Designing tight-binding ligands is a primary objective of small-molecule drug discovery. Over the past few decades, free-energy calculations have benefited from improved force fields and sampling ...algorithms, as well as the advent of low-cost parallel computing. However, it has proven to be challenging to reliably achieve the level of accuracy that would be needed to guide lead optimization (∼5× in binding affinity) for a wide range of ligands and protein targets. Not surprisingly, widespread commercial application of free-energy simulations has been limited due to the lack of large-scale validation coupled with the technical challenges traditionally associated with running these types of calculations. Here, we report an approach that achieves an unprecedented level of accuracy across a broad range of target classes and ligands, with retrospective results encompassing 200 ligands and a wide variety of chemical perturbations, many of which involve significant changes in ligand chemical structures. In addition, we have applied the method in prospective drug discovery projects and found a significant improvement in the quality of the compounds synthesized that have been predicted to be potent. Compounds predicted to be potent by this approach have a substantial reduction in false positives relative to compounds synthesized on the basis of other computational or medicinal chemistry approaches. Furthermore, the results are consistent with those obtained from our retrospective studies, demonstrating the robustness and broad range of applicability of this approach, which can be used to drive decisions in lead optimization.
As the number and diversity of animal species meriting conservation intervention increases, improving the success of translocation efforts is vital and understanding the role of physiological stress ...in translocation failure is essential. Though the short-term
acute
stress response is critical for survival in the wild,
chronic stress results in pathology and occurs when the physiological stress response system is pushed beyond the normal capacity and becomes dysregulated. As this review discusses, translocation may inevitably lead to a state of chronic stress; however, this translocation-induced stress does not doom an animal to post-release failure or preclude translocation as a conservation tool. Rather, because chronic stress in translocated animals may actually be the norm rather than the exception, “stress” can be considered a predictable factor to incorporate into translocation planning. In terms of translocation failure, we argue that the role of stress is an indirect one. Translocation-induced chronic stress increases the overall
vulnerability of the individuals and, as a result, decreases the probability that the population will become self-sustaining. In this review, we further propose techniques to potentially decrease the total number and magnitude of stressor exposures throughout the translocation procedure in order to diminish the incidence of chronic stress-related pathology. Aspects of the translocation activities, such as capture techniques and care procedures during captivity, can be adjusted to accomplish this. Though stress may be an inevitable component of translocation, reducing the impact and time course of chronic stress on the physiology and behavior of translocated animals will increase the likelihood of translocation success as measured by the formation of a new, self-sustaining population
The field of stress physiology has rapidly expanded, particularly in those fields interested in identifying chronic stress in wild animals. Despite this expansion, stress remains difficult to assess ...and understand, due in large part to the temporal complexities of common stress measurement techniques.
While the stress response happens on a short time‐scale, chronic stress results over longer time‐scales. Therefore, the temporal dynamics of techniques used to assess ‘stress’ need to be fully understood in order to be applied correctly.
In this review, we provide information on 37 physiological and behavioural metrics that are commonly used to measure stress, especially in wild free‐living vertebrates, with a particular focus on which time‐scale they integrate stress.
We organize these metrics into seven broad categories based on which physiological system they are most closely associated with (glucocorticoids, sympathetic/parasympathetic nervous system, immune, metabolic, cellular/molecular, tissue development and behaviour).
We conclude by summarizing which kind of biological questions and variation each technique is most suitable for.
This review will enable researchers to understand the temporal dynamics of stress measurement techniques for better design of future studies.
A free Plain Language Summary can be found within the Supporting Information of this article.
A free Plain Language Summary can be found within the Supporting Information of this article.
We used captive European starlings (Sturnus vulgaris) to test whether corticosterone responses differed in birds held under normal laboratory conditions or conditions of chronic stress. Surprisingly, ...both basal corticosterone concentrations and corticosterone responses to acute stress were significantly reduced when birds were chronically stressed. To determine the mechanism underlying this reduced response, animals under both conditions were injected with lactated Ringer's solution (control), adrenocorticotropin (ACTH), arginine vasotocin (AVT), or dexamethasone (DEX). ACTH increased corticosterone concentrations above stress-induced levels in both cases, although maximum responses were lower in chronically stressed birds. AVT did not augment the corticosterone response under nonchronically stressed conditions, but it did under chronically stressed conditions. DEX reduced maximal corticosterone concentrations in both cases. Neither ovine nor rat corticotropin-releasing factor (CRF) altered normal stress responses. These data indicate that changes in responsiveness of the hypothalamic-pituitary-adrenal axis to ACTH and AVT serve to downregulate corticosterone responses during chronic stress. Furthermore, these data lead to the following hypothesis: ACTH output from the pituitary limits maximum corticosterone concentrations under normal conditions, but reduced AVT release from the hypothalamus regulates lower corticosterone concentrations under chronic stress conditions.
The aim of this paper was to analyze the biomethanization process of food waste (FW) from a university campus restaurant in six reactors with three different total solid percentages (20%, 25% and 30% ...TS) and two different inoculum percentages (20–30% of mesophilic sludge). The experimental procedure was programmed to select the initial performance parameters (total solid and inoculum contents) in a lab-reactor with V: 1100mL and, later, to validate the optimal parameters in a lab-scale batch reactor with V: 5000mL. The best performance for food waste biodegradation and methane generation was the reactor with 20% of total solid and 30% of inoculum: give rise to an acclimation stage with acidogenic/acetogenic activity between 20 and 60 days and methane yield of 0.49L CH4/g VS. Also, lab-scale batch reactor (V: 5000mL) exhibit the classical waste decomposition pattern and the process was completed with high values of methane yield (0.22L CH4/g VS). Finally, a protocol was proposed to enhance the start-up phase for dry thermophilic anaerobic digestion of food waste.
The magnitude and direction of carbon cycle feedbacks under climate warming remain uncertain due to insufficient knowledge about the temperature sensitivities of soil microbial processes. Enzymatic ...rates could increase at higher temperatures, but this response could change over time if soil microbes adapt to warming. We used the Arrhenius relationship, biochemical transition state theory, and thermal physiology theory to predict the responses of extracellular enzyme Vmax and Km to temperature. Based on these concepts, we hypothesized that Vmax and Km would correlate positively with each other and show positive temperature sensitivities. For enzymes from warmer environments, we expected to find lower Vmax, Km, and Km temperature sensitivity but higher Vmax temperature sensitivity. We tested these hypotheses with isolates of the filamentous fungus Neurospora discreta collected from around the globe and with decomposing leaf litter from a warming experiment in Alaskan boreal forest. For Neurospora extracellular enzymes, Vmax Q10 ranged from 1.48 to 2.25, and Km Q10 ranged from 0.71 to 2.80. In agreement with theory, Vmax and Km were positively correlated for some enzymes, and Vmax declined under experimental warming in Alaskan litter. However, the temperature sensitivities of Vmax and Km did not vary as expected with warming. We also found no relationship between temperature sensitivity of Vmax or Km and mean annual temperature of the isolation site for Neurospora strains. Declining Vmax in the Alaskan warming treatment implies a short‐term negative feedback to climate change, but the Neurospora results suggest that climate‐driven changes in plant inputs and soil properties are important controls on enzyme kinetics in the long term. Our empirical data on enzyme Vmax, Km, and temperature sensitivities should be useful for parameterizing existing biogeochemical models, but they reveal a need to develop new theory on thermal adaptation mechanisms.
Understanding whether soil enzymes can adapt to warming temperatures is important for predicting biogeochemical feedbacks to climate change. Biochemical and physiological theory suggests that enzymes should exhibit thermal adaptation. We found support for this theory in decaying leaf litter from an Alaskan warming experiment but not among strains of Neurospora fungi isolated from different thermal environments. Our work reveals a need for improved theory and implies that thermal adaptation is unlikely to alleviate positive feedbacks between biogeochemical cycles and climate warming.
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•Low salinity waterflooding (LSW) in secondary mode boots production rate and recovery.•Multi-component ionic exchange (MIE) is the mechanism causing wettability reversal.•LSW ...triggers the removal of Ca 2+and Mg2+ links from the sand surface making it water wet.
Low salinity waterflooding (LSW) is a promising enhanced oil recovery process. The LSW advantage has been associated to changes in rock wettability toward a more water wet state. This study evaluated the effect of different flooding schemes on the performance of LSW in terms of production rate and incremental oil recovery from sand-pack systems. This work also investigated the main mechanism prompting sand wettability changes during LSW.
Flooding Scheme-1 consisted of high salinity waterflooding, low salinity waterflooding, alkali aided low salinity waterflooding, and low salinity waterflooding. Flooding Scheme-2 consisted of low salinity waterflooding, alkali aided low salinity waterflooding, and low salinity waterflooding. Flooding Scheme-3 consisted of alkali aided low salinity flooding and low salinity waterflooding. The main mechanism causing wettability reversal was verified employing contact angle analysis, inductively coupled plasma spectrometry, and scanning electron microscopy.
This new study reveals in a straightforward manner the effect of low salinity waterflooding schemes on both production rate and incremental oil recovery. LSW in secondary mode, as conducted in FS-2, expedited the oil production rate by 15% and increased the overall oil recovery by 20% relative to flooding schemes FS-1 and FS-3. Furthermore, this study determined that multi-component ionic exchange was the dominant mechanism for the reversal of sand wettability to a more water wet state.
This paper provides new insights for heavy oil producers on the relevance of the flooding schemes during LSW and on the dominant mechanism for wettability alteration during the recovery of heavy oil from unconsolidated sands.
Although it is known that the first case of cancer was recorded in ancient Egypt around 1600 BC, it was not until 1917 during the First World War and the development of mustard gas that chemotherapy ...against cancer became relevant; however, its properties were not recognised until 1946 to later be used in patients. In this sense, the use of metallopharmaceuticals in cancer therapy was extensively explored until the 1960s with the discovery of cisplatin and its anticancer activity. From that date to the present, the search for more effective, more selective metallodrugs with fewer side effects has been an area of continuous exploration. Efforts have led to considering a wide variety of metals from the periodic table, mainly from the d‐block, as well as a wide variety of organic ligands, preferably with proven biological activity. In this sense, various research groups have found an ideal binder in Schiff bases, since their raw materials are easily accessible, their synthesis conditions are friendly and their denticity can be manipulated. Therefore, in this review, we have explored the anticancer and antitumor activity reported in the literature for coordination complexes of d‐block metals coordinated with tridentate Schiff bases (O N O and O N N) derived from salicylaldehyde. For this work, we have used the main scientific databases CCDC® and SciFinder®.
The search for more effective and selective metal‐based anticancer drugs with fewer side effects has been an area of continuous exploration. This has led to the exploration of a wide range of metals from the periodic table, mainly from the d‐block, as well as a wide variety of organic ligands, preferably with proven biological activity. Herein we review d‐block transition metal complexes including tridentate Schiff bases from salicylaldehyde (O N O and O N N) that exhibit good results in preliminary anticancer and antitumor activity assays.
Glucocorticoids are popular hormones to measure in both biomedical and ecological studies of stress. Many assumptions used to interpret glucocorticoid results are derived from biomedical data on ...humans or laboratory rodents, but these assumptions often fail for wild animals under field conditions. We discuss five common assumptions often made about glucocorticoids in ecological and conservation research that are not generally supported by the literature. (1) High acute elevations of glucocorticoids indicate an animal in distress. In fact: because glucocorticoids are needed to survive stressors, elevated concentrations often reflect adequate coping. (2) Low glucocorticoid concentrations indicate a healthy animal. In fact: because glucocorticoids are important in responding to stressors, low glucocorticoid concentrations might indicate the lack of adequate coping. (3) Sustained elevated glucocorticoids indicate chronically stressed animals. In fact: glucocorticoid concentrations by themselves have no predictive value in diagnosing chronic stress. (4) Glucocorticoids mobilize energy to survive short‐term stressors such as predator attacks. In fact: glucocorticoids' primary impact on energy regulation is to remove glucose transporters from cell surfaces. Not only is this process too slow to provide short‐term energy, but glucocorticoid‐induced increases in glucose reflect decreased, not increased, glucose utilization. (5) Glucocorticoid measurements in non‐blood tissues (e.g., feces, hair, feathers, etc.) are equivalent to blood concentrations. In fact: these alternative tissues present imperfect reflections of blood concentrations, and it is blood concentrations that interact with receptors to evoke biological change. In summary, proper consideration of these common assumptions will greatly aid in interpreting glucocorticoid data from ecological and conservation studies.
Two different scenarios to interpret glucocorticoid data.
Research Highlights
Presenting five ways in which glucocorticoid data in free‐living animals are often misinterpreted, including health status assigned by glucocorticoid concentration, glucocorticoids' metabolic role, and interpreting glucocorticoids in non‐blood tissues.
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