance in ES&T, Terry F. Bidleman’s article, “Atmospheric processes: wet and dry deposition of organic compounds are controlled by their vapor-particle partitioning”, has had a notable impact on the field of contaminant science. The paper has been cited in over 600 journal articles published by authors from every continent. Far from fading into obscurity, the paper’s influence has been remarkably consistent. Citations over the last year match the annual average attained since publication

Keratins and protein synthesis: the plot thickens

In addition to protecting epithelial cells from mechanical stress, keratins regulate cytoarchitecture, cell growth, proliferation, apoptosis, and organelle transport. In this issue, Vijayaraj et al. (2009. J. Cell Biol. doi:10.1083/jcb.200906094) expand our understanding of how keratin proteins participate in the regulation of protein synthesis through their analysis of mice lacking the entire type II keratin gene cluster

Gas-Particle Partitioning of Atmospheric Hg(II) and Its Effect on Global Mercury Deposition

Atmospheric deposition of Hg(II) represents a major input of mercury to surface environments. The phase of Hg(II) (gas or particle) has important implications for deposition. We use long-term observations of reactive gaseous mercury (RGM, the gaseous component of Hg(II)), particle-bound mercury (PBM, the particulate component of Hg(II)), fine particulate matter (PM2.5), and temperature (T) at five sites in North America to derive an empirical gas-particle partitioning relationship log10(K−1) = (10±1)–(2500±300)/T where K = (PBM/PM2.5)/RGM with PBM and RGM in common mixing ratio units, PM2.5 in μg m−3, and T in K. This relationship is within the range of previous work but is based on far more extensive data from multiple sites. We implement this empirical relationship in the GEOS-Chem global 3-D Hg model to partition Hg(II) between the gas and particle phases. The resulting gas-phase fraction of Hg(II) ranges from over 90 % in warm air with little aerosol to less than 10 % in cold air with high aerosol. Hg deposition to high latitudes increases because of more efficient scavenging of particulate Hg(II) by precipitating snow. Model comparison to Hg observations at the North American surface sites suggests that subsidence from the free troposphere (warm air, low aerosol) is a major factor driving the seasonality of RGM, while elevated PBM is mostly associated with high aerosol loads. Simulation of RGM and PBM at these sites is improved by including fast in-plume reduction of Hg(II) emitted from coal combustion and by assuming that anthropogenic particulate Hg(p) behaves as semi-volatile Hg(II) rather than as a refractory particulate component. We improve the simulation of Hg wet deposition fluxes in the US relative to a previous version of GEOS-Chem; this largely reflects independent improvement of the washout algorithm. The observed wintertime minimum in wet deposition fluxes is attributed to inefficient snow scavenging of gas-phase Hg(II).Earth and Planetary SciencesEngineering and Applied Science

Different atmospheric moisture divergence responses to extreme and moderate El Niños

On seasonal and inter-annual time scales, vertically integrated moisture divergence provides a useful measure of the tropical atmospheric hydrological cycle. It reflects the combined dynamical and thermodynamical effects, and is not subject to the limitations that afflict observations of evaporation minus precipitation. An empirical orthogonal function (EOF) analysis of the tropical Pacific moisture divergence fields calculated from the ERA-Interim reanalysis reveals the dominant effects of the El Niño-Southern Oscillation (ENSO) on inter-annual time scales. Two EOFs are necessary to capture the ENSO signature, and regression relationships between their Principal Components and indices of equatorial Pacific sea surface temperature (SST) demonstrate that the transition from strong La Niña through to extreme El Niño events is not a linear one. The largest deviation from linearity is for the strongest El Niños, and we interpret that this arises at least partly because the EOF analysis cannot easily separate different patterns of responses that are not orthogonal to each other. To overcome the orthogonality constraints, a self-organizing map (SOM) analysis of the same moisture divergence fields was performed. The SOM analysis captures the range of responses to ENSO, including the distinction between the moderate and strong El Niños identified by the EOF analysis. The work demonstrates the potential for the application of SOM to large scale climatic analysis, by virtue of its easier interpretation, relaxation of orthogonality constraints and its versatility for serving as an alternative classification method. Both the EOF and SOM analyses suggest a classification of “moderate” and “extreme” El Niños by their differences in the magnitudes of the hydrological cycle responses, spatial patterns and evolutionary paths. Classification from the moisture divergence point of view shows consistency with results based on other physical variables such as SST