Fasting is deeply entrenched in evolution, yet its potential applications to today's most common, disabling neurological diseases remain relatively unexplored. Fasting induces an altered metabolic ...state that optimizes neuron bioenergetics, plasticity, and resilience in a way that may counteract a broad array of neurological disorders. In both animals and humans, fasting prevents and treats the metabolic syndrome, a major risk factor for many neurological diseases. In animals, fasting probably prevents the formation of tumors, possibly treats established tumors, and improves tumor responses to chemotherapy. In human cancers, including cancers that involve the brain, fasting ameliorates chemotherapy-related adverse effects and may protect normal cells from chemotherapy. Fasting improves cognition, stalls age-related cognitive decline, usually slows neurodegeneration, reduces brain damage and enhances functional recovery after stroke, and mitigates the pathological and clinical features of epilepsy and multiple sclerosis in animal models. Primarily due to a lack of research, the evidence supporting fasting as a treatment in human neurological disorders, including neurodegeneration, stroke, epilepsy, and multiple sclerosis, is indirect or non-existent. Given the strength of the animal evidence, many exciting discoveries may lie ahead, awaiting future investigations into the viability of fasting as a therapy in neurological disease.
In modern evolutionary divergence analysis the role of geological information extends beyond providing a timescale, to informing molecular rate variation across the tree. Here I consider the ...implications of this development. I use fossil calibrations to test the accuracy of models of molecular rate evolution for placental mammals, and reveal substantial misspecification associated with life history rate correlates. Adding further calibrations to reduce dating errors at specific nodes unfortunately tends to transfer underlying rate errors to adjacent branches. Thus, tight calibration across the tree is vital to buffer against rate model errors. I argue that this must include allowing maximum bounds to be tight when good fossil records permit, otherwise divergences deep in the tree will tend to be inflated by the interaction of rate errors and asymmetric confidence in minimum and maximum bounds. In the case of placental mammals I sought to reduce the potential for transferring calibration and rate model errors across the tree by focusing on well-supported calibrations with appropriately conservative maximum bounds. The resulting divergence estimates are younger than others published recently, and provide the long-anticipated molecular signature for the placental mammal radiation observed in the fossil record near the 66 Ma Cretaceous-Paleogene extinction event.
4-Chloroisocoumarin compounds have broad inhibitory properties against serine proteases. Here, we show that selected 3-alkoxy-4-chloroisocoumarins preferentially inhibit the activity of the conserved ...serine protease High-temperature requirement A of
. The synthesis of a new series of isocoumarin-based scaffolds has been developed, and their anti-chlamydial properties were investigated. The structure of the alkoxy substituent was found to influence the potency of the compounds against High-temperature requirement A, and modifications to the C-7 position of the 3-alkoxy-4-chloroisocoumarin structure attenuate anti-chlamydial properties.
Modern healthcare systems are founded on a disease-centric paradigm, which has conferred many notable successes against infectious disorders in the past. However, today's leading causes of death are ...dominated by non-infectious "lifestyle" disorders, broadly represented by the metabolic syndrome, atherosclerosis, cancer, and neurodegeneration. Our disease-centric paradigm regards these disorders as distinct disease processes, caused and driven by disease targets that must be suppressed or eliminated to clear the disease. By contrast, a health-centric paradigm recognizes the lifestyle disorders as a series of hormonal and metabolic responses to a singular, lifestyle-induced disease of mitochondria dysfunction, a disease target that must be restored to improve health, which may be defined as optimized mitochondria function. Seen from a health-centric perspective, most drugs target a response rather than the disease, whereas metabolic strategies, such as fasting and carbohydrate-restricted diets, aim to restore mitochondria function, mitigating the impetus that underlies and drives the lifestyle disorders. Substantial human evidence indicates either strategy can effectively mitigate the metabolic syndrome. Preliminary evidence also indicates potential benefits in atherosclerosis, cancer, and neurodegeneration. Given the existing evidence, integrating metabolic strategies into modern healthcare systems should be identified as a global health priority.
Glioblastoma (GBM) is the most common primary malignant brain tumour in adults. The standard of care consists of surgical resection and concurrent chemoradiation, followed by adjuvant temozolomide ...chemotherapy. This protocol is associated with a median survival of 12-15 months, and <5% of patients survive >3 years. Ketogenic metabolic therapy (KMT) targets cancer cell metabolism by restricting glucose availability and evoking differential stress resistance and sensitization, which may augment the standard treatments and lead to therapeutic benefit. The present study reports the case of a 64-year-old woman with isocitrate dehydrogenase (IDH)-wildtype GBM who pursued the standard treatment protocol in conjunction with an intensive, multimodal KMT program for 3 years. The KMT program consisted of a series of prolonged (7-day, fluid-only) fasts, which were specifically timed to maximize the tolerability and efficacy of the standard treatments, combined with a time-restricted ketogenic diet on all other days. During the first and second treatment years the patient sustained a glucose ketone index (GKI) of 1.65 and 2.02, respectively, which coincided with complete clinical improvement, a healthy body-mass index and a high quality of life, with no visible progressive tumour detected on imaging at the end of the second year. In the setting of the death of an immediate family member leading to increased life stress, slightly relaxed KMT adherence, and a higher GKI of 3.20, slow cancer progression occurred during the third year. The adverse effects attributed to KMT were mild. Despite the limitations of this case report, it highlights the feasibility of implementing the standard treatment protocol for GBM in conjunction with an intensive, long-term, multimodal and specifically timed KMT program, the potential therapeutic efficacy of which may depend upon achieving as low a GKI as possible. Key words: glioblastoma, metabolic therapy, fasting, ketogenic diet, cancer
There has been growing interest in transcranial direct current stimulation (tDCS), a non-invasive technique purported to modulate neural activity via weak, externally applied electric fields. ...Although some promising preliminary data have been reported for applications ranging from stroke rehabilitation to cognitive enhancement, little is known about how tDCS affects the human brain, and some studies have concluded that it may have no effect at all. Here, we describe a macaque model of tDCS that allows us to simultaneously examine the effects of tDCS on brain activity and behavior. We find that applying tDCS to right prefrontal cortex improves monkeys’ performance on an associative learning task. While firing rates do not change within the targeted area, tDCS does induce large low-frequency oscillations in the underlying tissue. These oscillations alter functional connectivity, both locally and between distant brain areas, and these long-range changes correlate with tDCS’s effects on behavior. Together, these results are consistent with the idea that tDCS leads to widespread changes in brain activity and suggest that it may be a valuable method for cheaply and non-invasively altering functional connectivity in humans.
•tDCS improves animals’ behavior on an associative learning task•Stimulation has local effects on LFP power and coherence.•It also causes frequency-specific changes in connectivity between brain areas•Inter-area coherence in gamma frequencies is linked to behavioral improvement
Krause et al. test transcranial direct current stimulation (tDCS) in a realistic non-human primate model. Stimulation of prefrontal cortex (PFC) improved animals’ associative learning while altering coherence between PFC and sensory areas. Their data suggest that tDCS may act by altering long-range connectivity between PFC and other brain areas.
PDF
