3D printing can allow for the efficient manufacturing of elaborate structures difficult to realise conventionally without waste, such as the hollow geometries of nickel-based superalloy aeronautic ...components. To fully exploit this method, we must move towards new alloys and processes.
Biological soil crusts (biocrusts)—communities of mosses, lichens, cyanobacteria, and heterotrophs living at the soil surface—are fundamental components of drylands worldwide, and destruction of ...biocrusts dramatically alters biogeochemical processes, hydrology, surface energy balance, and vegetation cover. Although there has been long-standing concern over impacts of physical disturbances on biocrusts (e.g., trampling by livestock, damage from vehicles), there is increasing concern over the potential for climate change to alter biocrust community structure. Using long-term data from the Colorado Plateau, we examined the effects of 10 y of experimental warming and altered precipitation (in full-factorial design) on biocrust communities and compared the effects of altered climate with those of long-term physical disturbance (>10 y of replicated human trampling). Surprisingly, altered climate and physical disturbance treatments had similar effects on biocrust community structure. Warming, altered precipitation frequency an increase of small (1.2 mm) summer rainfall events, and physical disturbance from trampling all promoted early successional community states marked by dramatic declines in moss cover and increases in cyanobacteria cover, with more variable effects on lichens. Although the pace of community change varied significantly among treatments, our results suggest that multiple aspects of climate change will affect biocrusts to the same degree as physical disturbance. This is particularly disconcerting in the context of warming, as temperatures for drylands are projected to increase beyond those imposed as treatments in our study.
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A broad range of synthetic trabecular-like metallic lattices are 3D printed, to study the extra design freedom conferred by this new manufacturing process. The aim is to propose new ...conceptual types of implant structures for superior bio-mechanical matching and osseo-integration: synthetic bone. The target designs are 3D printed in Ti-6Al-4V alloy using a laser-bed process. Systematic evaluation is then carried out: (i) their accuracy is characterised at high spatial resolution using computed X-ray tomography, to assess manufacturing robustness with respect to the original geometrical design intent and (ii) the mechanical properties – stiffness and strength – are experimentally measured, evaluated, and compared. Finally, this new knowledge is synthesised in a conceptual framework to allow the construction of so-called implant design maps, to define the processing conditions of bone tailored substitutes, with focus on spine fusion devices. The design criteria emphasise the bone stiffness-matching, preferred range of pore structure for bone in-growth, manufacturability of the device and choice of inherent materials properties which are needed for durable implants. Examples of the use of such maps are given with focus on spine fusion devices, emphasising the stiffness-matching, osseo-integration properties and choice of inherent materials properties which are needed for durable implants.
We present a conceptual bio-engineering design methodology for new biomedical lattices produced by additive manufacturing, which addresses some of the critical points in currently existing porous implant materials. Amongst others: (i) feasibility and accuracy of manufacturing, (ii) design to the elastic properties of bone, and (iii) sensible pores sizes for osseointegration. This has inspired new and novel geometrical latticed designs which aim at improving the properties of intervertebral fusion devices. In their fundamental form, these structures are here fabricated and tested. When integrated into medical devices, these concepts could offer superior medical outcomes.
Purpose
To investigate the effect of prolonged glucocorticoid treatment for patients with acute respiratory distress syndrome (ARDS).
Methods
We conducted two sets of intention-to-treat analyses: (1) ...a primary analysis of individual patients’ data (IPD) of four randomized controlled trials (RCTs) which investigated methylprednisolone treatment (
n
= 322) and (2) a trial-level meta-analysis incorporating four additional RCTs which investigated hydrocortisone treatment in early ARDS (
n
= 297). We standardized definitions to derive outcomes in all datasets. The primary outcome for the IPD analysis was time to achieving unassisted breathing (UAB) by study day 28. Secondary outcomes included mechanical ventilation (MV) and intensive care unit (ICU)-free days, hospital mortality, and time to hospital mortality by day 28.
Results
By study day 28, compared to the placebo group, the methylprednisolone group had fewer patients who died before achieving UAB (12 vs. 29 %;
p
< 0.001) and more patients who achieved UAB (80 vs. 50 %;
p
< 0.001). In the methylprednisolone group, time to achieving UAB was shorter hazard ratio 2.59, 95 % confidence interval (CI) 1.95–3.43;
p
< 0.001, and hospital mortality was decreased (20 vs. 33 %;
p
= 0.006), leading to increased MV (13.3 ± 11.8 vs. 7.6 ± 5.7;
p
< 0.001) and ICU-free days (10.8 ± 0.71 vs. 6.4 ± 0.85;
p
< 0.001). In those patients randomized before day 14 of ARDS onset, the trial-level meta-analysis indicated decreased hospital mortality (36 vs. 49 %; risk ratio 0.76, 95 % CI 0.59–0.98,
I
2
= 17 %,
p
= 0.035; moderate certainty). Treatment was not associated with increased risk for infections (risk ratio 0.77, 95 % CI 0.56–1.08,
I
2
= 26 %;
p
= 0.13; moderate certainty).
Conclusions
Prolonged methylprednisolone treatment accelerates the resolution of ARDS, improving a broad spectrum of interrelated clinical outcomes and decreasing hospital mortality and healthcare utilization.
BCL-2 was the first antideath gene dis-covered, a milestone that effectively launched a new era in cell death research. Since its discovery more than 2 decades ago, multiple members of the human ...Bcl-2 family of apoptosis-regulating proteins have been identified, including 6 antiapoptotic proteins, 3 structurally similar proapoptotic proteins, and several structurally diverse proapoptotic interacting proteins that operate as upstream agonists or antagonists. Bcl-2–family proteins regulate all major types of cell death, including apoptosis, necrosis, and autophagy. As such, they operate as nodal points at the convergence of multiple pathways with broad relevance to biology and medicine. Bcl-2 derives its name from its original discovery in the context of B-cell lymphomas, where chromosomal translocations commonly activate the BCL-2 protooncogene, endowing B cells with a selective survival advantage that promotes their neoplastic expansion. The concept that defective programmed cell death contributes to malignancy was established by studies of Bcl-2, representing a major step forward in current understanding of tumorigenesis. Experimental therapies targeting Bcl-2 family mRNAs or proteins are currently in clinical testing, raising hopes that a new class of anticancer drugs may be near.
Nitrogen (N) availability is thought to frequently limit terrestrial ecosystem processes, and explicit consideration of N biogeochemistry, including biological N
2
fixation, is central to ...understanding ecosystem responses to environmental change. Yet, the importance of free-living N
2
fixation-a process that occurs on a wide variety of substrates, is nearly ubiquitous in terrestrial ecosystems, and may often represent the dominant pathway for acquiring newly available N-is often underappreciated. Here, we draw from studies that investigate free-living N
2
fixation from functional, physiological, genetic, and ecological perspectives. We show that recent research and analytical advances have generated a wealth of new information that provides novel insight into the ecology of N
2
fixation as well as raises new questions and priorities for future work. These priorities include a need to better integrate free-living N
2
fixation into conceptual and analytical evaluations of the N cycle's role in a variety of global change scenarios.
The accumulation of unfolded proteins in the endoplasmic reticulum (ER) represents a cellular stress induced by multiple stimuli and pathological conditions. These include hypoxia, oxidative injury, ...high-fat diet, hypoglycaemia, protein inclusion bodies and viral infection. ER stress triggers an evolutionarily conserved series of signal-transduction events, which constitutes the unfolded protein response. These signalling events aim to ameliorate the accumulation of unfolded proteins in the ER; however, when these events are severe or protracted they can induce cell death. With the increasing recognition of an association between ER stress and human diseases, and with the improved understanding of the diverse underlying molecular mechanisms, novel targets for drug discovery and new strategies for therapeutic intervention are beginning to emerge.
Bcl-2-family proteins are central regulators of cell life and death. At least three major classes of Bcl-2-family proteins have been delineated, including proapoptotic proteins that contain several ...conserved regions of sequence similarity (termed 'multidomain'). In mammals, the multidomain proteins (MDPs) of the Bcl-2 family include Bax, Bak, and Bok. The founding member of the MDP group of Bcl-2-family proteins was discovered by Stanley Korsmeyer and co-workers, initiating an exciting area of cell death research. The status of current knowledge about the mechanisms and functions of MDPs is reviewed here, and some areas for future research are outlined. Therapeutic opportunities emerging from a growing understanding of MDPs with respect to their three-dimensional structures, biochemical actions, and roles in disease raise hopes that the foundation of basic research laid by Korsmeyer and others will eventually be translated into clinical benefits, leaving a legacy that benefits the world for many decades.
A hallmark of cancer is the deregulation of cell-cycle machinery, ultimately facilitating aberrant proliferation that fuels tumorigenesis and disease progression. Particularly, in breast cancers, ...cyclin D1 has a crucial role in the development of disease. Recently, a highly specific inhibitor of CDK4/6 activity (PD-0332991) has been developed that may have efficacy in the treatment of breast cancer. To interrogate the utility of PD-0332991 in treating breast cancers, therapeutic response was evaluated on a panel of breast cancer cell lines. These analyses showed that the chronic loss of Rb is specifically associated with evolution to a CDK4/6-independent state and, ultimately, resistance to PD-0332991. However, to interrogate the functional consequence of Rb directly, knockdown experiments were performed in models that represent immortalized mammary epithelia and multiple subtypes of breast cancer. These studies showed a highly specific role for Rb in mediating the response to CDK4/6 inhibition that was dependent on transcriptional repression manifest through E2F, and the ability to attenuate CDK2 activity. Acquired resistance to PD-03322991 was specifically associated with attenuation of CDK2 inhibitors, indicating that redundancy in CDK functions represents a determinant of therapeutic failure. Despite these caveats, in specific models, PD-0332991 was a particularly effective therapy, which induced Rb-dependent cytostasis. Combined, these findings indicate the critical importance of fully understanding cell-cycle regulatory pathways in directing the utilization of CDK inhibitors in the clinic.
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