Narrow Time Window Research Articles

Salidroside facilitates neuroprotective effects in ischemic stroke by promoting axonal sprouting through promoting autophagy

BackgroundIschemic stroke is a common cerebrovascular disease characterized by high incidence, disability, mortality, and recurrence. The limitations of current pharmacological treatments, which have primarily single neuroprotective action and a narrow therapeutic time window, lead to unsatisfactory therapeutic efficacy. Activation of autophagy can facilitate neural regeneration. ObjectiveTo clarify whether salidroside can promote axonal sprouting through autophagy resulting in protecting neurons. MethodsIn vivo, a Middle Cerebral Artery Occlusion/reperfusion (MCAO/IR) model was used, and in vitro, an Oxygen-Glucose Deprivation/Reoxygenation (OGD/R)-induced primary neuronal cell model was employed to evaluate the neuroprotective effects of salidroside. BDA neurotracer, immunofluorescence, and Western blot (WB) were utilized to determine its impact on axonal sprouting and the levels of related proteins (MAP2, GAP43, and PSD-95). Proteomics, transmission electron microscopy (TEM), and WB were applied to identify the effects on autophagy-related proteins (beclin1, LC3, p62, and LAMP2), autophagosomes and lysosomes. The mechanism of salidroside in promoting axonal sprouting through inducing autophagy was further confirmed by blocking with the autophagy inhibitor 3-MA. ResultsSalidroside reduced neurologic deficits and infarct volume induced by MCAO/IR in vivo and protected OGD/R induced primary neuronal cells in vitro. Both in vivo and in vitro, it increased the number and length of axons and upregulated the expression of key axonal proteins (MAP2, GAP43, and PSD-95) and mediated autophagy-related proteins. Mechanistic studies showed that the promoting effects of salidroside on autophagy and axonal sprouting disappeared after the blockade by 3-MA. ConclusionThis study reports for the first time that the neuroprotective effect of salidroside in ischemic stroke can be executed through mediating autophagy-related protein (beclin1, LC3, p62, and LAMP2), resulting in induced axonal sprouting or mature protein (MAP2, GAP43, and PSD-95).

Characteristics of exposure to radioactive iodine during a nuclear incident.

During a nuclear accident, numerous products of nuclear fission are released, including isotopes of radioactive iodine. Among them is iodine-131, with a half-life of 8.02 days, which emits β radiation. For decades, it has been effectively and safely used in medicine. However, in the event of a nuclear accident, uncontrolled exposure can have harmful biological effects. The main sources of internal contamination with iodine-131 are contaminated air, food and water. The most exposed organ is the thyroid gland, where radioactive iodine accumulates via the Na+/I- symporter (NIS). NIS does not distinguish between radioactive iodine isotopes and the stable isotope iodine-127, which is essential for the synthesis of thyroid hormones. Exposure to radioactive iodine during a nuclear accident is primarily associated with papillary thyroid cancer, whose incidence begins to increase a few years after exposure. Children and adolescents are at the highest risk, and the risk is particularly significant for individuals living in iodine-deficient areas. Ensuring an adequate iodine supply is therefore crucial for lowering the risk of the harmful effects of exposure to radioactive iodine at the population level. Protecting the thyroid with potassium iodide tablets significantly reduces radiation exposure, as stable iodine prevents the entry of radioactive iodine into the thyroid. Such protection is effective only within a narrow time window - a few hours before and after the exposure and is recommended only for those under 40 years of age, as the risks of excessive iodine intake outweigh the potential benefits in older individuals.

An oil-in-gel type of organohydrogel loaded with methylprednisolone for the treatment of secondary injuries following spinal cord traumas

The secondary injuries following traumatic spinal cord injury (SCI) is a multiphasic and complex process that is difficult to treat. Although methylprednisolone (MP) is the only available pharmacological regime for SCI treatment, its efficacy remains controversial due to its very narrow therapeutic time window and safety concerns associated with high dosage. In this study, we have developed an oil-in-gel type of organohydrogel (OHG) in which the binary oleic-water phases coexist, for the local delivery of MP. This new OHG is fabricated by a glycol chitosan/oxidized hyaluronic acid hydrophilic network that is uniformly embedded with a biocompatible oil phase, and it can be effectively loaded with MP or other hydrophobic compounds. In addition to spatiotemporally control MP release, this biodegradable OHG also provides a brain tissue-mimicking scaffold that can promote tissue regeneration. OHG remarkably decreases the therapeutic dose of MP in animals and extends its treatment course over 21 d, thereby timely manipulating microglia/macrophages and their associated with signaling molecules to restore immune homeostasis, leading to a long-term functional improvement in a complete transection SCI rat model. Thus, this OHG represents a new type of gel for clinical treatment of secondary injuries in SCI.

Progesterone Receptor Agonist, Nestorone, Exerts Long-Term Neuroprotective Effects Against Permanent Focal Cerebral Ischemia in Adult and Aged Male Rats.

Stroke is a leading cause of death and disability worldwide. Tissue plasminogen activator (tPA) is currently the most effective medicine for stroke; however, it has a narrow therapeutic time window (4.5h after symptom onset). We demonstrated that nestorone, a progesterone (P4) receptor agonist, exerted neuroprotective effects against transient focal cerebral ischemia 6h post-ischemic administration in adult male rats. This study examines its effects on permanent focal cerebral ischemia in adult and aged male rats, which are better models for evaluating treatment outcomes in typical stroke patients. Adult (6-month-old) or aged (18-month-old) male rats subjected to permanent middle cerebral artery occlusion (pMCAO) were continuously administered nestorone (10µg/day) or its vehicle (30% hydroxypropyl-β-cyclodextrin) for 7days via an osmotic pump subcutaneously implanted, starting at 18h post-pMCAO. Nestorone-treated adult male rats showed marked improvements in behavioral outcomes in the adhesive removal and rotarod tests and a significant reduction in infarct size compared to vehicle-treated rats 9 and 30days post-pMCAO. The same administration of nestorone resulted in apparently comparable neuroprotective effects in aged male rats. The inflammatory mediator NF-κB/p65 was increased in Iba-1 positive cells 24h post-pMCAO, but was significantly suppressed by subcutaneous injection of nestorone. These results suggested that nestorone exerts long-term neuroprotective effects against permanent focal cerebral ischemia in adult and aged male rats. Nestorone is thus a promising agent for post-stroke treatment owing to its wide age-independent therapeutic time window (18h after symptom onset), which is longer than that of tPA therapy.

Lu-Hf and U-Pb dating of the Zayanderud eclogites: Implications for Jurassic subduction initiation along the Neotethys margin in Iran

The time at which the Neotethys Ocean started to subduct along the southern margin of Eurasia within Iran has been debated in recent years. This margin, referred to as the Sanandaj-Sirjan Zone (SaSZ), features a series of Jurassic calc-alkaline igneous formations which were emplaced at c. 170 Ma. However, an alternative model suggests that subduction initiation occurred during the Cretaceous period. To address this age controversy, we utilized the Lu-Hf isochron method and employed SIMS U-Pb zircon and rutile geochronology to determine the metamorphic history of the earliest known Neotethyan eclogite outcrop along the upper Zayanderud River section of the SaSZ. Two eclogites separated by ∼25 km yielded Lu-Hf garnet dates of 175.1 ± 1.0 Ma and 172.5 ± 0.6 Ma. Rare <20 μm eclogitic zircon crystals in one of the eclogites are strongly zoned and yielded U-Pb dates for which a 177 ± 10 Ma rim age was deconvolved. The relatively low Dy/Yb of these zircon rims suggests that they crystallized prior to garnet formation, or retrograde in disequilibrium with garnet. Homogeneous U-Pb rutile ages averaging 162 ± 7 Ma are only marginally younger than the Lu-Hf garnet ages, consistent with the petrographic observation that rutile is predominantly found in the matrix or within garnet rims, and open-system behavior of radiogenic Pb during cooling. The newly obtained ages are close to previously published 40Ar/39Ar phengite dates and indicate a narrow time window during the Middle Jurassic for deep burial within a subduction channel, followed by eclogitization and rapid exhumation. These new constraints on the metamorphic history support subduction initiation along the SaSZ margin in the Jurassic period.

Medulloblastomas Initiated by Homologous Recombination Defects in Mice

Germline mutations of homologous-recombination (HR) genes are among the top contributors to medulloblastomas. A significant portion of human medulloblastomas exhibited genomic signatures of HR defects. We asked whether ablation of Brca2, Palb2, and their related Brca1 and Bccip genes, in the mouse brain can differentially initiate medulloblastomas. We established conditional knockout mouse models of these HR-genes, and a conditional knockdown of Bccip (shBccip-KD). Deletion of any of these genes led to microcephaly and neurological defects, with Brca1- and Bccip- producing the worst. Trp53 co-deletion significantly rescued the microcephaly with Brca1, Palb2, and Brca2 deficiency, but it exhibited limited impact on Bccip- mice. For the first time, inactivation of either Brca1 or Palb2 with Trp53 was found to induce medulloblastomas. Bccip/Trp53 deletions failed, despite that shBccip-CKD was highly penetrative, to induce medulloblastomas. The tumors displayed diverse immunohistochemical features and chromosome copy number variation. While there were widespread upregulations of cell proliferative pathways, most of the tumors expressed biomarkers of the Sonic Hedgehog subgroup. The MBs developed from Brca1-, Palb2-, and Brca2- mice were highly sensitive to a PARP inhibitor, but not the ones from shBccip-CKD mice. Our models recapitulate the spontaneous medulloblastoma development with high penetrance and narrow time-window, providing ideal platforms to test therapeutic agents with the ability to differentiate HR defective and proficient tumors.

An N-terminal heptad repeat trimer-based peptide fusion inhibitor exhibits potent anti-H1N1 activity

Influenza viruses are susceptible to seasonal influenza, which has repeatedly caused global pandemics and jeopardized human health. Vaccines are only used as preventive medicine due to the extreme mutability of influenza viruses, and antiviral medication is the most significant clinical treatment to reduce influenza morbidity and mortality. Nevertheless, the clinical application of anti-influenza virus agents is characterized by the narrow therapeutic time window, the susceptibility to drug resistance, and relatively limited effect on severe influenza. Therefore, it is of great significance to develop novel anti-influenza virus drugs to fulfill the urgent clinical needs. Influenza viruses enter host cells through the hemagglutinin (HA) mediated membrane fusion process, and fusion inhibitors function antivirally by blocking hemagglutinin deformation, promising better therapeutic efficacy and resolving drug resistance, with targets different from marketed medicines. Previous studies have shown that unnatural peptides derived from Human Immunodeficiency Virus Type 1 (HIV-1) membrane fusion proteins exhibit anti-HIV-1 activity. Based on the similarity of the membrane fusion protein deformation process between HIV-1 and H1N1, we selected sequences derived from the gp41 subunit in the HIV-1 fusion protein, and then constructed N-trimer spatial structure through inter-helical isopeptide bond modification, to design the novel anti-H1N1 fusion inhibitors. The results showed that the novel peptides could block 6-HB formation during H1N1 membrane fusion procedure, and thus possessed significant anti-H1N1 activity, comparable to the positive control oseltamivir. Our study demonstrates the design viability of peptide fusion inhibitors based on similar membrane fusion processes among viruses, and furthermore provides an important idea for the novel anti-H1N1 inhibitors development.

Systematic Insights into the Relationship between the Microbiota-Gut-Brain Axis and Stroke with the Focus on Tryptophan Metabolism.

Stroke, as a serious cerebral vascular disease with high incidence and high rates of disability and mortality, has limited therapeutic options due to the narrow time window. Compelling evidence has highlighted the significance of the gut microbiota and gut-brain axis as critical regulatory factors affecting stroke. Along the microbiota-gut-brain axis, tryptophan metabolism further acquires increasing attention for its intimate association with central nervous system diseases. For the purpose of exploring the potential role of tryptophan metabolism in stroke and providing systematic insights into the intricate connection of the microbiota-gut-brain axis with the pathological procedure of stroke, this review first summarized the practical relationship between microbiota and stroke by compiling the latest case-control research. Then, the microbiota-gut-brain axis, as well as its interaction with stroke, were comprehensively elucidated on the basis of the basic anatomical structure and physiological function. Based on the crosstalk of microbiota-gut-brain, we further focused on the tryptophan metabolism from the three major metabolic pathways, namely, the kynurenine pathway, serotonin pathway, and microbial pathway, within the axis. Moreover, the effects of tryptophan metabolism on stroke were appreciated and elaborated here, which is scarcely found in other reviews. Hopefully, the systematic illustration of the mechanisms and pathways along the microbiota-gut-brain axis will inspire more translational research from metabolic perspectives, along with more attention paid to tryptophan metabolism as a promising pharmaceutical target in order to reduce the risk of stroke, mitigate the stroke progression, and ameliorate the stroke prognosis.

Prenatal depression outcomes in the next generation: A critical review of recent DOHaD studies and recommendations for future research

Prenatal depression, a common pregnancy-related risk with a prevalence of 10–20 %, may affect in utero development and socioemotional and neurodevelopmental outcomes in the next generation. Although there is a growing body of work that suggests prenatal depression has an independent and long-lasting effect on offspring outcomes, important questions remain, and findings often do not converge. The present review examines work carried out in the last decade, with an emphasis on studies focusing on mechanisms and leveraging innovative technologies and study designs to fill in gaps in research. Overall, the past decade of research continues to suggest that prenatal depression increases risk for offspring socioemotional problems and may alter early brain development by affecting maternal-fetal physiology during pregnancy. However, important limitations remain; lack of diversity in study samples, inconsistent consideration of potential confounders (e.g., genetics, postnatal depression, parenting), and restriction of examination to narrow time windows and single exposures. On the other hand, exciting work has begun uncovering potential mechanisms underlying transmission, including alterations in mitochondria functioning, epigenetics, and the prenatal microbiome. We review the evidence to date, identify limitations, and suggest strategies for the next decade of research to detect mechanisms as well as sources of plasticity and resilience to ensure this work translates into meaningful, actionable science that improves the lives of families.

Overexpression of olfactory receptor 78 ameliorates brain injury in cerebral ischaemia-reperfusion rats by activating Prkaca-mediated cAMP/PKA-MAPK pathway.

Ischemic stroke is one of the main causes of disability and death. However, recanalization of occluded cerebral arteries is effective only within a very narrow time window. Therefore, it is particularly important to find neuroprotective biological targets for cerebral artery recanalization. Here, gene expression profiles of datasets GSE160500 and GSE97537 were downloaded from the GEO database, which were related to ischemic stroke in rats. Olfactory receptor 78 (Olfr78) was screened, and which highly associated with Calcium signalling pathway and MAPK pathway. Interacting protein of Olfr78, Prkaca, was predicted by STRING, and their interaction was validated by Co-IP analysis. Then, a rat model of middle cerebral artery occlusion/reperfusion (MCAO/R) and a neuronal cell model stimulated by oxygen-glucose deprivation/reoxygenation (OGD/R) were constructed, and the results showed that expression of Olfr78 and Prkaca was downregulated in MCAO rats and OGD/R-stimulated neurons. Overexpression of Olfr78 or Prkaca inhibited the secretion of inflammatory factors, Ca2+ overload, and OGD/R-induced neuronal apoptosis. Moreover, Overexpression of Prkaca increased protein levels of cAMP, PKA and phosphorylated p38 in OGD/R-stimulated neurons, while SB203580, a p38 inhibitor, treatment inhibited activation of the cAMP/PKA-MAPK pathway and counteracted the effect of Olfr78 overexpression on improvement of neuronal functions. Meanwhile, overexpression of Olfr78 or Prkaca markedly inhibited neuronal apoptosis and improved brain injury in MCAO/R rats. In conclusion, overexpression of Olfr78 inhibited Ca2+ overload and reduced neuronal apoptosis in MCAO/R rats by promoting Prkaca-mediated activation of the cAMP/PKA-MAPK pathway, thereby improving brain injury in cerebral ischaemia-reperfusion.

Bottlenose dolphins (Tursiops truncatus) display gaze alternation and referential communication in an impossible task

Gaze cues play a vital role in conveying critical information about objects and locations necessary for survival, such as food sources, predators, and the attentional states of conspecific and heterospecific individuals. During referential intentional communication, the continuous alternation of gaze between a communicative partner and a specific object or point of interest attracts the partner's attention towards the target. This behaviour is considered by many as essential for understanding intentions and is thought to involve mental planning. Here, we investigated the behavioural responses of seven bottlenose dolphins (Tursiops truncatus) that were given an impossible task in the presence of two experimenters (a ‘commanding experimenter’ and a ‘non-commanding experimenter’), whose attentional state towards the dolphins varied. We found that the dolphins spontaneously displayed gaze alternation, specifically triadic referential pointing, only when the human commanding experimenter was facing them. However, they ceased to alternate their gaze between the impossible object and the commanding experimenter when the experimenter had their back turned. Notably, the dolphins' behaviour differed from general pointing and gaze, as their triadic sequence occurred within a narrow time window. These findings suggest that the dolphins were sensitive to human attentional cues and utilized their own gaze cue (pointing) as a salient signal to attract the attention of the commanding experimenter towards a specific location.

Stingless bee foragers experience more thermally stressful microclimates and have wider thermal tolerance breadths than other worker subcastes

IntroductionThe current state of anthropogenic climate change is particularly concerning for tropical insects, species predicted to be the most negatively affected. Researching climatic tolerance in social insects is challenging because adaptations exist at both individual and societal levels. Division of labor research helps to bridge the gap between our understanding of these adaptations at different scales, which is important because social insects comprise a tremendous portion of global animal biomass, biodiversity, and ecosystem services. Considering how individual physiologies construct group-level adaptations can improve climate change impact assessments for social species. Tetragonisca angustula is a neotropical stingless bee species that exhibits high worker subcaste specialization with a morphologically distinct soldier caste.MethodsWe used this species to investigate 1) whether age- and size-differentiated subcastes differ in thermal tolerance, 2) which worker subcaste operates closest to their thermal limits, and 3) the extent to which this species selects active foraging times to offset thermal stress. We measured the thermal tolerance (CTmax and CTmin) of small-bodied foragers and two soldier subcastes (hovering guards and standing guards) in T. angustula.Results and discussionDespite body size differences between foragers and guards, no differences in the upper or lower thermal limits were observed. However, the average thermal tolerance breadth of foragers was significantly larger than that of guards, and foraging sites were more thermally variable than nest sites, supporting the Climatic Variability Hypothesis at a microclimate scale and in the context of division of labor. Warming tolerance was significantly lower among small-bodied foragers compared to hovering and standing guards. The magnitude of warming tolerances indicated low risk of imminent climate change impacts in this environment but suggests that increasing temperatures and heatwave prevalence may cause foragers to meet their upper thermal limits before other subcastes. Foraging occurred at a narrower range of temperatures than would challenge critical temperatures, with higher morning activity. Directionally increasing temperatures will likely confine these preferred foraging temperatures to a narrower time window. Further study is needed to elucidate how foragers may shift times of activity in response to anthropogenic warming, but changing climates may impact plant pollination rates in natural and agricultural systems.

Deep learning-based spatiotemporal multi-event reconstruction for delay line detectors

Accurate observation of two or more particles within a very narrow time window has always been a challenge in modern physics. It creates the possibility of correlation experiments, such as the ground-breaking Hanbury Brown–Twiss experiment, leading to new physical insights. For low-energy electrons, one possibility is to use a Microchannel plate with subsequent delay lines for the readout of the incident particle hits, a setup called a Delay Line Detector. The spatial and temporal coordinates of more than one particle can be fully reconstructed outside a region called the dead radius. For interesting events, where two electrons are close in space and time, the determination of the individual positions of the electrons requires elaborate peak finding algorithms. While classical methods work well with single particle hits, they fail to identify and reconstruct events caused by multiple nearby particles. To address this challenge, we present a new spatiotemporal machine learning model to identify and reconstruct the position and time of such multi-hit particle signals. This model achieves a much better resolution for nearby particle hits compared to the classical approach, removing some of the artifacts and reducing the dead radius a factor of eight. We show that machine learning models can be effective in improving the spatiotemporal performance of delay line detectors.

Multimodal Tetrahedral DNA Nanoplatform for Surprisingly Rapid and Significant Treatment of Acute Liver Failure.

Acute liver failure (ALF) is a life-threatening disease associated with the rapid development of inflammatory storms, level elevation of reactive oxygen species (ROS), and hepatocyte necrosis, which results in high short-term mortality. Except for liver transplantation, no effective strategies are available for ALF therapy due to the rapid disease progression and narrow window of therapeutic time. Therefore, there is an urgent demand to explore the fast and effective modalities for ALF treatment. Herein, a multifunctional tetrahedral DNA nanoplatform (TDN) is constructed by incorporating tumor necrosis factor-α siRNA (siTNF-α) through DNA hybridization and antioxidant manganese porphyrin (MnP4) via π-π stacking interaction with G-quadruplex (G4) for surprisingly rapid and significant ALF therapy. TDN-siTNF-α/-G4-MnP4 silences TNF-α of macrophages by siTNF-α and polarizes them to the anti-inflammatory M2 phenotype, providing appropriate microenvironments for hepatocyte viability. Additionally, TDN-siTNF-α/-G4-MnP4 scavenges intracellular ROS by MnP4, protecting hepatocytes from oxidative-stress-associated cell death. Furthermore, TDN itself promotes hepatocyte proliferation by modulating the cell cycle. TDN-siTNF-α/-G4-MnP4 shows almost complete liver accumulation after intravenous injection and exhibits excellent therapeutic efficacy of ALF within 2h. The multifunctional DNA nanoformulation provides an effective strategy for rapid ALF therapy, expanding its application for innovative treatments of liver diseases.

The Yin and Yang of the oxytocin and stress systems: opposites, yet interdependent and intertwined determinants of lifelong health trajectories.

During parturition and the immediate post-partum period there are two opposite, yet interdependent and intertwined systems that are highly active and play a role in determining lifelong health and behaviour in both the mother and her infant: the stress and the anti-stress (oxytocin) system. Before attempting to understand how the environment around birth determines long-term health trajectories, it is essential to understand how these two systems operate and how they interact. Here, we discuss together the hormonal and neuronal arms of both the hypothalamic-pituitary-adrenal (HPA) axis and the oxytocinergic systems and how they interact. Although the HPA axis and glucocorticoid stress axis are well studied, the role of oxytocin as an extremely powerful anti-stress hormone deserves more attention. It is clear that these anti-stress effects depend on oxytocinergic nerves emanating from the supraoptic nucleus (SON) and paraventricular nucleus (PVN), and project to multiple sites at which the stress system is regulated. These, include projections to corticotropin releasing hormone (CRH) neurons within the PVN, to the anterior pituitary, to areas involved in sympathetic and parasympathetic nervous control, to NA neurons in the locus coeruleus (LC), and to CRH neurons in the amygdala. In the context of the interaction between the HPA axis and the oxytocin system birth is a particularly interesting period as, for both the mother and the infant, both systems are very strongly activated within the same narrow time window. Data suggest that the HPA axis and the oxytocin system appear to interact in this early-life period, with effects lasting many years. If mother-child skin-to-skin contact occurs almost immediately postpartum, the effects of the anti-stress (oxytocin) system become more prominent, moderating lifelong health trajectories. There is clear evidence that HPA axis activity during this time is dependent on the balance between the HPA axis and the oxytocin system, the latter being reinforced by specific somatosensory inputs, and this has long-term consequences for stress reactivity.

Design of prehospital spectral CT with a rotation-free rectangular gantry and deep learning reconstruction

Treatment of stroke depends on a narrow therapeutic time window and requires urgent intervention to be emergently pursued. Despite recent “fast” initiatives that have underscored “time is brain,” many patients still fail to present within the narrow time window to receive maximum treatment benefit from advanced stroke therapies. The convergence of emergency medical services, telemedicine, and mobile technology, including transportable computed tomography scanners, has presented a unique opportunity to advance patient stroke care in the prehospital field by shortening the time to hyperacute stroke treatment with a mobile stroke unit. However, in order to facilitate the integration of computed tomography (CT) scanners into small ambulances, their geometry should be streamlined and made compact. Additionally, it is imperative that radiation exposure from prehospital CT scans comply with established radiation protection guidelines to safeguard both patients and healthcare workers. In this study, we propose a newly designed CT system for a rotation-free rectangular gantry with a photon-counting detector (PCD) and a deep-learning reconstruction approach for undersampled projections. Undersampled projections obtained using the designed CT system were implemented using a deep learning method. The deep learning approach showed superior image quality without distortion compared to state-of-the-art reconstruction methods. Finally, we implemented imaging of brain microhemorrhages using low- and high-energy images obtained from the PCD. Our results indicate that the proposed scanner effectively shows potential for acute stroke detection in prehospital ambulances. Its effectiveness was validated by comparing its image performance with those of other methods such as FBP and compressed sensing.

A Telegrapher’s equations-based implicit finite difference solution for fault location with current transformer saturation

This paper introduces a fault location method based on time analysis, utilizing synchronized data collected from both ends of the faulted line. The data is obtained either from Common Format for Transient Data Exchange (COMTRADE) files or Sampled Measured Value (SMV) of the IEC-61850 protocol. The method proposed in this study employs the implicit finite difference solution to the Telegrapher’s equations. In certain fault scenarios, such as when one or both transformers experience saturation, a narrow time window of data can be utilized to accurately pinpoint the fault location. The implicit solution method is unconditionally stable and therefore decouples the choice of the line discretization step from the sampling time interval, which is commonly required to maintain numerical stability of the explicit strategies for fault location. Furthermore, the numerical stability of the implicit process allows for devising a systematic search procedure that improves the accuracy of the calculated fault location, regardless of the transmission line length. By conducting numerical comparisons with an explicit time-domain fault locator and recent frequency-domain algorithms, the superiority of the proposed approach becomes evident. The results highlight the significant improvements achieved through the utilization of this method. Specifically, the results demonstrate that Telegrapher’s Equations implicit finite difference solution maintains accuracy under current transformer saturation, as it can locate the fault using data from a brief interval where the current transformer is not saturated.

Dispersal pathways of European green crab larvae into and throughout the eastern Salish Sea

The invasive European green crab (Carcinus maenas) was first detected on the US west coast around 1989 and has expanded its range northward from central California to southern Alaska. The eastern Salish Sea was initially thought to be protected from invasion by the dominant seaward surface current in the Strait of Juan de Fuca (SJdF). However, this “oceanographic barrier” has been breached as established green crab populations have been detected in the eastern Salish Sea in recent years. Here we carried out particle-tracking simulations to understand possible natural pathways of green crab larvae invading the eastern Salish Sea. Both diel vertical migration and temperature-dependent mortality were considered in these simulations. Our results suggest that green crab larvae from the outer coast (outside the Salish Sea) and Sooke Basin (in SJdF) could be carried into the eastern Salish Sea in a narrow time window during the later cold season (esp. in March) when frequent flow reversals in SJdF occur and the seasonally rising water temperature becomes relatively favorable for green crab larvae. The major pathway for larvae to reach the eastern Salish Sea is along the southern coast of SJdF. The probability of live larvae reaching the eastern Salish Sea is highly sensitive to water temperature. Sensitivity simulations indicate that a temperature increase of 0.5–1 °C would double or quadruple the probability of successful arrival in the eastern Salish Sea. This suggests that invading green crabs might have taken advantage of the mild winter conditions in recent warm years. Our results also suggest that the warming climate in the near future may facilitate green crab larval exchange across the Salish Sea.

Applications and Mechanisms of Taohong Siwu Decoction in the Treatment of Ischemic Stroke

Ischemic stroke is a kind of sudden vascular disease of the brain brought on by ischemic hypoxic necrosis of the brain tissue which is becoming a significant global source of death and long-term impairment. Present common treatment options for cerebral ischemia including thrombolytic therapy, mechanical embolization, and intracranial arterioplasty can only benefit a few patients due to the narrow therapeutic time windows. Traditional Chinese Medicine (TCM) prescriptions possess the qualities of multi-ingredients, multi-targets, synergistic and multi-efficacy advantages as a means of treating ischemic stroke. Taohong Siwu Decoction (THSWD) is a famous TCM prescription that promotes blood flow, removes blood clots, adds nourishment, and tonifies blood. Clinical and laboratory research results show the significant advantages of THSWD in ischemic stroke treatment. This review summarizes THSWD’s natural materials and processing methods, pharmacological effects, and related mechanisms to treat ischemic stroke. Its mechanism of action focuses on improving hemorheology, anti-inflammatory response, reducing excitotoxicity, anti-calcium overload, anti-oxidative stress, etc. Moreover, we systematically summarize THSWD and its use in combination with other treatments. Finally, the research obstacles of THSWD in the treatment of ischemic stroke are summarized, and the application prospects in the medical field are prospected.

Optimal Service Time Windows

Because customers must usually arrange their schedules to be present for home services, they desire an accurate estimate of when the service will take place. However, even when firms quote large service time windows, they are often missed, leading to customer dissatisfaction. Wide time windows and frequent failures occur because time windows must be communicated to customers in the face of several uncertainties: future customer requests are unknown, final service plans are not yet determined, and when fulfillment is outsourced to a third party, the firm has limited control over routing procedures and eventual fulfillment times. Even when routing is performed in-house, time windows often do not receive explicit consideration. In this paper, we show how companies can communicate reliable and narrow time windows to customers in the face of arrival time uncertainty when time window decisions are decoupled from routing procedures. Under assumptions on the shape of arrival time distributions, our main result characterizes the optimal policy, identifying structure that reduces a high-dimensional stochastic nonlinear optimization problem to a root-finding problem in one dimension. The result inspires a practice-ready heuristic for the more general case. Relative to the industry standard of communicating uniform time windows to all customers, and to other policies applied in practice, our method of quoting customer-specific time windows yields a substantial increase in customer convenience without sacrificing reliability of service. Our results show that time windows should be tailored to individual customers, time window sizes should be proportional to the service level, larger time windows should be assigned to earlier requests and smaller time windows to later requests, larger time windows should be assigned to customers further from the depot of operation and smaller time windows to closer customers, high quality time windows can be identified even with limited data, and cost savings afforded by routing efficiency should be measured against potential losses to customer convenience. Funding: M. W. Ulmer’s work is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) Emmy Noether Programme, [project 444657906]. Supplemental Material: The e-companion is available at https://doi.org/10.1287/trsc.2023.0004 .