The role of RNA processing and regulation in metastatic dormancy.

Tumor dormancy is a major contributor to the lethality of metastatic disease, especially for cancer patients who develop metastases years-to-decades after initial diagnosis. Indeed, tumor cells can disseminate during early disease stages and persist in new microenvironments at distal sites for months, years, or even decades before initiating metastatic outgrowth. This delay between primary tumor remission and metastatic relapse is known as "dormancy," during which disseminated tumor cells (DTCs) acquire quiescent states in response to intrinsic (i.e., cellular) and extrinsic (i.e., microenvironmental) signals. Maintaining dormancy-associated phenotypes requires DTCs to activate transcriptional, translational, and post-translational mechanisms that engender cellular plasticity. RNA processing is emerging as an essential facet of cellular plasticity, particularly with respect to the initiation, maintenance, and reversal of dormancy-associated phenotypes. Moreover, dysregulated RNA processing, particularly that associated with alternative RNA splicing and expression of noncoding RNAs (ncRNAs), can occur in DTCs to mediate intrinsic and extrinsic metastatic dormancy. Here we review the pathophysiological impact of alternative RNA splicing and ncRNAs in promoting metastatic dormancy and disease recurrence in human cancers.

A non-natural nucleotide uses a specific pocket to selectively inhibit telomerase activity.

Telomerase, a unique reverse transcriptase that specifically extends the ends of linear chromosomes, is up-regulated in the vast majority of cancer cells. Here, we show that an indole nucleotide analog, 5-methylcarboxyl-indolyl-2'-deoxyriboside 5'-triphosphate (5-MeCITP), functions as an inhibitor of telomerase activity. The crystal structure of 5-MeCITP bound to the Tribolium castaneum telomerase reverse transcriptase reveals an atypical interaction, in which the nucleobase is flipped in the active site. In this orientation, the methoxy group of 5-MeCITP extends out of the canonical active site to interact with a telomerase-specific hydrophobic pocket formed by motifs 1 and 2 in the fingers domain and T-motif in the RNA-binding domain of the telomerase reverse transcriptase. In vitro data show that 5-MeCITP inhibits telomerase with a similar potency as the clinically administered nucleoside analog reverse transcriptase inhibitor azidothymidine (AZT). In addition, cell-based studies show that treatment with the cell-permeable nucleoside counterpart of 5-MeCITP leads to telomere shortening in telomerase-positive cancer cells, while resulting in significantly lower cytotoxic effects in telomerase-negative cell lines when compared with AZT treatment.

Informing conservation decisions to target private lands of highest ecological value and risk of loss.

Natural habitats on private lands are potentially important components of national biodiversity conservation strategies, yet they are being rapidly lost to development. Conservation easements and other means of protecting these habitats have expanded in use and will be most effective if they target private lands of highest biodiversity value and risk of loss. We developed a Biodiversity Conservation Priority Index (BCPI) based on ecological value and risk of habitat loss for remaining areas of natural vegetation cover (NVC) in the northwestern United States and addressed two questions: (1) Which remaining NVC on private lands is the highest priority for biodiversity conservation based on ecological value and risk of development? And (2) are conservation easements in NVC placed preferentially in locations of high biodiversity conservation priority? Drawing on the concept of ecological integrity, we integrated five metrics of ecological structure, function, and composition to quantify ecological value of NVC. These included net primary productivity, species richness, ecosystem type representation, imperiled species range rarity, and connectivity among "Greater Wildland Ecosystems." Risk of habitat loss was derived from analysis of biophysical and sociodemographic predictors of NVC loss. Ecological value and risk of loss were combined into the BCPI. We then analyzed spatial patterns of BCPI to identify the NVC highest in biodiversity conservation priority and examined the relationship between BCPI and conservation easement status. We found that BCPI varied spatially across the study area and was highest in western and southern portions of the study area. High BCPI was associated with suburban and rural development, roads, urban proximity, valley bottom landforms, and low intensity of current development. Existing conservation easements were distributed more towards lower BCPI values than unprotected NVC at both the study area and region scales. The BCPI can be used to better inform land use decision making at local, regional, and potentially national scales in order to better achieve biodiversity goals.

Multispectral high resolution sensor fusion for smoothing and gap-filling in the cloud.

Remote sensing optical sensors onboard operational satellites cannot have high spectral, spatial and temporal resolutions simultaneously. In addition, clouds and aerosols can adversely affect the signal contaminating the land surface observations. We present a HIghly Scalable Temporal Adaptive Reflectance Fusion Model (HISTARFM) algorithm to combine multispectral images of different sensors to reduce noise and produce monthly gap free high resolution (30 m) observations over land. Our approach uses images from the Landsat (30 m spatial resolution and 16 day revisit cycle) and the MODIS missions, both from Terra and Aqua platforms (500 m spatial resolution and daily revisit cycle). We implement a bias-aware Kalman filter method in the Google Earth Engine (GEE) platform to obtain fused images at the Landsat spatial-resolution. The added bias correction in the Kalman filter estimates accounts for the fact that both model and observation errors are temporally auto-correlated and may have a non-zero mean. This approach also enables reliable estimation of the uncertainty associated with the final reflectance estimates, allowing for error propagation analyses in higher level remote sensing products. Quantitative and qualitative evaluations of the generated products through comparison with other state-of-the-art methods confirm the validity of the approach, and open the door to operational applications at enhanced spatio-temporal resolutions at broad continental scales.

Patterns of rangeland productivity and land ownership: Implications for conservation and management.

Rangelands cover 40-50% of the Earth's terrestrial surface. While often characterized by limited, yet variable resource availability, rangelands are vital for humans, providing numerous ecosystem goods and services. In the conterminous United States (CONUS), the dominant component of rangeland conservation is a network of public rangelands, concentrated in the west. Public rangelands are interspersed with private and tribal rangelands resulting in a complex mosaic of land tenure and management priorities. We quantify ownership patterns of rangeland production at multiple scales across CONUS and find that both total production and average productivity of private rangelands is more than twice that of public and tribal rangelands. At finer scales, private rangelands are consistently more productive than their public counterparts. We also demonstrate an inverse relationship between public rangeland acreage and productivity. While conserving acreage is crucial to rangeland conservation, just as critical are broad-scale ecological patterns and processes that sustain ecosystem services. Across CONUS, ownership regimes capture distinct elements of these patterns and services, demonstrated through disparate production dynamics. As ownership determines the range of feasible conservation actions, and the technical and financial resources available to implement them, understanding ownership-production dynamics is critical for effective and sustained conservation of rangeland ecosystem services.

Activity-dependent phosphorylation of MeCP2 threonine 308 regulates interaction with NCoR.

Rett syndrome (RTT) is an X-linked human neurodevelopmental disorder with features of autism and severe neurological dysfunction in females. RTT is caused by mutations in methyl-CpG-binding protein 2 (MeCP2), a nuclear protein that, in neurons, regulates transcription, is expressed at high levels similar to that of histones, and binds to methylated cytosines broadly across the genome. By phosphotryptic mapping, we identify three sites (S86, S274 and T308) of activity-dependent MeCP2 phosphorylation. Phosphorylation of these sites is differentially induced by neuronal activity, brain-derived neurotrophic factor, or agents that elevate the intracellular level of 3',5'-cyclic AMP (cAMP), indicating that MeCP2 may function as an epigenetic regulator of gene expression that integrates diverse signals from the environment. Here we show that the phosphorylation of T308 blocks the interaction of the repressor domain of MeCP2 with the nuclear receptor co-repressor (NCoR) complex and suppresses the ability of MeCP2 to repress transcription. In knock-in mice bearing the common human RTT missense mutation R306C, neuronal activity fails to induce MeCP2 T308 phosphorylation, suggesting that the loss of T308 phosphorylation might contribute to RTT. Consistent with this possibility, the mutation of MeCP2 T308A in mice leads to a decrease in the induction of a subset of activity-regulated genes and to RTT-like symptoms. These findings indicate that the activity-dependent phosphorylation of MeCP2 at T308 regulates the interaction of MeCP2 with the NCoR complex, and that RTT in humans may be due, in part, to the loss of activity-dependent MeCP2 T308 phosphorylation and a disruption of the phosphorylation-regulated interaction of MeCP2 with the NCoR complex.

Means to the ends: The role of telomeres and telomere processing machinery in metastasis.

Despite significant clinical advancements, cancer remains a leading cause of mortality throughout the world due largely to the process of metastasis and the dissemination of cancer cells from their primary tumor of origin to distant secondary sites. The clinical burden imposed by metastasis is further compounded by a paucity of information regarding the factors that mediate metastatic progression. Linear chromosomes are capped by structures known as telomeres, which dictate cellular lifespan in humans by shortening progressively during successive cell divisions. Although telomere shortening occurs in nearly all somatic cells, telomeres may be elongated via two seemingly disjoint pathways: (i) telomerase-mediated extension, and (ii) homologous recombination-based alternative lengthening of telomeres (ALT). Both telomerase and ALT are activated in various human cancers, with more recent evidence implicating both pathways as potential mediators of metastasis. Here we review the known roles of telomere homeostasis in metastasis and posit a mechanism whereby metastatic activity is determined by a dynamic fluctuation between ALT and telomerase, as opposed to the mere activation of a generic telomere elongation program. Additionally, the pleiotropic nature of the telomere processing machinery makes it an attractive therapeutic target for metastasis, and as such, we also explore the therapeutic implications of our proposed mechanism.

(R)-ß-lysine-modified elongation factor P functions in translation elongation.

Post-translational modification of bacterial elongation factor P (EF-P) with (R)-ß-lysine at a conserved lysine residue activates the protein in vivo and increases puromycin reactivity of the ribosome in vitro. The additional hydroxylation of EF-P at the same lysine residue by the YfcM protein has also recently been described. The roles of modified and unmodified EF-P during different steps in translation, and how this correlates to its physiological role in the cell, have recently been linked to the synthesis of polyproline stretches in proteins. Polysome analysis indicated that EF-P functions in translation elongation, rather than initiation as proposed previously. This was further supported by the inability of EF-P to enhance the rate of formation of fMet-Lys or fMet-Phe, indicating that the role of EF-P is not to specifically stimulate formation of the first peptide bond. Investigation of hydroxyl-(ß)-lysyl-EF-P showed 30% increased puromycin reactivity but no differences in dipeptide synthesis rates when compared with the ß-lysylated form. Unlike disruption of the other genes required for EF-P modification, deletion of yfcM had no phenotypic consequences in Salmonella. Taken together, our findings indicate that EF-P functions in translation elongation, a role critically dependent on post-translational ß-lysylation but not hydroxylation.

A human cadaveric model for venous air embolism detection tool development.

PURPOSE: A human cadaveric model combining standard lung protective mechanical ventilation and modified cardiac bypass techniques was developed to allow investigation into automated modes of detection of venous air emboli (VAE) prior to in vivo human or animal investigations. METHODS: In this study, in order to create an artificial cardiopulmonary circuit in a cadaver that could mimic VAE physiology, the direction of flow was reversed from conventional cardiac bypass. Normal saline was circulated in isolation through the heart and lungs as opposed to the peripheral organs by placing the venous cannula into the aorta and the arterial cannula into the inferior vena cava with selective ligation of other vessels. RESULTS: Mechanical ventilation and this reversed cardiac bypass scheme allowed preliminary detection of VAE independently but not in concert in our current simulation scheme due to pulmonary edema in the cadaver. A limited dissection approach was used initially followed by a radical exposure of the great vessels, and both proved feasible in terms of air signal detection. We used electrical impendence as a preliminary tool to validate detection in this cadaveric model however we theorize that it would work for echocardiographic, intravenous ultrasound or other novel modalities as well. CONCLUSION: A cadaveric model allows monitoring technology development with reduced use of animal and conventional human testing.

Infected stent graft and severe aortitis after transcaval glue embolization of type II endoleak: a case report.

Background: Type II endoleaks are common and embolization is often performed if treatment is necessary. Although transarterial embolization is common, other methods including trans-caval embolization are also utilized. Complications can occur and we report a case of infection that was challenging to diagnose and treat. There is no data regarding the risk of aortic stent graft infection after trans-caval embolization with n-butyl 2-cyanoacrylate (n-BCA) glue of a type II endoleak. Case Description: We report a rare case of infected, Gore Excluder infrarenal stent graft after transcaval embolization with coil and n-BCA glue to treat a type II endoleak in a 71-year-old male. The endoleak caused a rapid sac enlargement. The stent graft was placed 5 years earlier electively. Soon after the endoleak embolization, the patient experienced abdominal pain and malaise. There was an intense inflammatory reaction involving the aneurysm wall and the adjacent bowel mesentery. Our differential included normal inflammation after embolization vs. infection and this was difficult to distinguish. The infection was confirmed by positron emission tomography scan and tissue biopsy. The patient was deemed high-risk for surgery because of his extensive cardiac history, status post coronary bypass and tissue mitral valve replacement, congestive heart failure with residual left ventricular ejection fraction of 36%. He was optimized by correcting fluid status, administration of intravenous antibiotic, and nutrition consultation with dietary supplementation before surgery over the course of 2 weeks. The graft was explanted through a transabdominal approach, and the aorta was reconstructed with cryopreserved allograft. Interestingly, the small and large intestine with their mesentery were found to be plastered to the aneurysm sac. The post-operative course was unremarkable except for a transient acute kidney injury that resolved within 1 week. Follow-up computed tomography scan at 6 months showed widely patent bypass. Conclusions: Glue embolization induces inflammation promoting thrombus formation inside the aneurysm sac. With a transcaval approach to the sac, there is the risk of extravasation of glue outside the sac as well as contamination of the graft with instrumentation. Differentiating between inflammation and infection can be difficult, and tissue biopsy provided the most conclusive diagnosis. Risk minimization considerations include, pre-operative optimization, a transabdominal approach, ureteral stenting, and tissue buttressing of anastomosis.

Treatment Patterns and Clinical Outcomes in Patients With EGFR-Mutated Non-Small-Cell Lung Cancer After Progression on Osimertinib.

INTRODUCTION: For patients with advanced epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) who progress on first-line osimertinib, the optimal second-line treatment regimen after progression is not known. We sought to assess practice patterns and evaluate the association between different therapies and survival in patients with EGFR-mutated NSCLC following progression on first-line osimertinib. METHODS: Retrospective cohort study of patients who received first-line treatment with osimertinib using a population-based, multicenter nationwide electronic health record-derived deidentified database. RESULTS: We identified 2373 patients who received first-line osimertinib. The majority (n = 2279) received osimertinib monotherapy. A total of 538 patients received first-line osimertinib and had second-line treatment data available. Second-line treatment regimens were varied: 65% (n = 348) included chemotherapy, 37% (n = 197) included an immune checkpoint inhibitor (ICI), and 44% (n = 234) included an EGFR tyrosine kinase inhibitor (TKI). We then analyzed the 333 patients with performance status 0-2 who received chemotherapy with osimertinib (n = 107, 32%) versus chemotherapy without osimertinib (n = 226, 68%). The continuation of osimertinib with chemotherapy was associated with superior progression-free survival (PFS; median: 10.1 versus 5.9 months, Hazard Ratio [HR]: 0.48, 95% Confidence Interval [CI]: [0.34, 0.68], P < .001) and overall survival (OS; median: 17.0 versus 12.8 months, HR: 0.64, 95% CI: [0.44, 0.93], P = .018) compared to other chemotherapy approaches without osimertinib. This effect was most pronounced in patients with an EGFR exon 19 deletion. CONCLUSIONS: Following progression on osimertinib, a wide variety of treatment regimens were used. The continuation of osimertinib with chemotherapy in the second line was associated with increased PFS and OS.

Amplification and Quantitation of Telomeric Extrachromosomal Circles.

Telomeres are structures that cap the ends of linear chromosomes and play critical roles in maintaining genome integrity and establishing the replicative lifespan of cells. In stem and cancer cells, telomeres are actively elongated by either telomerase or the alternative lengthening of telomeres (ALT) pathway. This pathway is characterized by several hallmark features, including extrachromosomal C-rich circular DNAs that can be probed to assess ALT activity. These so-called C-circles are the product of ALT-associated DNA damage repair processes and simultaneously serve as potential templates for iterative telomere extension. This bifunctional nature makes C-circles highly sensitive and specific markers of ALT. Here, we describe a C-circle assay, adapted from previous reports, that enables the quantitation of C-circle abundance in mammalian cells subjected to a wide range of experimental perturbations. This protocol combines the Quick C-circle Preparation (QCP) method for DNA isolation with fluorometry-based DNA quantification, rolling circle amplification (RCA), and detection of C-circles using quantitative PCR. Moreover, the inclusion of internal standards with well-characterized telomere maintenance mechanisms (TMMs) allows for the reliable benchmarking of cells with unknown TMM status. Overall, our work builds upon existing protocols to create a generalizable workflow for in vitro C-circle quantitation and ascertainment of TMM identity.

A human cadaveric model for venous air embolism tool development.

Purpose: A human cadaveric model combining standard lung protective mechanical ventilation and modified cardiac bypass techniques was developed to allow investigation into automated modes of detection of venous air emboli (VAE) prior to in vivo human or animal investigations. Methods: In this study, in order to create an artificial cardiopulmonary circuit in a cadaver that could mimic VAE physiology, the direction of flow was reversed from conventional cardiac bypass. Saline was circulated in isolation through the heart and lungs as opposed to the peripheral organs by placing the venous cannula into the aorta and the arterial cannula into the inferior vena cava with selective ligation of other vessels. Results: Mechanical ventilation and this reversed cardiac bypass scheme allowed preliminary detection of VAE independently but not in concert in our current simulation scheme due to pulmonary edema in the cadaver. A limited dissection approach was used initially followed by a radical exposure of the great vessels, and both proved feasible in terms of air signal detection. We used electrical impendence as a preliminary tool to validate detection in this cadaveric model however we theorize that it would work for echocardiographic, intravenous ultrasound or other novel modalities as well. Conclusion: A cadaveric model allows monitoring technology development with reduced use of animal and conventional human testing.

Telomerase in Cancer: Function, Regulation, and Clinical Translation.

During the process of malignant transformation, cells undergo a series of genetic, epigenetic, and phenotypic alterations, including the acquisition and propagation of genomic aberrations that impart survival and proliferative advantages. These changes are mediated in part by the induction of replicative immortality that is accompanied by active telomere elongation. Indeed, telomeres undergo dynamic changes to their lengths and higher-order structures throughout tumor formation and progression, processes overseen in most cancers by telomerase. Telomerase is a multimeric enzyme whose function is exquisitely regulated through diverse transcriptional, post-transcriptional, and post-translational mechanisms to facilitate telomere extension. In turn, telomerase function depends not only on its core components, but also on a suite of binding partners, transcription factors, and intra- and extracellular signaling effectors. Additionally, telomerase exhibits telomere-independent regulation of cancer cell growth by participating directly in cellular metabolism, signal transduction, and the regulation of gene expression in ways that are critical for tumorigenesis. In this review, we summarize the complex mechanisms underlying telomere maintenance, with a particular focus on both the telomeric and extratelomeric functions of telomerase. We also explore the clinical utility of telomeres and telomerase in the diagnosis, prognosis, and development of targeted therapies for primary, metastatic, and recurrent cancers.

Humid tropical vertebrates are at lower risk of extinction and population decline in forests with higher structural integrity.

Reducing deforestation underpins global biodiversity conservation efforts. However, this focus on retaining forest cover overlooks the multitude of anthropogenic pressures that can degrade forest quality and imperil biodiversity. We use remotely sensed indices of tropical rainforest structural condition and associated human pressures to quantify the relative importance of forest cover, structural condition and integrity (the cumulative effect of condition and pressures) on vertebrate species extinction risk and population trends across the global humid tropics. We found that tropical rainforests of high integrity (structurally intact and under low pressures) were associated with lower likelihood of species being threatened and having declining populations, compared with forest cover alone (without consideration of condition and pressures). Further, species were more likely to be threatened or have declining populations if their geographic ranges contained high proportions of degraded forest than if their ranges contained lower proportions of forest cover but of high quality. Our work suggests that biodiversity conservation policies to preserve forest integrity are now urgently required alongside ongoing efforts to halt deforestation in the hyperdiverse humid tropics.

Morning Exercise Reduces Abdominal Fat and Blood Pressure in Women; Evening Exercise Increases Muscular Performance in Women and Lowers Blood Pressure in Men.

The ideal exercise time of day (ETOD) remains elusive regarding simultaneous effects on health and performance outcomes, especially in women. Purpose: Given known sex differences in response to exercise training, this study quantified health and performance outcomes in separate cohorts of women and men adhering to different ETOD. Methods: Thirty exercise-trained women (BMI = 24 ± 3 kg/m2; 42 ± 8 years) and twenty-six men (BMI = 25.5 ± 3 kg/m2; 45 ± 8 years) were randomized to multimodal ETOD in the morning (0600-0800 h, AM) or evening (1830-2030 h, PM) for 12 weeks and analyzed as separate cohorts. Baseline (week 0) and post (week 12) muscular strength (1-RM bench/leg press), endurance (sit-ups/push-ups) and power (squat jumps, SJ; bench throws, BT), body composition (iDXA; fat mass, FM; abdominal fat, Abfat), systolic/diastolic blood pressure (BP), respiratory exchange ratio (RER), profile of mood states (POMS), and dietary intake were assessed. Results: Twenty-seven women and twenty men completed the 12-week intervention. No differences at baseline existed between groups (AM vs PM) for both women and men cohorts. In women, significant interactions (p < 0.05) existed for 1RM bench (8 ± 2 vs 12 ± 2, ∆kg), pushups (9 ± 1 vs 13 ± 2, ∆reps), BT (10 ± 6 vs 45 ± 28, ∆watts), SJ (135 ± 6 vs 39 ± 8, ∆watts), fat mass (-1.0 ± 0.2 vs -0.3 ± 0.2, ∆kg), Abfat (-2.6 ± 0.3 vs -0.9 ± 0.5, ∆kg), diastolic (-10 ± 1 vs-5 ± 5, ∆mmHg) and systolic (-12.5 ± 2.7 vs 2.3 ± 3, mmHg) BP, AM vs PM, respectively. In men, significant interactions (p < 0.05) existed for systolic BP (-3.5 ± 2.6 vs -14.9 ± 5.1, ∆mmHg), RER (-0.01 ± 0.01 vs -0.06 ± 0.01, ∆VCO2/VO2), and fatigue (-0.8 ± 2 vs -5.9 ± 2, ∆mm), AM vs PM, respectively. Macronutrient intake was similar among AM and PM groups. Conclusion: Morning exercise (AM) reduced abdominal fat and blood pressure and evening exercise (PM) enhanced muscular performance in the women cohort. In the men cohort, PM increased fat oxidation and reduced systolic BP and fatigue. Thus, ETOD may be important to optimize individual exercise-induced health and performance outcomes in physically active individuals and may be independent of macronutrient intake.

Electrolysis-reducing electrodes for electrokinetic devices.

Direct current electrokinetic systems generally require Faradaic reactions to occur at a pair of electrodes to maintain an electric field in an electrolyte connecting them. The vast majority of such systems, e.g. electrophoretic separations (capillary electrophoresis) or electroosmotic pumps (EOPs), employ electrolysis of the solvent in these reactions. In many cases, the electrolytic products, such as H+ and OH⁻ in the case of water, can negatively influence the chemical or biological species being transported or separated, and gaseous products such as O2 and H2 can break the electrochemical circuit in microfluidic devices. This article presents an EOP that employs the oxidation/reduction of the conjugated polymer poly(3,4-ethylenedioxythiophene), rather than electrolysis of a solvent, to drive flow in a capillary. Devices made with poly(3,4-ethylenedioxythiophene) electrodes are compared with devices made with Pt electrodes in terms of flow and local pH change at the electrodes. Furthermore, we demonstrate that flow is driven for applied potentials under 2 V, and the electrodes are stable for potentials of at least 100 V. Electrochemically active electrodes like those presented here minimize the disadvantage of integrated EOP in, e.g. lab-on-a-chip applications, and may open new possibilities, especially for battery-powered disposable point-of-care devices.

Early Outcomes of Scapholunate Injuries With Concomitant Distal Radius Fractures.

Background: There is limited literature regarding the treatment of concomitant scapholunate ligament (SL) injuries in acute distal radius fractures (DRFs). We hypothesized that surgical treatment of SL injuries in adult patients with DRFs leads to improved functional outcomes. Methods: A retrospective review was made of 42 adult patients who underwent surgical treatment of a DRF with a SL injury between 2005 and 2013. In all, 39 of the 42 patients sustained an intra-articular DRF (AO B or C). SL injury was diagnosed by SL diastasis > 3 mm on posteroanterior (PA) radiographs, magnetic resonance imaging, or with wrist arthroscopy. Patients were divided into 3 groups: 23 had a SL repair and were treated within 21 days of injury (acute), 8 underwent SL repair greater than 21 days from injury (subacute/chronic), and 11 did not undergo repair (non-operative). Median overall time to clinical follow-up was 5.1 years. Mayo Wrist Scores (MWS) and Disabilities of the Arm, Shoulder and Hand (DASH) scores were used to evaluate functional outcome. Results: Clinical outcomes measured by the MWS at final follow-up (6 months-12 years) showed no significant differences between the 3 groups. Of patients treated acutely, 17.3% had good to excellent MWS. MWS at 1-year follow-up was 68.4, 70, and 64 in the acute, subacute/chronic, and non-operative groups, respectively. DASH scores were 16.7, 14.3, and 11.8 in the acute, subacute/chronic, and nonoperative groups, respectively, at a mean of 7.8 years. Conclusions: At mid-term follow-up, all 3 treatment groups had similar DASH scores to the general population. There were no statistical functional differences between any of the groups based upon MWS or DASH scores.

SLX4IP promotes RAP1 SUMOylation by PIAS1 to coordinate telomere maintenance through NF-κB and Notch signaling.

The maintenance of telomere length supports repetitive cell division and therefore plays a central role in cancer development and progression. Telomeres are extended by either the enzyme telomerase or the alternative lengthening of telomeres (ALT) pathway. Here, we found that the telomere-associated protein SLX4IP dictates telomere proteome composition by recruiting and activating the E3 SUMO ligase PIAS1 to the SLX4 complex. PIAS1 SUMOylated the telomere-binding protein RAP1, which disrupted its interaction with the telomere-binding protein TRF2 and facilitated its nucleocytoplasmic shuttling. In the cytosol, RAP1 bound to IκB kinase (IKK), resulting in activation of the transcription factor NF-κB and its induction of Jagged-1 expression, which promoted Notch signaling and the institution of ALT. This axis could be targeted therapeutically in ALT-driven cancers and in tumor cells that develop resistance to antitelomerase therapies. Our results illuminate the mechanisms underlying SLX4IP-dependent telomere plasticity and demonstrate the role of telomere proteins in directly coordinating intracellular signaling and telomere maintenance dynamics.

The dynamic organic p-n junction.

Static p-n junctions in inorganic semiconductors are exploited in a wide range of today's electronic appliances. Here, we demonstrate the in situ formation of a dynamic p-n junction structure within an organic semiconductor through electrochemistry. Specifically, we use scanning kelvin probe microscopy and optical probing on planar light-emitting electrochemical cells (LECs) with a mixture of a conjugated polymer and an electrolyte connecting two electrodes separated by 120 microm. We find that a significant portion of the potential drop between the electrodes coincides with the location of a thin and distinct light-emission zone positioned >30 microm away from the negative electrode. These results are relevant in the context of a long-standing scientific debate, as they prove that electrochemical doping can take place in LECs. Moreover, a study on the doping formation and dissipation kinetics provides interesting detail regarding the electronic structure and stability of the dynamic organic p-n junction, which may be useful in future dynamic p-n junction-based devices.