Red Cooler Bag Young, Megan E.
Journal of the American Geriatrics Society (JAGS),
April 2021, 2021-Apr, 2021-04-00, 20210401, Letnik:
69, Številka:
4
Journal Article
The chemical diversity and known safety profiles of drugs previously tested in humans make them a valuable set of compounds to explore potential therapeutic utility in indications outside those ...originally targeted, especially neglected tropical diseases. This practice of “drug repurposing” has become commonplace in academic and other nonprofit drug-discovery efforts, with the appeal that significantly less time and resources are required to advance a candidate into the clinic. Here, we report a comprehensive open-access, drug repositioning screening set of 12,000 compounds (termed ReFRAME; Repurposing, Focused Rescue, and Accelerated Medchem) that was assembled by combining three widely used commercial drug competitive intelligence databases (Clarivate Integrity, GVK Excelra GoStar, and Citeline Pharmaprojects), together with extensive patent mining of small molecules that have been dosed in humans. To date, 12,000 compounds (∼80% of compounds identified from data mining) have been purchased or synthesized and subsequently plated for screening. To exemplify its utility, this collection was screened against Cryptosporidium spp., a major cause of childhood diarrhea in the developing world, and two active compounds previously tested in humans for other therapeutic indications were identified. Both compounds, VB-201 and a structurally related analog of ASP-7962, were subsequently shown to be efficacious in animal models of Cryptosporidium infection at clinically relevant doses, based on available human doses. In addition, an open-access data portal (https://reframedb.org) has been developed to share ReFRAME screen hits to encourage additional follow-up and maximize the impact of the ReFRAME screening collection.
An imbalance in pyrite weathering and burial is a primary mechanism responsible for oxygenation of the atmosphere and oceans, but key processes governing the terrestrial sulfur cycle remain nebulous. ...Here, we investigate components of the terrestrial sulfur cycle in a highly productive, glacier‐fed catchment, and use a global mass balance model to constrain riverine sulfur fluxes. Chemistry of stream water and plant debris in the Jostedal watershed, Norway suggests sulfur isotope discrimination is occurring in the porewater. Global models also corroborate additional, previously overlooked pyrite burial with a modest isotope fractionation (<20‰), similar to values reported from freshwater ecosystems. Collectively, our results indicate that a significant amount of sulfate produced by weathering remains trapped in terrestrial environments. This terrestrial sulfur sink might have waxed and waned over geologic time in response to major biogeochemical events such as terrestrial afforestation.
Plain Language Summary
The amount of oxygen in Earth’s surface environments is governed by the balance between formation of sulfur‐bearing pyrite and its exposure to the atmosphere and consequent destruction (rusting). Pyrite commonly forms during bacterial activity in oxygen‐free conditions, for example, in bogs, soil, and sediment. Here, we study the destruction and formation of pyrite by examining the chemistry of stream water, meltwater of snow and glacial ice, rain water, sediment, rock, soil, and plants within a glacial meltwater stream environment. Sulfur isotope compositions indicate that a large amount of pyrite forms by bacterial activity in this river system. Modeling of the global sulfur budget also supports our findings that, on the global scale, a significant amount of pyrite has formed in such systems throughout Earth’s history, affecting the balance between formation and destruction of pyrite, thus playing a key role in climate and environmental changes.
Key Points
Glacier‐driven weathering (both pyrite and silicate) and sulfur cycle were examined in a meltwater system
δ34S of the natural reservoirs indicates microbial sulfate reduction and burial of reduced sulfur occurring in the watershed
Results of global sulfur cycle model confirm a significant flux of terrestrial sulfur burial driven by microbial reduction
Lower-limb amputation limits inherent motor abundance in the locomotor system and impairs walking mechanics. Able-bodied walkers vary ankle torque to adjust step-to-step leg force production as ...measured by resultant ground reaction forces. Simultaneously, knee torque covaries with ankle torque to act as a brake, resulting in consistent peak leg power output measured by external mechanical power generated on the center of mass. Our objective was to test how leg force control during gait is affected by joint torque variance structure in the amputated limb. Within the framework of the uncontrolled manifold analysis, we measured the Index of Motor Abundance (IMA) to quantify joint torque variance structure of amputated legs and its effect on leg force, where IMA > 0 indicates a stabilizing structure. We further evaluated the extent to which IMA in amputated legs used individual (INV) and coordinated (COV) joint control strategies. Amputated legs produced IMA and INV values similar to intact legs, indicating that torque deviations of the prosthetic ankle can modulate leg force at the end of stance phase. However, we observed much lower COV values in the amputated leg relative to intact legs indicating that biological knee joint torque of the amputated leg does not covary with prosthetic ankle torque. This observation suggests inter-joint coordination during gait is significantly limited as a result of transtibial amputation and may help explain the higher rate of falls and impaired balance recovery in this population, pointing to a greater need to focus on inter-joint coordination within the amputated limb.
Functional neuroimaging studies indicate that interconnected parts of the subcallosal anterior cingulate cortex (ACC), striatum, and amygdala play a fundamental role in affect in health and disease. ...Yet, although the patterns of neural activity engaged in the striatum and amygdala during affective processing are well established, especially during reward anticipation, less is known about subcallosal ACC. Here, we recorded neural activity in non-human primate subcallosal ACC and compared this with interconnected parts of the basolateral amygdala and rostromedial striatum while macaque monkeys performed reward-based tasks. Applying multiple analysis approaches, we found that neurons in subcallosal ACC and rostromedial striatum preferentially signal anticipated reward using short bursts of activity that form temporally specific patterns. By contrast, the basolateral amygdala uses a mixture of both temporally specific and more sustained patterns of activity to signal anticipated reward. Thus, dynamic patterns of neural activity across populations of neurons are engaged in affect, especially in subcallosal ACC.
Neuronal activity is a potent extrinsic regulator of oligodendrocyte generation and central nervous system myelination. Clinically, repetitive transcranial magnetic stimulation (rTMS) is delivered to ...noninvasively modulate neuronal activity; however, the ability of rTMS to facilitate adaptive myelination has not been explored. By performing cre‐lox lineage tracing, to follow the fate of oligodendrocyte progenitor cells in the adult mouse brain, we determined that low intensity rTMS (LI‐rTMS), administered as an intermittent theta burst stimulation, but not as a continuous theta burst or 10 Hz stimulation, increased the number of newborn oligodendrocytes in the adult mouse cortex. LI‐rTMS did not alter oligodendrogenesis per se, but instead increased cell survival and enhanced myelination. These data suggest that LI‐rTMS can be used to noninvasively promote myelin addition to the brain, which has potential implications for the treatment of demyelinating diseases such as multiple sclerosis.
Main Points
The impact that low intensity repetitive transcranial magnetic stimulation (LI‐rTMS) has on cells of the oligodendrocyte lineage is stimulation frequency and cell‐stage specific.
LI‐rTMS does not affect oligodendrocyte progenitor cell proliferation or density.
LI‐rTMS, delivered in an intermittent theta burst pattern, promotes the survival of premyelinating oligodendrocytes and enhances myelin internode extension by newly myelinating oligodendrocytes.
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