A dose-adjusted, open-label, pilot study of the safety, tolerability, and pharmacokinetics of STC3141 in critically ill patients with sepsis.

Increased circulating histones correlate with sepsis severity and are a potential therapeutic target. Pre-clinical studies showed benefit with a histone-neutralizing polyanion molecule (STC3141). We aimed to investigate the safety, tolerability, and pharmacokinetics of STC3141 in critically ill patients with sepsis.

53BP1 deficiency leads to hyperrecombination using break-induced replication (BIR).

Break-induced replication (BIR) is mutagenic, and thus its use requires tight regulation, yet the underlying mechanisms remain elusive. Here we uncover an important role of 53BP1 in suppressing BIR after end resection at double strand breaks (DSBs), distinct from its end protection activity, providing insight into the mechanisms governing BIR regulation and DSB repair pathway selection. We demonstrate that loss of 53BP1 induces BIR-like hyperrecombination, in a manner dependent on Polα-primase-mediated end fill-in DNA synthesis on single-stranded DNA (ssDNA) overhangs at DSBs, leading to PCNA ubiquitination and PIF1 recruitment to activate BIR.

Research to Confront Climate Change Complexity: Intersectionality, Integration, and Innovative Governance.

Climate impacts increasingly unfold in interlinked systems of people, nature, and infrastructure. The cascading consequences are revealing sometimes surprising connections across sectors and regions, and prospects for climate responses also depend on complex, difficult-to-understand interactions. In this commentary, we build on the innovations of the United States Fifth National Climate Assessment to suggest a framework for understanding and responding to complex climate challenges.

BDNF and TRiC-inspired reagent rescue cortical synaptic deficits in a mouse model of Huntington's disease.

Synaptic changes are early manifestations of neuronal dysfunction in Huntington's disease (HD). However, the mechanisms by which mutant HTT protein impacts synaptogenesis and function are not well understood. Herein we explored HD pathogenesis in the BACHD mouse model by examining synaptogenesis and function in long term primary cortical cultures.

Impacts of HO, SARM1 inhibition, and high NAm concentrations on Huntington's disease laser-induced degeneration.

Axonal degeneration is a key component of neurodegenerative diseases such as Huntington's disease (HD), Alzheimer's disease, and amyotrophic lateral sclerosis. Nicotinamide, an NAD+ precursor, has long since been implicated in axonal protection and reduction of degeneration. However, studies on nicotinamide (NAm) supplementation in humans indicate that NAm has no protective effect.

Full-field stimulus threshold testing: a scoping review of current practice.

The full-field stimulus threshold (FST) is a psychophysical measure of whole-field retinal light sensitivity. It can assess residual visual function in patients with severe retinal disease and is increasingly being adopted as an endpoint in clinical trials. FST applications in routine ophthalmology clinics are also growing, but as yet there is no formalised standard guidance for measuring FST.

Developing and testing scales for home support service continuity (HSSC): cross-sectional studies in Canada and UK.

Objectives: Ensuring the continuity of home support services has become increasingly important due to challenges arising from ageing demographics and healthcare staffing shortages. However, there is a lack of validated measurements specifically designed for assessing service continuity in this context. The primary objective of this study is to develop and validate scales that capture the multidimensional nature of home support service continuity (HSSC), incorporating informational continuity, management continuity and relational continuity as its underlying components.

Integrating social and ecological considerations in floodplain relocation and restoration programs.

In the United States, most floodplain relocation (or buyout) programs focus on moving homeowners, then deal separately with what happens with the land afterward. These programs typically divide processes for relocation planning, engagement, funding, and implementation from those related to post-buyout land management and restoration. The structural and operational conditions that lead to this separation of roles and responsibilities miss out on opportunities to create more synergistic socio-ecological strategies that may produce healthier outcomes for both people and the environment.

High rate of false-positive postoperative venous thromboembolism identified using hospital ICD-10 coding.

The Health Roundtable, a national benchmarking body, identified our institution as an outlier with a high number of postoperative venous thromboembolism (VTE) events. We performed a retrospective study to determine the accuracy of hospital coding for the incidence and severity of postoperative VTE. Of 232 patients identified from ICD-10 coding, 52 (22.

Equitable buyouts? Learning from state, county, and local floodplain management programs.

Climate change-exacerbated flooding has renewed interest in property buyouts as a pillar of managed retreat from coastal zones and floodplains in the United States. However, federal buyout programs are widely critiqued for being inaccessible and inequitable. To learn whether and how subnational buyout programs overcome these limitations, we examined five leading US state, county, and local buyout programs to see what they teach us about redesigning future federal policies.

A single cell death is disruptive to spontaneous Ca activity in astrocytes.

Astrocytes in the brain are rapidly recruited to sites of injury where they phagocytose damaged material and take up neurotransmitters and ions to avoid the spreading of damaging molecules. In this study we investigate the calcium (Ca) response in astrocytes to nearby cell death. To induce cell death in a nearby cell we utilized a laser nanosurgery system to photolyze a selected cell from an established astrocyte cell line (Ast1).

Mitochondria dysfunction in Charcot Marie Tooth 2B Peripheral Sensory Neuropathy.

Rab7 GTPase regulates mitochondrial morphology and function. Missense mutation(s) of Rab7 underlies the pathogenesis of Charcot Marie Tooth 2B (CMT2B) peripheral neuropathy. Herein, we investigate how mitochondrial morphology and function are impacted by the CMT2B associated Rab7 mutation.

Mechanosensor Piezo1 mediates bimodal patterns of intracellular calcium and FAK signaling.

Piezo1 belongs to mechano-activatable cation channels serving as biological force sensors. However, the molecular events downstream of Piezo1 activation remain unclear. In this study, we used biosensors based on fluorescence resonance energy transfer (FRET) to investigate the dynamic modes of Piezo1-mediated signaling and revealed a bimodal pattern of Piezo1-induced intracellular calcium signaling.

Inequalities through the lens of science.

Inequalities are ubiquitous in every society on Earth, and the COVID-2019 pandemic has exposed the marginalized communities that suffer the most. A warming planet will only magnify this gap. On the eve of the 26th session of the Conference of the Parties to the UNFCCC, this Voices asks: how can science inform and address inequalities?

Transformative climate adaptation in the United States: Trends and prospects.

As climate change intensifies, civil society is increasingly calling for transformative adaptation that redresses drivers of climate vulnerability. We review trends in how U.S.

Laser-Induced Shockwave (LIS) to Study Neuronal Ca Responses.

Laser-induced shockwaves (LIS) can be utilized as a method to subject cells to conditions similar to those occurring during a blast-induced traumatic brain injury. The pairing of LIS with genetically encoded biosensors allows researchers to monitor the immediate molecular events resulting from such an injury. In this study, we utilized the genetically encoded Ca FRET biosensor D3CPV to study the immediate Ca response to laser-induced shockwave in cortical neurons and Schwann cells.

Calcium Dynamics in Astrocytes During Cell Injury.

The changes in intracellular calcium concentration ([Ca]) following laser-induced cell injury in nearby cells were studied in primary mouse astrocytes selectively expressing the Ca sensitive GFAP-Cre Salsa6f fluorescent tandem protein, in an Ast1 astrocyte cell line, and in primary mouse astrocytes loaded with Fluo4. Astrocytes in these three systems exhibit distinct changes in [Ca] following induced death of nearby cells. Changes in [Ca] appear to result from release of Ca from intracellular organelles, as opposed to influx from the external medium.

Beyond flood risk reduction: How can green infrastructure advance both social justice and regional impact?

Green infrastructure is being pulled in divergent directions. As climate impacts intensify, advocates are promoting larger, ecosystem-scale strategies to help mitigate flood risks. Yet, research on existing urban greening projects finds that they can cause gentrification and displacement, suggesting that smaller projects may be more desirable from an equity perspective.

Visualizing Spatiotemporal Dynamics of Intercellular Mechanotransmission upon Wounding.

During cell-to-cell communications, the interplay between physical and biochemical cues is essential for informational exchange and functional coordination, especially in multicellular organisms. However, it remains a challenge to visualize intercellular signaling dynamics in single live cells. Here, we report a photonic approach, based on laser microscissors and Förster resonance energy transfer (FRET) microscopy, to study intercellular signaling transmission.

LSD1 mediated changes in the local redox environment during the DNA damage response.

The redox state of the cell can be affected by many cellular conditions. In this study we show that detectable reactive oxygen species (ROS) are also generated in response to DNA damage by the chromatin remodeling factor and monoamine oxidase LSD1/KDM1A. This raised the possibility that the localized generation of hydrogen peroxide produced by LSD1 may affect the function of proximally located DNA repair proteins.

A positive-feedback-based mechanism for constriction rate acceleration during cytokinesis in .

To ensure timely cytokinesis, the equatorial actomyosin contractile ring constricts at a relatively constant rate despite its progressively decreasing size. Thus, the per-unit-length constriction rate increases as ring perimeter decreases. To understand this acceleration, we monitored cortical surface and ring component dynamics during the first cytokinesis of the embryo.

A Mouse Model for Dietary Xenosialitis: ANTIBODIES TO XENOGLYCAN CAN REDUCE FERTILITY.

Humans can incorporate the xenoglycan N-glycolylneuraminic acid (Neu5Gc) from the diet into reproductive tissues and secretions. Most humans also have circulating antibodies specific for this dietary xenoglycan. The potential for inflammation induced by incorporated Neu5Gc and circulating anti-Neu5Gc antibodies, termed xenosialitis, has been discussed as a factor influencing several human diseases.

Rat embryonic hippocampus and induced pluripotent stem cell derived cultured neurons recover from laser-induced subaxotomy.

Axonal injury and stress have long been thought to play a pathogenic role in a variety of neurodegenerative diseases. However, a model for studying single-cell axonal injury in mammalian cells and the processes of repair has not been established. The purpose of this study was to examine the response of neuronal growth cones to laser-induced axonal damage in cultures of embryonic rat hippocampal neurons and induced pluripotent stem cell (iPSC) derived human neurons.

Laser-induced shockwave paired with FRET: a method to study cell signaling.

Cells within the body are subject to various forces; however, the details concerning the way in which cells respond to mechanical stimuli are not well understood. We demonstrate that laser-induced shockwaves (LIS) combined with biosensors based on fluorescence resonance energy transfer (FRET) is a promising new approach to study biological processes in single live cells. As "proof-of-concept," using a FRET biosensor, we show that in response to LIS, cells release intracellular calcium.