Updates in the use of cannabis for insomnia.

PURPOSE OF REVIEW: This review aims to summarize recent updates in the area of cannabis use for insomnia. RECENT FINDINGS: Cannabis products have continued to become more potent, particularly in regard to delta-9- tetrahydrocannabinol (THC) concentration. Additionally, the use of cannabis has continued to become more accepted with less legal restrictions. The reported use of cannabis for relief of symptoms in sleep disorders appears to be increasing, however the specific effects of cannabinoids on sleep varies with cannabinoid type and concentration. Some evidence supports claims of efficacy of cannabinoids in sleep disorders such as insomnia, while other evidence is either lacking or in some cases contradictory. Regular cannabis use has been associated with withdrawal which can profoundly alter sleep. Also, clinicians should be aware of the potential effects of cannabis on the metabolism of other medications as well as the fact that cannabis use has been reported in a significant number of women in the periods before, during, and after pregnancy. SUMMARY: Cannabis use has been becoming more and more prevalent in the setting of relaxed restrictions and easier consumer level access to cannabis and cannabis products. A relative paucity of high quality evidence regarding the effects of cannabis on sleep and the treatment of insomnia symptoms remains. The optimal type, concentration, ratio, and dosage form of cannabinoids in the treatment of insomnia symptoms needs further clarification. As the trend of acceptance and use of cannabis continues, more high quality evidence to help guide clinicians in their recommendations will hopefully become available.

New pharmacologic agents for insomnia and hypersomnia.

PURPOSE OF REVIEW: Insomnia and hypersomnia are conditions with multifactorial causes that can be difficult to treat. There have been recent developments and changes in the treatment of both conditions, including the addition of some agents that have a novel mechanism of action. This review summarizes recent changes and highlights pertinent updates. RECENT FINDINGS: Benzodiazepine receptor agonists received a warning in 2019 regarding the possibility of complex sleep behaviors, such as sleepwalking. Zolpidem has been marketed in new dosage forms that include sublingual tablets and oral spray formulations. Orexin receptor antagonists appear to be well tolerated with a good safety profile. Suvorexant received an approval for the treatment of patients with comorbid insomnia and dementia. Lemborexant was demonstrated to be effective for maintenance insomnia. Trazodone was shown to affect the oligomerization of tau proteins thus suggesting potential implications in attenuating dementia pathology. Pitolisant, a novel histamine-3 receptor antagonist/inverse agonist, gained approval for the treatment of excessive daytime sleepiness in adults with narcolepsy as well as obstructive sleep apnea. Solriamfetol, a new norepinephrine and dopamine reuptake inhibitor, was approved for hypersomnolence based on good efficacy, but with cardiovascular warnings. SUMMARY: Recent advancements in the treatment of insomnia includes agents with novel mechanisms, new indications, and new dosage forms. Risk of complex sleep behaviors, and possible next-day driving impairment, should be discussed for all agents used for insomnia, including orexin receptor antagonists. Novel agents also are available for hypersomnia and there are options beyond traditional stimulants that may have great utility.

Discovery of human cell selective effector molecules using single cell multiplexed activity metabolomics.

Discovering bioactive metabolites within a metabolome is challenging because there is generally little foreknowledge of metabolite molecular and cell-targeting activities. Here, single-cell response profiles and primary human tissue comprise a response platform used to discover novel microbial metabolites with cell-type-selective effector properties in untargeted metabolomic inventories. Metabolites display diverse effector mechanisms, including targeting protein synthesis, cell cycle status, DNA damage repair, necrosis, apoptosis, or phosphoprotein signaling. Arrayed metabolites are tested against acute myeloid leukemia patient bone marrow and molecules that specifically targeted blast cells or nonleukemic immune cell subsets within the same tissue biopsy are revealed. Cell-targeting polyketides are identified in extracts from biosynthetically prolific bacteria, including a previously unreported leukemia blast-targeting anthracycline and a polyene macrolactam that alternates between targeting blasts or nonmalignant cells by way of light-triggered photochemical isomerization. High-resolution cell profiling with mass cytometry confirms response mechanisms and is used to validate initial observations.

The use of fluorescently-tagged apoptolidins in cellular uptake and response studies.

The apoptolidins are glycomacrolide microbial metabolites reported to be selectively cytotoxic against tumor cells. Using fluorescently tagged active derivatives we demonstrate selective uptake of these four tagged glycomacrolides in cancer cells over healthy human blood cells. We also demonstrate the utility of these five fluorescently tagged glycomacrolides in fluorescent flow cytometry to monitor cellular uptake of the six glycomacrolides and cellular response.

Fluorescent probes of the apoptolidins and their utility in cellular localization studies.

Apoptolidin A has been described among the top 0.1% most-cell-selective cytotoxic agents to be evaluated in the NCI 60 cell line panel. The molecular structure of apoptolidin A consists of a 20-membered macrolide with mono- and disaccharide moieties. In contrast to apoptolidin A, the aglycone (apoptolidinone) shows no cytotoxicity (>10 µM) when evaluated against several tumor cell lines. Apoptolidin H, the C27 deglycosylated analogue of apoptolidin A, displayed sub-micromolar activity against H292 lung carcinoma cells. Selective esterification of apoptolidins A and H with 5-azidopentanoic acid afforded azido-functionalized derivatives of potency equal to that of the parent macrolide. They also underwent strain-promoted alkyne-azido cycloaddition reactions to provide access to fluorescent and biotin-functionalized probes. Microscopy studies demonstrate apoptolidins A and H localize in the mitochondria of H292 human lung carcinoma cells.

Atomistic simulations of liquid crystal mixtures of alkoxy substituted phenylpyrimidines 2PhP and PhP14.

We study liquid crystal mixtures of alkoxy substituted phenylpyrimidines 2-[4-(butyloxy)phenyl]-5-(octyloxy)pyrimidine (2PhP) and 2-[4-(tetradecyloxy)phenyl]-5-(tetradecyloxy)pyrimidine (PhP14) using molecular dynamics simulations at the all atom level. The molecular length of PhP14 is 1.8 times that of 2PhP, resulting in an interesting binary mixture phase diagram. Our simulations are composed of 1000-1600 molecules for a total of 80,000-130,000 atomic sites, with total simulation times of 60-100 ns. We first show that a pure 2PhP system self-assembles into isotropic, nematic, smectic A and smectic C phases, and a pure PhP14 system self-assembles into isotropic and smectic C phases. Binary mixtures of PhP14 and 2PhP display a stabilization of the smectic A phase at the expense of the smectic C and nematic phases. We determine that the concentration-induced phase transition from the smectic C to the smectic A phase in the mixture is driven by an out-of-layer fluctuation arrangement of the molecules. We also observe that the tilt angle in the smectic C phases formed in the mixtures is concentration dependent. The results of our simulations are in good agreement with the experimental findings of Kapernaum et al. [J. Org. Chem. 5, 65 (2009)], thus showing that atomistic simulations are capable of reproducing the phase behavior of liquid crystal mixtures and can also provide microscopic details regarding the mechanisms that govern phase stability.

Solvent-shift Monte Carlo: a cluster algorithm for solvated systems.

We present a cluster algorithm for the efficient simulation of solvated systems that we term solvent-shift Monte Carlo (SSMC). The algorithm involves a conformational change in a solvated solute molecule of interest, followed by a concerted movement of solvent particles about a rotation axis. The method satisfies detailed balance and can be applied to existing schemes to sample conformational space, where an axis or plane of rotation can be defined. We demonstrate that the algorithm significantly enhances the sampling of phase space in solvated systems, and may be easily combined with other advanced sampling techniques.

Self-assembled chiral superstructures composed of rigid achiral molecules and molecular scale chiral induction by dopants.

We explore the phase behavior of a rigid achiral bent-core model system. Nematic and smectic phases form at higher densities, whereas micelles and columns composed of chiral clusters of these molecules self-assemble at lower densities. No nucleation mechanism requiring transient chirality is possible in the formation of these chiral superstructures due to the rigid achiral nature of the substituents. We show the chiral micelles are minima of the potential energy surface using energy minimization and parallel tempering simulations. Chiral dopants were found to induce the system to adopt a consistent chiral twist direction, the first molecular scale computer simulation of this effect.

Monte Carlo simulations.

A description of Monte Carlo methods for simulation of proteins is given. Advantages and disadvantages of the Monte Carlo approach are presented. The theoretical basis for calculating equilibrium properties of biological molecules by the Monte Carlo method is presented. Some of the standard and some of the more recent ways of performing Monte Carlo on proteins are presented. A discussion of the estimation of errors in properties calculated by Monte Carlo is given.

Perspective: after a century of criticizing premedical education, are we missing the point?

Ever since Abraham Flexner formalized the idea of premedical education in 1910, medical educators have argued about how best to prepare students for medical school. This back-and-forth about the premedical years has focused almost exclusively on the range and content of the required course work; noticeably absent from the debate is consideration of the ways in which the experience of the premedical years-including the curricular and noncurricular demands placed on students-shape the moral education of the next generation of physicians. The authors review the century-long conversation about premedical education, highlighting the themes of that discussion and the important aspects of being a "premed" that have not been a part of the conversation. From their systematic review of college and university Web sites designed for premedical students and from comments collected from a symposium on the premedical years, the authors describe how life as a premedical student, and not just curricular content, teaches important lessons about what it means to be a professional. The authors also report important disparities in attitudes about premedical education; for example, premedical advisors regard the "sifting process" of premedical education as a "journey of discovery," whereas students describe their premedical years as a competition. The authors' work suggests a new approach to premedical education, an approach that combines the coursework needed to succeed in medical school with formal opportunities to reflect on both the positive and pernicious effects of the premedical years.

The effect of dielectric properties of sintering additives on microwave sintered silicon nitride ceramics.

Silicon nitride requires the use of susceptive additives for microwave liquid phase sintering due to the material's low dielectric loss. In this article, we report the effect of complex dielectric properties of two compositions of sintering aids on 2.45 GHz microwave sintered Si3N4 with respect to power absorption, temperature distribution and densification behavior. The temperature dependent dielectric properties were measured from 25 degrees C to 1400 degrees C using a conventional cavity perturbation technique. Finite Difference Time Domain (FDTD) electromagnetic simulations coupled with a thermal solver was used to predict the microwave power absorption and the corresponding temperature evolution inside the samples. The additive with higher dielectric loss (4 wt% MgO, 6 wt% Y2O3 and 2.5 wt% ZrO2) produces a greater sintered density than the lower loss additive (4 wt% MgO and 6 wt% Y2O3) or pure Si3N4. Although microwave loss at temperatures below 600 degrees C is insignificant with or without the additives, the loss begins to increase at higher temperatures when the additives are present and has a strong upward trend above 1000 degrees C. Above 1200 degrees C the sample containing ZrO2 exhibited the greatest loss. Numerical simulations at the peak sintering temperature show greater microwave power absorption and higher temperature in the sample with the highest loss additive. The simulation results correlate to the difference in densification behavior observed. The simulation was also useful because the material temperature was not accurately provided by optical pyrometer measurements of the crucible sample holder.

Modeling microscopic swimmers at low Reynolds number.

The authors employ three numerical methods to explore the motion of low Reynolds number swimmers, modeling the hydrodynamic interactions by means of the Oseen tensor approximation, lattice Boltzmann simulations, and multiparticle collision dynamics. By applying the methods to a three bead linear swimmer, for which exact results are known, the authors are able to compare and assess the effectiveness of the different approaches. They then propose a new class of low Reynolds number swimmers, generalized three bead swimmers that can change both the length of their arms and the angle between them. Hence they suggest a design for a microstructure capable of moving in three dimensions. They discuss multiple bead, linear microstructures and show that they are highly efficient swimmers. They then turn to consider the swimming motion of elastic filaments. Using multiparticle collision dynamics the authors show that a driven filament behaves in a qualitatively similar way to the micron-scale swimming device recently demonstrated by Dreyfus et al. [Nature (London) 437, 862 (2005)].

Quantifying influenza vaccine efficacy and antigenic distance.

We introduce a new measure of antigenic distance between influenza A vaccine and circulating strains. The measure correlates well with efficacies of the H3N2 influenza A component of the annual vaccine between 1971 and 2004, as do results of a theory of the immune response to influenza following vaccination. This new measure of antigenic distance is correlated with vaccine efficacy to a greater degree than are current state of the art phylogenetic sequence analyses or ferret antisera inhibition assays. We suggest that this new measure of antigenic distance be used in the design of the annual influenza vaccine and in the interpretation of vaccine efficacy monitoring.

Glassy dynamics in the adaptive immune response prevents autoimmune disease.

The immune system normally protects the human host against death by infection. However, when an immune response is mistakenly directed at self-antigens, autoimmune disease can occur. We describe a model of protein evolution to simulate the dynamics of the adaptive immune response to antigens. Computer simulations of the dynamics of antibody evolution show that different evolutionary mechanisms, namely, gene segment swapping and point mutation, lead to different evolved antibody binding affinities. Although a combination of gene segment swapping and point mutation can yield a greater affinity to a specific antigen than point mutation alone, the antibodies so evolved are highly cross reactive and would cause autoimmune disease, and this is not the chosen dynamics of the immune system. We suggest that in the immune system's search for antibodies, a balance has evolved between binding affinity and specificity.

Induced and spontaneous deracemization in bent-core liquid crystal phases and in other phases doped with bent-core molecules.

Recently discovered chiral properties of several bent-core smectic liquid crystal phases are summarized and discussed in detail under the assumption that typical bent-core molecules may exist in chiral conformational states and are achiral only on average. Results of atomistic computer simulations are presented which indicate the existence of strongly chiral conformational states for typical bent-core mesogens. A theory is developed which describes a possible shift of equilibrium between left- and right-handed conformations in a macroscopically chiral phase. The theory describes a chirality induction in the B2 bent-core phase and a reduction of the helical pitch in cholesteric and chiral SmC* phases doped with bent-core molecules. Finally, the possibility of spontaneous deracemization in bent-core smectic phases is discussed in detail.

Markov chains of infinite order and asymptotic satisfaction of balance: application to the adaptive integration method.

Adaptive Monte Carlo methods can be viewed as implementations of Markov chains with infinite memory. We derive a general condition for the convergence of a Monte Carlo method whose history dependence is contained within the simulated density distribution. In convergent cases, our result implies that the balance condition need only be satisfied asymptotically. As an example, we show that the adaptive integration method converges.

Parallel tempering: theory, applications, and new perspectives.

We review the history of the parallel tempering simulation method. From its origins in data analysis, the parallel tempering method has become a standard workhorse of physicochemical simulations. We discuss the theory behind the method and its various generalizations. We mention a selected set of the many applications that have become possible with the introduction of parallel tempering, and we suggest several promising avenues for future research.

Evolvability is a selectable trait.

Concomitant with the evolution of biological diversity must have been the evolution of mechanisms that facilitate evolution, because of the essentially infinite complexity of protein sequence space. We describe how evolvability can be an object of Darwinian selection, emphasizing the collective nature of the process. We quantify our theory with computer simulations of protein evolution. These simulations demonstrate that rapid or dramatic environmental change leads to selection for greater evolvability. The selective pressure for large-scale genetic moves such as DNA exchange becomes increasingly strong as the environmental conditions become more uncertain. Our results demonstrate that evolvability is a selectable trait and allow for the explanation of a large body of experimental results.