60 research outputs found
Stability-based approaches in chemoproteomics
\ua9 The Author(s), 2024. Published by Cambridge University Press. Target deconvolution can help understand how compounds exert therapeutic effects and can accelerate drug discovery by helping optimise safety and efficacy, revealing mechanisms of action, anticipate off-target effects and identifying opportunities for therapeutic expansion. Chemoproteomics, a combination of chemical biology with mass spectrometry has transformed target deconvolution. This review discusses modification-free chemoproteomic approaches that leverage the change in protein thermodynamics induced by small molecule ligand binding. Unlike modification-based methods relying on enriching specific protein targets, these approaches offer proteome-wide evaluations, driven by advancements in mass spectrometry sensitivity, increasing proteome coverage and quantitation methods. Advances in methods based on denaturation/precipitation by thermal or chemical denaturation, or by protease degradation are evaluated, emphasising the evolving landscape of chemoproteomics and its potential impact on future drug-development strategies
Out of Their Depth? Isolated Deep Populations of the Cosmopolitan Coral Desmophyllum dianthus May Be Highly Vulnerable to Environmental Change
Deep sea scleractinian corals will be particularly vulnerable to the effects of
climate change, facing loss of up to 70% of their habitat as the
Aragonite Saturation Horizon (below which corals are unable to form calcium
carbonate skeletons) rises. Persistence of deep sea scleractinian corals will
therefore rely on the ability of larvae to disperse to, and colonise, suitable
shallow-water habitat. We used DNA sequence data of the internal transcribed
spacer (ITS), the mitochondrial ribosomal subunit (16S) and mitochondrial
control region (MtC) to determine levels of gene flow both within and among
populations of the deep sea coral Desmophyllum dianthus in SE
Australia, New Zealand and Chile to assess the ability of corals to disperse
into different regions and habitats. We found significant genetic subdivision
among the three widely separated geographic regions consistent with isolation
and limited contemporary gene flow. Furthermore, corals from different depth
strata (shallow <600 m, mid 1000–1500 m, deep >1500 m) even on the
same or nearby seamounts were strongly differentiated, indicating limited
vertical larval dispersal. Genetic differentiation with depth is consistent with
the stratification of the Subantarctic Mode Water, Antarctic Intermediate Water,
the Circumpolar Deep and North Pacific Deep Waters in the Southern Ocean, and we
propose that coral larvae will be retained within, and rarely migrate among,
these water masses. The apparent absence of vertical larval dispersal suggests
deep populations of D. dianthus are unlikely to colonise
shallow water as the aragonite saturation horizon rises and deep waters become
uninhabitable. Similarly, assumptions that deep populations will act as refuges
for shallow populations that are impacted by activities such as fishing or
mining are also unlikely to hold true. Clearly future environmental management
strategies must consider both regional and depth-related isolation of deep-sea
coral populations
Combined analgesics in (headache) pain therapy: shotgun approach or precise multi-target therapeutics?
<p>Abstract</p> <p>Background</p> <p>Pain in general and headache in particular are characterized by a change in activity in brain areas involved in pain processing. The therapeutic challenge is to identify drugs with molecular targets that restore the healthy state, resulting in meaningful pain relief or even freedom from pain. Different aspects of pain perception, i.e. sensory and affective components, also explain why there is not just one single target structure for therapeutic approaches to pain. A network of brain areas ("pain matrix") are involved in pain perception and pain control. This diversification of the pain system explains why a wide range of molecularly different substances can be used in the treatment of different pain states and why in recent years more and more studies have described a superior efficacy of a precise multi-target combination therapy compared to therapy with monotherapeutics.</p> <p>Discussion</p> <p>In this article, we discuss the available literature on the effects of several fixed-dose combinations in the treatment of headaches and discuss the evidence in support of the role of combination therapy in the pharmacotherapy of pain, particularly of headaches. The scientific rationale behind multi-target combinations is the therapeutic benefit that could not be achieved by the individual constituents and that the single substances of the combinations act together additively or even multiplicatively and cooperate to achieve a completeness of the desired therapeutic effect.</p> <p>As an example the fixesd-dose combination of acetylsalicylic acid (ASA), paracetamol (acetaminophen) and caffeine is reviewed in detail. The major advantage of using such a fixed combination is that the active ingredients act on different but distinct molecular targets and thus are able to act on more signalling cascades involved in pain than most single analgesics without adding more side effects to the therapy.</p> <p>Summary</p> <p>Multitarget therapeutics like combined analgesics broaden the array of therapeutic options, enable the completeness of the therapeutic effect, and allow doctors (and, in self-medication with OTC medications, the patients themselves) to customize treatment to the patient's specific needs. There is substantial clinical evidence that such a multi-component therapy is more effective than mono-component therapies.</p
Exploring new physics frontiers through numerical relativity
The demand to obtain answers to highly complex problems within strong-field gravity has been met with significant progress in the numerical solution of Einstein's equations - along with some spectacular results - in various setups. We review techniques for solving Einstein's equations in generic spacetimes, focusing on fully nonlinear evolutions but also on how to benchmark those results with perturbative approaches. The results address problems in high-energy physics, holography, mathematical physics, fundamental physics, astrophysics and cosmology
Pooled analysis of WHO Surgical Safety Checklist use and mortality after emergency laparotomy
Background The World Health Organization (WHO) Surgical Safety Checklist has fostered safe practice for 10 years, yet its place in emergency surgery has not been assessed on a global scale. The aim of this study was to evaluate reported checklist use in emergency settings and examine the relationship with perioperative mortality in patients who had emergency laparotomy. Methods In two multinational cohort studies, adults undergoing emergency laparotomy were compared with those having elective gastrointestinal surgery. Relationships between reported checklist use and mortality were determined using multivariable logistic regression and bootstrapped simulation. Results Of 12 296 patients included from 76 countries, 4843 underwent emergency laparotomy. After adjusting for patient and disease factors, checklist use before emergency laparotomy was more common in countries with a high Human Development Index (HDI) (2455 of 2741, 89.6 per cent) compared with that in countries with a middle (753 of 1242, 60.6 per cent; odds ratio (OR) 0.17, 95 per cent c.i. 0.14 to 0.21, P <0001) or low (363 of 860, 422 per cent; OR 008, 007 to 010, P <0.001) HDI. Checklist use was less common in elective surgery than for emergency laparotomy in high-HDI countries (risk difference -94 (95 per cent c.i. -11.9 to -6.9) per cent; P <0001), but the relationship was reversed in low-HDI countries (+121 (+7.0 to +173) per cent; P <0001). In multivariable models, checklist use was associated with a lower 30-day perioperative mortality (OR 0.60, 0.50 to 073; P <0.001). The greatest absolute benefit was seen for emergency surgery in low- and middle-HDI countries. Conclusion Checklist use in emergency laparotomy was associated with a significantly lower perioperative mortality rate. Checklist use in low-HDI countries was half that in high-HDI countries.Peer reviewe
- …