Storage and transportation of hydrogen is a major obstacle for its use as a fuel. An increasingly considered alternative for the direct handling of hydrogen is to use carbon dioxide (CO₂) as an ...intermediate storage material. However, CO₂ is thermodynamically stable, and developed chemical catalysts often require high temperatures, pressures, and/or additives for high catalytic rates. Here, we present the discovery of a bacterial hydrogen-dependent carbon dioxide reductase from Acetobacterium woodii directly catalyzing the hydrogenation of CO₂. We also demonstrate a whole-cell system able to produce formate as the sole end product from dihydrogen (H₂) and CO₂ as well as syngas. This discovery opens biotechnological alternatives for efficient CO₂ hydrogenation either by using the isolated enzyme or by employing whole-cell catalysis.
In the primary analysis of the HER2CLIMB trial, tucatinib added to trastuzumab and capecitabine significantly improved overall survival (OS) and progression-free survival (PFS) in patients with human ...epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer. We report efficacy and safety outcomes, including the final OS and safety outcomes from follow-up in HER2CLIMB.
HER2CLIMB is a randomized, double-blind, placebo-controlled trial in patients with locally advanced or metastatic HER2+ breast cancer, including patients with brain metastases. Patients were randomized 2 : 1 to receive tucatinib or placebo, in combination with trastuzumab and capecitabine. After the primary analysis (median follow-up of 14 months), the protocol was amended to allow for unblinding sites to treatment assignment and cross-over from the placebo combination to the tucatinib combination. Protocol prespecified descriptive analyses of OS, PFS (by investigator assessment), and safety were carried out at ∼2 years from the last patient randomized.
Six hundred and twelve patients enrolled in the HER2CLIMB trial. At a median OS follow-up of 29.6 months, median duration of OS was 24.7 months for the tucatinib combination group versus 19.2 months for the placebo combination group hazard ratio (HR) for death: 0.73, 95% confidence interval (CI): 0.59-0.90, P = 0.004 and OS at 2 years was 51% and 40%, respectively. HRs for OS across prespecified subgroups were consistent with the HR for the overall study population. Median duration of PFS was 7.6 months for the tucatinib combination group versus 4.9 months for the placebo combination group (HR for progression or death: 0.57, 95% CI: 0.47-0.70, P < 0.00001) and PFS at 1 year was 29% and 14%, respectively. The tucatinib combination was well tolerated with a low rate of discontinuation due to adverse events.
With additional follow-up, the tucatinib combination provided a clinically meaningful survival benefit for patients with HER2+ metastatic breast cancer.
•Tucatinib combination shows continued prolongation of overall survival in patients with HER2+ metastatic breast cancer.•Overall survival benefit was consistent across all prespecified subgroups, including patients with brain metastases.•The tucatinib combination was well tolerated with a low rate of discontinuation due to adverse events (5.9%).
Details about molecular membrane dynamics in living cells, such as lipid-protein interactions, are often hidden from the observer because of the limited spatial resolution of conventional far-field ...optical microscopy. The superior spatial resolution of stimulated emission depletion (STED) nanoscopy can provide new insights into this process. The application of fluorescence correlation spectroscopy (FCS) in focal spots continuously tuned down to 30 nm in diameter distinguishes between free and anomalous molecular diffusion due to, for example, transient binding of lipids to other membrane constituents, such as lipids and proteins. We compared STED-FCS data recorded on various fluorescent lipid analogs in the plasma membrane of living mammalian cells. Our results demonstrate details about the observed transient formation of molecular complexes. The diffusion characteristics of phosphoglycerolipids without hydroxyl-containing headgroups revealed weak interactions. The strongest interactions were observed with sphingolipid analogs, which showed cholesterol-assisted and cytoskeleton-dependent binding. The hydroxyl-containing headgroup of gangliosides, galactosylceramide, and phosphoinositol assisted binding, but in a much less cholesterol- and cytoskeleton-dependent manner. The observed anomalous diffusion indicates lipid-specific transient hydrogen bonding to other membrane molecules, such as proteins, and points to a distinct connectivity of the various lipids to other membrane constituents. This strong interaction is different from that responsible for forming cholesterol-dependent, liquid-ordered domains in model membranes.
To date, projections of human migration induced by sea-level change (SLC) largely suggest large-scale displacement away from vulnerable coastlines. However, results from our model of Bangladesh ...suggest counterintuitively that people will continue to migrate toward the vulnerable coastline irrespective of the flooding amplified by future SLC under all emissions scenarios until the end of this century. We developed an empirically calibrated agent-based model of household migration decision-making that captures the multi-faceted push, pull and mooring influences on migration at a household scale. We then exposed ∼4800 000 simulated migrants to 871 scenarios of projected 21st-century coastal flooding under future emissions pathways. Our model does not predict flooding impacts great enough to drive populations away from coastlines in any of the scenarios. One reason is that while flooding does accelerate a transition from agricultural to non-agricultural income opportunities, livelihood alternatives are most abundant in coastal cities. At the same time, some coastal populations are unable to migrate, as flood losses accumulate and reduce the set of livelihood alternatives (so-called 'trapped' populations). However, even when we increased access to credit, a commonly-proposed policy lever for incentivizing migration in the face of climate risk, we found that the number of immobile agents actually rose. These findings imply that instead of a straightforward relationship between displacement and migration, projections need to consider the multiple constraints on, and preferences for, mobility. Our model demonstrates that decision-makers seeking to affect migration outcomes around SLC would do well to consider individual-level adaptive behaviors and motivations that evolve through time, as well as the potential for unintended behavioral responses.
MAGE-A (melanoma-associated antigen-A) are promising targets for specific immunotherapy and their expression may be induced by the epigenetic factor BORIS.
To determine their relevance for breast ...cancer, we quantified the levels of MAGE-A1, -A2, -A3, -A12 and BORIS mRNA, as well as microRNAs let-7b and miR-202 in pre- and postoperative serum of 102 and 34 breast cancer patients, respectively, and in serum of 26 patients with benign breast diseases and 37 healthy women by real-time PCR. The mean follow-up time of the cancer patients was 6.2 years.
The serum levels of MAGE-A and BORIS mRNA, as well as let-7b were significantly higher in patients with invasive carcinomas than in patients with benign breast diseases or healthy women (P<0.001), whereas the levels of miR-202 were elevated in both patient cohorts (P<0.001). In uni- and multivariate analyses, high levels of miR-202 significantly correlated with poor overall survival (P=0.0001). Transfection of breast cancer cells with synthetic microRNAs and their inhibitors showed that let-7b and miR-202 did not affect the protein expression of MAGE-A1.
Based on their cancer-specific increase in breast cancer patients, circulating MAGE-A and BORIS mRNAs may be further explored for early detection of breast cancer and monitoring of MAGE-directed immunotherapies. Moreover, serum miR-202 is associated with prognosis.
Background
Nowadays, Pelvic Floor Muscle Training (PFMT) is a first line, level 1 evidence‐based treatment for urinary incontinence (UI), but adherence to PFMT is often problematic. Today, there are ...several mobile applications (mApps) for PFMT, but many lack specific strategies for enhancing adherence.
Aims
To review available mApps for improvement of adherence to PFMT, and to introduce a new App so called iPelvis.
Methods
Review study all available mApps for PFMT and relevant literature regarding adherence by electronic search through the databases Pubmed, Embase, CINAHL, LILACS, PEDro, and Scielo. Based on these results, development of a mApp, called “iPelvis” for Apple™ and Android™ systems, implementing relevant strategies to improve adherence.
Results
Based on the current adherence literature we were able to identify 12 variables helping to create the optimal mApp for PFMT. None of the identified 61 mApps found for Android™ and 16 for Apple™ has all these 12 variables. iPelvis mApp and websites were constructed taking into consideration those 12 variables and its construct is now being subject to ongoing validation studies.
Conclusion
MApps for PFMT are an essential part of first‐line, efficient interventions of UI and have potentials to improve adherence, in case these respect the principles of PFMT, motor learning and adherence to PFMT. iPelvis has been constructed respecting all essential variables related to adherence to PFMT and may enhance the effects of UI treatment.
This paper is the second in a series in which we perform an extensive comparison of various galaxy-based cluster mass estimation techniques that utilize the positions, velocities and colours of ...galaxies. Our aim is to quantify the scatter, systematic bias and completeness of cluster masses derived from a diverse set of 25 galaxy-based methods using two contrasting mock galaxy catalogues based on a sophisticated halo occupation model and a semi-analytic model. Analysing 968 clusters, we find a wide range in the rms errors in log M
200c delivered by the different methods (0.18–1.08 dex, i.e. a factor of ∼1.5–12), with abundance-matching and richness methods providing the best results, irrespective of the input model assumptions. In addition, certain methods produce a significant number of catastrophic cases where the mass is under- or overestimated by a factor greater than 10. Given the steeply falling high-mass end of the cluster mass function, we recommend that richness- or abundance-matching-based methods are used in conjunction with these methods as a sanity check for studies selecting high-mass clusters. We see a stronger correlation of the recovered to input number of galaxies for both catalogues in comparison with the group/cluster mass, however, this does not guarantee that the correct member galaxies are being selected. We do not observe significantly higher scatter for either mock galaxy catalogues. Our results have implications for cosmological analyses that utilize the masses, richnesses, or abundances of clusters, which have different uncertainties when different methods are used.
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