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The Millennium Drought lasted more than a decade and is notable for causing persistent shifts in the relationship between rainfall and runoff in many southeastern Australian catchments. Research to date has successfully characterised where and when shifts occurred and explored relationships with potential drivers, but a convincing physical explanation for observed changes in catchment behaviour is still lacking. Originating from a large multi-disciplinary workshop, this paper presents and evaluates a range of hypothesised process explanations of flow response to the Millennium Drought. The hypotheses consider climatic forcing, vegetation, soil moisture dynamics, groundwater, and anthropogenic influence. The hypotheses are assessed against evidence both temporally (e.g. why was the Millennium Drought different to previous droughts?) and spatially (e.g. why did rainfall–runoff relationships shift in some catchments but not in others?). Thus, the strength of this work is a large-scale assessment of hydrologic changes and potential drivers. Of 24 hypotheses, 3 are considered plausible, 10 are considered inconsistent with evidence, and 11 are in a category in between, whereby they are plausible yet with reservations (e.g. applicable in some catchments but not others). The results point to the unprecedented length of the drought as the primary climatic driver, paired with interrelated groundwater processes, including declines in groundwater storage, altered recharge associated with vadose zone expansion, and reduced connection between subsurface and surface water processes. Other causes include increased evaporative demand and harvesting of runoff by small private dams. Finally, we discuss the need for long-term field monitoring, particularly targeting internal catchment processes and subsurface dynamics. We recommend continued investment in the understanding of hydrological shifts, particularly given their relevance to water planning under climate variability and change.

The Modular Assessment of Rainfall–Runoff Models Toolbox (MARRMoT) is a flexible modelling framework reproducing the behaviour of 47 established hydrological models. This toolbox can be used to calibrate and run models in a user-friendly and consistent way and is designed to facilitate the sharing of model code for reproducibility and to support intercomparison between hydrological models. Additionally, it allows users to create or modify models using components of existing ones. We present a new MARRMoT release (v2.1) designed for improved speed and ease of use. While improved computational efficiency was the main driver for this redevelopment, MARRMoT v2.1 also succeeds in drastically reducing the verbosity and repetitiveness of the code, which improves readability and facilitates debugging. The process to create new models or modify existing ones within the toolbox is also simplified in this version, making MARRMoT v2.1 accessible for researchers and practitioners at all levels of expertise. These improvements were achieved by implementing an object-oriented structure and aggregating all common model operations into a single class definition from which all models inherit. The new modelling framework maintains and improves on several good practices built into the original MARRMoT and includes a number of new features such as the possibility of retrieving more output in different formats that simplifies troubleshooting, and a new functionality that simplifies the calibration process. We compare outputs of 36 of the models in the framework to an earlier published analysis and demonstrate that MARRMoT v2.1 is highly consistent with the previous version of MARRMoT (v1.4), while achieving a 3.6-fold improvement in runtime on average. The new version of the toolbox and user manual, including several workflow examples for common application, are available from GitHub (https://github.com/wknoben/MARRMoT, last access: 12 May 2022; https://doi.org/10.5281/zenodo.6484372, Trotter and Knoben, 2022b).

Groundwater recharge is one of the important factors determining the groundwater development potential of an area. Even though recharge plays a key role in controlling groundwater system dynamics, much uncertainty remains regarding the relationships between groundwater recharge and its governing factors at a large scale. Therefore, this study aims to identify the most influential factors of groundwater recharge, and to develop an empirical model to estimate diffuse rainfall recharge at a global scale. Recharge estimates reported in the literature from various parts of the world (715 sites) were compiled and used in model building and testing exercises. Unlike conventional recharge estimates from water balance, this study used a multimodel inference approach and information theory to explain the relationship between groundwater recharge and influential factors, and to predict groundwater recharge at 0.5° resolution. The results show that meteorological factors (precipitation and potential evapotranspiration) and vegetation factors (land use and land cover) had the most predictive power for recharge. According to the model, long-term global average annual recharge (1981–2014) was 134 mm yr−1 with a prediction error ranging from −8 to 10 mm yr−1 for 97.2 % of cases. The recharge estimates presented in this study are unique and more reliable than the existing global groundwater recharge estimates because of the extensive validation carried out using both independent local estimates collated from the literature and national statistics from the Food and Agriculture Organization (FAO). In a water-scarce future driven by increased anthropogenic development, the results from this study will aid in making informed decisions about groundwater potential at a large scale.

Many biological mechanisms rely on the precise control of conformational changes in proteins. Understanding such dynamic processes requires methods for determining structures and their temporal evolution. In this study, we introduce a novel approach to time-resolved ion mobility mass spectrometry. We validated the method on a simple photoreceptor model and applied it to a more complex system, the animal-like cryptochrome from Chlamydomonas reinhardtii ( Cr aCRY), to determine the role of specific amino acids affecting the conformational dynamics as reaction to blue light activation. In our setup, using a high-power LED mounted in the source region of an ion mobility mass spectrometer, we allow a time-resolved evaluation of mass and ion mobility spectra. Cryptochromes like Cr aCRY are a widespread type of blue light photoreceptors and mediate various light-triggered biological functions upon excitation of their inbuilt flavin chromophore. Another hallmark of cryptochromes is their flexible carboxy-terminal extension (CTE), whose structure and function as well as the details of its interaction with the photolyase homology region are not yet fully understood and differ among different cryptochromes types. Here, we addressed the highly conserved C-terminal domain of Cr aCRY, to study the effects of single mutations on the structural transition of the C-terminal helix α22 and the attached CTE upon lit-state formation. We show that D321, the putative proton acceptor of the terminal proton-coupled electron transfer event from Y373, is essential for triggering the large-scale conformational changes of helix α22 and the CTE in the lit state, while D323 influences the timing.

Cryptochromes are a ubiquitously occurring class of photoreceptors. Together with photolyases, they form the Photolyase Cryptochrome Superfamily (PCSf) by sharing a common protein architecture and binding mode of the FAD chromophore. Despite these similarities, PCSf members exert different functions. Photolyases repair UV-induced DNA damage by photocatalytically driven electron transfer between FADH ¯ and the DNA lesion, whereas cryptochromes are light-dependent signaling molecules and trigger various biological processes by photoconversion of their FAD redox and charge states. Given that most cryptochromes possess a C-terminal extension (CTE) of varying length, the functions of their CTE have not yet been fully elucidated and are hence highly debated. In this study, the role of the CTE was investigated for a novel subclass of the PCSf, the CryP-like cryptochromes, by hydrogen/deuterium exchange and mass-spectrometric analysis. Striking differences in the relative deuterium uptake were observed in different redox states of CryP from the diatom Phaeodactylum tricornutum. Based on these measurements we propose a model for light-triggered conformational changes in CryP-like cryptochromes that differs from other known cryptochrome families like the insect or plant cryptochromes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Machine learning (ML) models are poised to transform surgical pathology practice. The most successful use attention mechanisms to examine whole slides, identify which areas of tissue are diagnostic, and use them to guide diagnosis. Tissue contaminants, such as floaters, represent unexpected tissue. Although human pathologists are extensively trained to consider and detect tissue contaminants, we examined their impact on ML models. We trained 4 whole-slide models. Three operate in placenta for the following functions: (1) detection of decidual arteriopathy, (2) estimation of gestational age, and (3) classification of macroscopic placental lesions. We also developed a model to detect prostate cancer in needle biopsies. We designed experiments wherein patches of contaminant tissue are randomly sampled from known slides and digitally added to patient slides and measured model performance. We measured the proportion of attention given to contaminants and examined the impact of contaminants in the t-distributed stochastic neighbor embedding feature space. Every model showed performance degradation in response to one or more tissue contaminants. Decidual arteriopathy detection--balanced accuracy decreased from 0.74 to 0.69 ± 0.01 with addition of 1 patch of prostate tissue for every 100 patches of placenta (1% contaminant). Bladder, added at 10% contaminant, raised the mean absolute error in estimating gestational age from 1.626 weeks to 2.371 ± 0.003 weeks. Blood, incorporated into placental sections, induced false-negative diagnoses of intervillous thrombi. Addition of bladder to prostate cancer needle biopsies induced false positives, a selection of high-attention patches, representing 0.033 mm 2 , and resulted in a 97% false-positive rate when added to needle biopsies. Contaminant patches received attention at or above the rate of the average patch of patient tissue. Tissue contaminants induce errors in modern ML models. The high level of attention given to contaminants indicates a failure to encode biological phenomena. Practitioners should move to quantify and ameliorate this problem., (Copyright © 2024 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Photolyases, a ubiquitous class of flavoproteins, use blue light to repair DNA photolesions. In this work, we determined the structural mechanism of the photolyase-catalyzed repair of a cyclobutane pyrimidine dimer (CPD) lesion using time-resolved serial femtosecond crystallography (TR-SFX). We obtained 18 snapshots that show time-dependent changes in four reaction loci. We used these results to create a movie that depicts the repair of CPD lesions in the picosecond-to-nanosecond range, followed by the recovery of the enzymatic moieties involved in catalysis, completing the formation of the fully reduced enzyme-product complex at 500 nanoseconds. Finally, back-flip intermediates of the thymine bases to reanneal the DNA were captured at 25 to 200 microseconds. Our data cover the complete molecular mechanism of a photolyase and, importantly, its chemistry and enzymatic catalysis at work across a wide timescale and at atomic resolution.

Parkinson's disease (PD) remains a significant unmet clinical need. Gut dysbiosis stands as a PD pathologic source and therapeutic target. Here, we assessed the role of the gut-brain axis in PD pathology and treatment. Adult transgenic (Tg) α-synuclein-overexpressing mice served as subjects and were randomly assigned to either transplantation of vehicle or human umbilical cord blood-derived stem cells and plasma. Behavioral and immunohistochemical assays evaluated the functional outcomes following transplantation. Tg mice displayed typical motor and gut motility deficits, elevated α-synuclein levels, and dopaminergic depletion, accompanied by gut dysbiosis characterized by upregulation of microbiota and cytokines associated with inflammation in the gut and the brain. In contrast, transplanted Tg mice displayed amelioration of motor deficits, improved sparing of nigral dopaminergic neurons, and downregulation of α-synuclein and inflammatory-relevant microbiota and cytokines in both gut and brain. Parallel in vitro studies revealed that cultured dopaminergic SH-SY5Y cells exposed to homogenates of Tg mouse-derived dysbiotic gut exhibited significantly reduced cell viability and elevated inflammatory signals compared to wild-type mouse-derived gut homogenates. Moreover, treatment with human umbilical cord blood-derived stem cells and plasma improved cell viability and decreased inflammation in dysbiotic gut-exposed SH-SY5Y cells. Intravenous transplantation of human umbilical cord blood-derived stem/progenitor cells and plasma reduced inflammatory microbiota and cytokine, and dampened α-synuclein overload in the gut and the brain of adult α-synuclein-overexpressing Tg mice. Our findings advance the gut-brain axis as a key pathological origin, as well as a robust therapeutic target for PD., (© 2022. The Author(s).)

Flavin coenzymes are universally found in biological redox reactions. DNA photolyases, with their flavin chromophore (FAD), utilize blue light for DNA repair and photoreduction. The latter process involves two single-electron transfers to FAD with an intermittent protonation step to prime the enzyme active for DNA repair. Here we use time-resolved serial femtosecond X-ray crystallography to describe how light-driven electron transfers trigger subsequent nanosecond-to-microsecond entanglement between FAD and its Asn/Arg-Asp redox sensor triad. We found that this key feature within the photolyase-cryptochrome family regulates FAD re-hybridization and protonation. After first electron transfer, the FAD •- isoalloxazine ring twists strongly when the arginine closes in to stabilize the negative charge. Subsequent breakage of the arginine-aspartate salt bridge allows proton transfer from arginine to FAD •- . Our molecular videos demonstrate how the protein environment of redox cofactors organizes multiple electron/proton transfer events in an ordered fashion, which could be applicable to other redox systems such as photosynthesis., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

The present in vitro study showed that IL-2/IL-2R antibody complex facilitates Treg-induced neuroprotection in the oxygen glucose deprivation/reoxygenation (OGD/R) model of stroke. First, we examined the role of IL-2/IL-2R-treated Tregs in OGD/R-exposed rat primary cortical cells (PCCs), which represent the cell type of the ischemic gray matter in the stroke brain. Here, OGD/R induced cell death, which was attenuated by Tregs and more robustly by IL-2/IL-2R-treated Tregs, but not by IL-2/IL-2R treatment alone. Second, we next assessed IL-2/IL-2R effects in OGD/R-exposed human oligodendrocyte progenitor cells (OPCs), which correspond to the white matter injury after stroke. Results revealed that a similar pattern neuroprotection as seen in the gray matter, in that OGD/R triggered cell death, which was ameliorated by Tregs and more effectively by IL-2/IL-2R-treated Tregs, but IL-2/IL-2R treatment alone was not therapeutic. Third, as we begin to understand the mechanism underlying IL-2/IL-2R engagement of Tregs, we investigated the inflammatory response in OGD/R-exposed human neural progenitor cells (NPCs), which recapitulate both ischemic gray and white matter damage in stroke. Similar to PCCs and OPCs, OGD/R produced cell death and was blocked by Tregs and more efficiently by IL-2/IL-2R-treated Tregs, whereas IL-2/IL-2R treatment alone did not alter the ischemic insult. Moreover, the inflammatory marker, TNF-α, was upregulated after OGD/R, dampened by both Tregs and more efficiently by IL-2/IL-2R-treated Tregs but more pronounced in the latter, and not affected by IL-2/IL-2R treatment alone, suggesting IL-2/IL-2R-Treg-mediated modulation of inflammatory response in stroke. Altogether, these observations support the use of IL-2/IL-2R treatment in enhancing the anti-inflammatory effects of Tregs in stroke., (© 2021. The Author(s).)

Stem cell therapy may present an effective treatment for metastatic brain cancer and glioblastoma. Here we posit the critical role of a leaky blood-brain barrier (BBB) as a key element for the development of brain metastases, specifically melanoma. By reviewing the immunological and inflammatory responses associated with BBB damage secondary to tumoral activity, we identify the involvement of this pathological process in the growth and formation of metastatic brain cancers. Likewise, we evaluate the hypothesis of regenerating impaired endothelial cells of the BBB and alleviating the damaged neurovascular unit to attenuate brain metastasis, using the endothelial progenitor cell (EPC) phenotype of bone marrow-derived mesenchymal stem cells. Specifically, there is a need to evaluate the efficacy for stem cell therapy to repair disruptions in the BBB and reduce inflammation in the brain, thereby causing attenuation of metastatic brain cancers. To establish the viability of stem cell therapy for the prevention and treatment of metastatic brain tumors, it is crucial to demonstrate BBB repair through augmentation of vasculogenesis and angiogenesis. BBB disruption is strongly linked to metastatic melanoma, worsens neuroinflammation during metastasis, and negatively influences the prognosis of metastatic brain cancer. Using stem cell therapy to interrupt inflammation secondary to this leaky BBB represents a paradigm-shifting approach for brain cancer treatment. In this review article, we critically assess the advantages and disadvantages of using stem cell therapy for brain metastases and glioblastoma., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sadanandan, Shear, Brooks, Saft, Cabantan, Kingsbury, Zhang, Anthony, Wang, Salazar, Lezama Toledo, Rivera Monroy, Vega Gonzales-Portillo, Moscatello, Lee and Borlongan.)

A novel acyl-CoA dehydrogenase involved in degradation of the auxin indoleacetate by Aromatoleum aromaticum was identified as a decarboxylating benzylmalonyl-CoA dehydrogenase (IaaF). It is encoded within the iaa operon coding for enzymes of indoleacetate catabolism. Using enzymatically produced benzylmalonyl-CoA, the reaction was characterized as simultaneous oxidation and decarboxylation of benzylmalonyl-CoA to cinnamoyl-CoA and CO 2 . Oxygen served as electron acceptor and was reduced to H 2 O 2 , whereas electron transfer flavoprotein or artificial dyes serving as electron acceptors for other acyl-CoA dehydrogenases were not used. The enzyme is homotetrameric, contains an FAD cofactor and is enantiospecific in benzylmalonyl-CoA turnover. It shows high catalytic efficiency and strong substrate inhibition with benzylmalonyl-CoA, but otherwise accepts only a few medium-chain alkylmalonyl-CoA compounds as alternative substrates with low activities. Its reactivity of oxidizing 2-carboxyacyl-CoA with simultaneous decarboxylation is unprecedented and indicates a modified reaction mechanism for acyl-CoA dehydrogenases, where elimination of the 2-carboxy group replaces proton abstraction from C2., (© 2021. The Author(s).)

NewPHL is a recently discovered subgroup of ancestral DNA photolyases. Its domain architecture displays pronounced differences from that of canonical photolyases, in particular at the level of the characteristic electron transfer chain, which is limited to merely two tryptophans, instead of the "classical" three or four. Using transient absorption spectroscopy, we show that the dynamics of photoreduction of the oxidized FAD cofactor in the NewPHL begins similarly as that in canonical photolyases, i.e., with a sub-ps primary reduction of the excited FAD cofactor by an adjacent tryptophan, followed by migration of the electron hole towards the second tryptophan in the tens of ps regime. However, the resulting tryptophanyl radical then undergoes an unprecedentedly fast deprotonation in less than 100 ps in the NewPHL. In spite of the stabilization effect of this deprotonation, almost complete charge recombination follows in two phases of ~ 950 ps and ~ 50 ns. Such a rapid recombination of the radical pair implies that the first FAD photoreduction step, i.e., conversion of the fully oxidized to the semi-quinone state, should be rather difficult in vivo. We hence suggest that the flavin chromophore likely switches only between its semi-reduced and fully reduced form in NewPHL under physiological conditions.

The Millennium Drought (southeastern Australia) provided a natural experiment to challenge the assumption that watershed streamflow always recovers from drought. Seven years after the drought, the runoff (as a fraction of precipitation) had not recovered in 37% of watersheds, and the number of recovered watersheds was not increasing. When recovery did occur, it was not explained by watershed wetness. For those watersheds not recovered, ~80% showed no evidence of recovering soon, suggesting persistence within a low-runoff state. The post-drought precipitation not going to runoff was found to be likely going to increased evapotranspiration per unit of precipitation. These findings show that watersheds can have a finite resilience to disturbances and suggest that hydrological droughts can persist indefinitely after meteorological droughts., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Various neurological disorders, such as stroke and Alzheimer's disease (AD), involve neuroinflammatory responses. The advent of the gut-brain axis enhances our understanding of neurological disease progression and secondary cell death. Gut microbiomes, especially those associated with inflammation, may reflect the dysbiosis of both the brain and the gut, opening the possibility to utilize inflammatory microbiomes as biomarkers and therapeutic targets. The gut-brain axis may serve as a contributing factor to disease pathology and offer innovative approaches in cell-based regenerative medicine for the treatment of neurological diseases. In reviewing the pathogenesis of stroke and AD, we also discuss the effects of gut microbiota on cognitive decline and brain pathology. Although the underlying mechanism of primary cell death from either disease is clearly distinct, both may be linked to gut-microbial dysfunction as a consequential aberration that is unique to each disease. Targeting peripheral cell death pathways that exacerbate disease symptoms, such as those arising from the gut, coupled with conventional central therapeutic approach, may improve stroke and AD outcomes., (© 2021 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.)

Stroke stands as one of the most common causes of death among adults worldwide. Currently, tissue plasminogen activator serves as the only approved drug by the Food and Drug Administration for the treatment of acute ischemic stroke. Stem cell therapy serves as a viable treatment option and has been deemed as a safe and effective treatment for stroke patients. Adult human bone marrow-derived NCS-01 cells serve as a potential treatment for stroke given their ability to reduce stroke-induced pathological deficits by increasing cell viability and mitochondrial activity. Recently, we demonstrated the use of adult bone marrow-derived NCS-01 cells both on both in vitro and in vivo models. Using NCS-01 cells in rat stroke models subjected to middle cerebral artery occlusion, an effective dosage of 7.5 × 10 6 cells/ml, administered through the intracarotid artery within 3 days poststroke, was shown to display significant improvements in motor and neurological behaviors, reductions in infarct area, and peri-infarct cell loss. NCS-01 cells, in comparison with other lines of stem cells (Li cells), are shown to produce greater therapeutic effects, most likely due to the observed filopodia formation that allows the stem cells to extend and target the ischemic cells. Given these findings, NCS-01 stem cells serve as a potential treatment for stroke through the demonstration of profound efficacy and further research that favors their filopodia-mediated mechanism of action., Competing Interests: Prof. Cesario V. Borlongan is Associate Editor of Brain Circulation., (Copyright: © 2021 Brain Circulation.)

Epilepsy stands as a life-threatening disease that is characterized by unprovoked seizures. However, an important characteristic of epilepsy that needs to be examined is the neuropsychiatric aspect. Epileptic patients endure aggression, depression, and other psychiatric illnesses. Therapies for epilepsy can be divided into two categories: antiepileptic medications and surgical resection. Antiepileptic drugs are used to attenuate heightened neuronal firing and to lessen seizure frequency. Alternatively, surgery can also be conducted to physically cut out the area of the brain that is assumed to be the root cause for the anomalous firing that triggers seizures. While both treatments serve as viable approaches that aim to regulate seizures and ameliorate the neurological detriments spurred by epilepsy, they do not serve to directly counteract epilepsy's neuropsychiatric traits. To address this concern, a potential new treatment involves the use of stem cells. Stem cell therapy has been employed in experimental models of neurological maladies, such as Parkinson's disease, and neuropsychiatric illnesses like depression. Cell-based treatments for epilepsy utilizing stem cells such as neural stem cells (NSCs), mesenchymal stem cells (MSCs), and interneuron grafts have been explored in preclinical and clinical settings, highlighting both the acute and chronic stages of epilepsy. However, it is difficult to create an animal model to capitalize on all the components of epilepsy due to the challenges in delineating the neuropsychiatric aspect. Therefore, further preclinical investigation into the safety and efficacy of stem cell therapy in addressing both the neurological and the neuropsychiatric components of epilepsy is warranted in order to optimize cell dosage, delivery, and timing of cell transplantation., Competing Interests: CB declares patents and patent applications related to stem cell therapy. Additionally, CB was funded and received royalties and stock options from Astellas, Asterias, Sanbio, Athersys, KMPHC, and International Stem Cell Corporation; and also received consultant compensation for Chiesi Farmaceutici. The other authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. The other authors declare no conflict of interest.The authors thank the entire staff of the Borlongan Neural Transplantation Laboratory for critical discussions of this manuscript., (Copyright © 2021 Sadanandan, Saft, Gonzales-Portillo and Borlongan.)

Stroke is a life-threatening condition that is characterized by secondary cell death processes that occur after the initial disruption of blood flow to the brain. The inability of endogenous repair mechanisms to sufficiently support functional recovery in stroke patients and the inadequate treatment options available are cause for concern. The pathology behind oxidative stress in stroke is of particular interest due to its detrimental effects on the brain. The oxidative stress caused by ischemic stroke overwhelms the neutralization capacity of the body's endogenous antioxidant system, which leads to an overproduction of reactive oxygen species (ROS) and reactive nitrogen species (RNS) and eventually results in cell death. The overproduction of ROS compromises the functional and structural integrity of brain tissue. Therefore, it is essential to investigate the mechanisms involved in oxidative stress to help obtain adequate treatment options for stroke. Here, we focus on the latest preclinical research that details the mechanisms behind secondary cell death processes that cause many central nervous system (CNS) disorders, as well as research that relates to how the neuroprotective molecular mechanisms of pituitary adenylate cyclase-activating polypeptides (PACAPs) could make these molecules an ideal candidate for the treatment of stroke.

The human population is in the midst of battling a rapidly-spreading virus- Severe Acute Respiratory Syndrome Coronavirus 2, responsible for Coronavirus disease 2019 or COVID-19. Despite the resurgences in positive cases after reopening businesses in May, the country is seeing a shift in mindset surrounding the pandemic as people have been eagerly trickling out from federally-mandated quarantine into restaurants, bars, and gyms across America. History can teach us about the past, and today's pandemic is no exception. Without a vaccine available, three lessons from the 1918 Spanish flu pandemic may arm us in our fight against COVID-19. First, those who survived the first wave developed immunity to the second wave, highlighting the potential of passive immunity-based treatments like convalescent plasma and cell-based therapy. Second, the long-term consequences of COVID-19 are unknown. Slow-progressive cases of the Spanish flu have been linked to bacterial pneumonia and neurological disorders later in life, emphasizing the need to reduce COVID-19 transmission. Third, the Spanish flu killed approximately 17 to 50 million people, and the lack of human response, overcrowding, and poor hygiene were key in promoting the spread and high mortality. Human behavior is the most important strategy for preventing the virus spread and we must adhere to proper precautions. This review will cover our current understanding of the pathology and treatment for COVID-19 and highlight similarities between past pandemics. By revisiting history, we hope to emphasize the importance of human behavior and innovative therapies as we wait for the development of a vaccine. Graphical Abstract.

Stem cell-based therapy stands as a robust experimental treatment for ischemic stroke. Stem cells derived from fetal, embryonic, and adult tissues serve as potential sources for transplantable cells in the setting of ischemic stroke. However, the search continues for finding an optimal cell line for clinical use. Muse cells, a distinct subset of mesenchymal stem cells found sporadically in the connective tissue of nearly every organ, may be a suitable candidate due to its safety and accessibility. These cells have been investigated for therapeutic usage in chronic kidney disease, liver disease, acute myocardial infarction, and stroke. Muse cells display the ability to engraft and differentiate into the host neural network unlike many other cell lines which only display bystander immunomodulating effects. Taking advantage of this unique engraftment and differentiation mechanism behind Muse cells' therapeutic effects on the central nervous system, as well as other organ systems, will undoubtedly advance the cells' utility for cell-based regenerative medicine in stroke., (© 2020. Springer Nature Switzerland AG.)

Traumatic brain injury (TBI) is a pervasive and damaging form of acquired brain injury (ABI). Acute, subacute, and chronic cell death processes, as a result of TBI, contribute to the disease progression and exacerbate outcomes. Extended neuroinflammation can worsen secondary degradation of brain function and structure. Mesenchymal stem cell transplantation has surfaced as a viable approach as a TBI therapeutic due to its immunomodulatory and regenerative features. This article examines the role of inflammation and cell death in ABI as well as the effectiveness of bone marrow-derived mesenchymal stem/stromal cell (BM-MSC) transplants as a treatment for TBI. Furthermore, we analyze new studies featuring transplanted BM-MSCs as a neurorestorative and anti-inflammatory therapy for TBI patients. Although clinical trials support BM-MSC transplants as a viable TBI treatment due to their promising regenerative characteristics, further investigation is imperative to uncover innovative brain repair pathways associated with cell-based therapy as stand-alone or as combination treatments.

Photolyases are ubiquitously occurring flavoproteins for catalyzing photo repair of UV-induced DNA damages. All photolyases described so far have a bilobal architecture with a C-terminal domain comprising flavin adenine dinucleotide (FAD) as catalytic cofactor and an N-terminal domain capable of harboring an additional antenna chromophore. Using sequence-similarity network analysis we discovered a novel subgroup of the photolyase/cryptochrome superfamily (PCSf), the NewPHLs. NewPHL occur in bacteria and have an inverted topology with an N-terminal catalytic domain and a C-terminal domain for sealing the FAD binding site from solvent access. By characterizing two NewPHL we show a photochemistry characteristic of other PCSf members as well as light-dependent repair of CPD lesions. Given their common specificity towards single-stranded DNA many bacterial species use NewPHL as a substitute for DASH-type photolyases. Given their simplified architecture and function we suggest that NewPHL are close to the evolutionary origin of the PCSf., (© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Stroke is a major public health problem worldwide with a high burden of neurological disability and mortality. Long noncoding RNAs (lncRNAs) have attracted much attention in the past decades because of their newly discovered roles in pathophysiological processes in many diseases. The abundance of lncRNAs in the nervous system indicates that they may be part of a complex regulatory network governing physiology and pathology of the brain. In particular, lncRNAs have been shown to play pivotal roles in the pathogenesis of stroke. In this article, we provide a review of the multifaceted functions of lncRNAs in the pathogenesis of ischemic stroke and intracerebral hemorrhage, highlighting their promising use as stroke diagnostic biomarkers and therapeutics. To this end, we discuss the potential of stem cells in aiding lncRNA applications in stroke., (Copyright © 2020 Fan, Saft, Sadanandan, Gonzales-Portillo, Park, Sanberg, Borlongan and Luo.)

Stroke is a life-threatening disease that leads to mortality, with survivors subjected to long-term disability. Microvascular damage is implicated as a key pathological feature, as well as a therapeutic target for stroke. In this review, we present evidence detailing subacute diaschisis in a focal ischemic stroke rat model with a focus on blood-brain barrier (BBB) integrity and related pathogenic processes in contralateral brain areas. Additionally, we discuss BBB competence in chronic diaschisis in a similar rat stroke model, highlighting the pathological changes in contralateral brain areas that indicate progressive morphological brain disturbances overtime after stroke onset. With diaschisis closely approximating stroke onset and progression, it stands as a treatment of interest for stroke. Indeed, the use of stem cell transplantation for the repair of microvascular damage has been investigated, demonstrating that bone marrow stem cells intravenously transplanted into rats 48 h post-stroke survive and integrate into the microvasculature. Ultrastructural analysis of transplanted stroke brains reveals that microvessels display a near-normal morphology of endothelial cells and their mitochondria. Cell-based therapeutics represent a new mechanism in BBB and microvascular repair for stroke.

Stroke serves as a life-threatening disease and continues to face many challenges in the development of safe and effective therapeutic options. The use of hyperbaric oxygen therapy (HBOT) demonstrates pre-clinical effectiveness for the treatment of acute ischemic stroke and reports reductions in oxidative stress, inflammation, and neural apoptosis. These pathophysiological benefits contribute to improved functional recovery. Current pre-clinical and clinical studies are testing the applications of HBOT for stroke neuroprotection, including its use as a preconditioning regimen. Mild oxidative stress may be able to prime the brain to tolerate full extensive oxidative stress that occurs during a stroke, and HBOT preconditioning has displayed efficacy in establishing such ischemic tolerance. In this review, evidence on the use of HBOT following an ischemic stroke is examined, and the potential for HBOT preconditioning as a neuroprotective strategy. Additionally, HBOT as a stem cell preconditioning is also discussed as a promising strategy, thus maximizing the use of HBOT for ischemic stroke.

Secreted by the pineal gland to regulate the circadian rhythm, melatonin is a powerful antioxidant that has been used to combat oxidative stress in the central nervous system. Melatonin-based therapies have been shown to provide neuroprotective effects in the setting of ischemic stroke by mitigating neuroinflammation and accelerating brain tissue restoration. Melatonin treatment includes injection of exogenous melatonin, pineal gland grafting and melatonin-mediated stem cell therapy. This review will discuss the current preclinical and clinical studies investigating melatonin-based therapeutics to treat stroke.

Stroke is a devastating condition characterized by widespread cell death after disruption of blood flow to the brain. The poor regenerative capacity of neural cells limits substantial recovery and prolongs disruptive sequelae. Current therapeutic options are limited and do not adequately address the underlying mitochondrial dysfunction caused by the stroke. These same mitochondrial impairments that result from acute cerebral ischemia are also present in retinal ischemia. In both cases, sufficient mitochondrial activity is necessary for cell survival, and while astrocytes are able to transfer mitochondria to damaged tissues to rescue them, they do not have the capacity to completely repair damaged tissues. Therefore, it is essential to investigate this mitochondrial transfer pathway as a target of future therapeutic strategies. In this review, we examine the current literature pertinent to mitochondrial repair in stroke, with an emphasis on stem cells as a source of healthy mitochondria. Stem cells are a compelling cell type to study in this context, as their ability to mitigate stroke-induced damage through non-mitochondrial mechanisms is well established. Thus, we will focus on the latest preclinical research relevant to mitochondria-based mechanisms in the treatment of cerebral and retinal ischemia and consider which stem cells are ideally suited for this purpose.

Aromatic amines like 2-phenylethylamine (2-PEA) and benzylamine (BAm) have been identified as novel growth substrates of the betaproteobacterium Aromatoleum aromaticum EbN1, which degrades a wide variety of aromatic compounds in the absence of oxygen under denitrifying growth conditions. The catabolic pathway of these amines was identified, starting with their oxidative deamination to the corresponding aldehydes, which are then further degraded via the enzymes of the phenylalanine or benzyl alcohol metabolic pathways. Two different periplasmic quinohemoprotein amine dehydrogenases involved in 2-PEA or BAm metabolism were identified and characterized. Both enzymes consist of three subunits, contain two heme c cofactors in their α-subunits, and exhibit extensive processing of their γ-subunits, generating four intramolecular thioether bonds and a cysteine tryptophylquinone (CTQ) cofactor. One of the enzymes was present in cells grown with 2-PEA or other substrates, showed an α 2 β 2 γ 2 composition, and had a rather broad substrate spectrum, which included 2-PEA, BAm, tyramine, and 1-butylamine. In contrast, the other enzyme was specifically induced in BAm-grown cells, showing an αβγ composition and activity only with BAm and 2-PEA. Since the former enzyme showed the highest catalytic efficiency with 2-PEA and the latter with BAm, they were designated 2-PEADH and benzylamine dehydrogenase (BAmDH). The catalytic properties and inhibition patterns of 2-PEADH and BAmDH showed considerable differences and were compared to previously characterized quinohemoproteins of the same enzyme family. IMPORTANCE The known substrate spectrum of A. aromaticum EbN1 is expanded toward aromatic amines, which are metabolized as sole substrates coupled to denitrification. The characterization of the two quinohemoprotein isoenzymes involved in degrading either 2-PEA or BAm expands the knowledge of this enzyme family and establishes for the first time that the necessary maturation of their quinoid CTQ cofactors does not require the presence of molecular oxygen. Moreover, the study revealed a highly interesting regulatory phenomenon, suggesting that growth with BAm leads to a complete replacement of 2-PEADH by BAmDH, which has considerably different catalytic and inhibition properties., (Copyright © 2019 American Society for Microbiology.)

The biochemical properties of a new tungsten-containing aldehyde oxidoreductase from the mesophilic betaproteobacterium Aromatoleum aromaticum EbN1 (AOR Aa ) are presented in this study. The enzyme was purified from phenylalanine-grown cells of an overexpressing mutant lacking the gene for an aldehyde dehydrogenase normally involved in anaerobic phenylalanine degradation. AOR Aa catalyzes the oxidation of a broad variety of aldehydes to the respective acids with either viologen dyes or NAD + as electron acceptors. In contrast to previously known AORs, AOR Aa is a heterohexameric protein consisting of three different subunits, a large subunit containing the W-cofactor and an Fe-S cluster, a small subunit containing four Fe-S clusters, and a medium subunit containing an FAD cofactor. The presence of the expected cofactors have been confirmed by elemental analysis and spectrophotometric methods. AOR Aa has a pH optimum of 8.0, a temperature optimum of 40°C and is completely inactive at 50°C. Compared to archaeal AORs, AOR Aa is remarkably resistant against exposure to air, exhibiting a half-life time of 1 h as purified enzyme and being completely unaffected in cell extracts. Kinetic parameters of AOR Aa have been obtained for the oxidation of one aliphatic and two aromatic aldehydes, resulting in about twofold higher k cat values with benzyl viologen than with NAD + as electron acceptor. Finally, we obtained evidence that AOR Aa is also catalyzing the reverse reaction, reduction of benzoate to benzaldehyde, albeit at very low rates and under conditions strongly favoring acid reduction, e.g., low pH and using Ti(III) citrate as electron donor of very low redox potential. AOR Aa appears to be a prototype of a new subfamily of bacterial AOR-like tungsten-enzymes, which differ from the previously known archaeal AORs mostly by their multi-subunit composition, their low sensitivity against oxygen, and the ability to use NAD + as electron acceptor.