Murine Neural Stem/Progenitor Cells Protect Neurons against Ischemia by HIF-1α–Regulated VEGF Signaling

Focal cerebral ischemia following middle cerebral artery occlusion (MCAO) stimulates a robust cytogenic response from the adult subventricular zone (SVZ) that includes massive proliferation of neural stem/progenitor cells (NSPCs) and cellular migration into the injury area. To begin to explore beneficial roles of NSPCs in this response, we investigated the ability of embryonic and postnatal NSPCs to promote neuronal survival under conditions of in vivo and in vitro ischemia. Intracerebral transplantation of NSPCs attenuated neuronal apoptosis in response to focal ischemia induced by transient MCAO, and prevented neuronal cell death of cortical neurons in response to oxygen-glucose deprivation (OGD) in culture. NSPC-mediated neuroprotection was blocked by the pharmacological inhibitors of vascular endothelial growth factor (VEGF), SU1498 and Flt-1Fc. Embryonic and postnatal NSPCs were both intrinsically resistant to brief OGD exposure, and constitutively expressed both hypoxia-inducible factor 1α (HIF-1α) transcription factor and its downstream target, VEGF. Genomic deletion of HIF-1α by Cre-mediated excision of exon 2 in NSPC cultures resulted in >50% reduction of VEGF production and ablation of NSPC-mediated neuroprotection. These findings indicate that NSPCs promote neuronal survival under ischemic conditions via HIF-1α-VEGF signaling pathways and support a role for NSPCs in promotion of neuronal survival following stroke

catena-Poly[[[diaqua­(di-2-pyridylamine-κ2 N,N′)nickel(II)]-μ-fumarato-κ2 O 1:O 4] tetra­hydrate]

In the crystal structure of the title compound, {[Ni(C4H2O4)(C10H9N3)(H2O)2]·4H2O}n, zigzag chains are built up from cis-[Ni(dpya)(H2O)2]2+ cations (dpya is di-2-pyridylamine) linked by bis-monodentate coordinated bridging fumarate ligands. The NiII atom is coordinated by one chelating dpya ligand, two aqua ligands in trans positions and two monodentate fumarate ligands in cis positions in the form of a deformed octa­hedron. The water mol­ecules, O atoms of the fumarate carboxyl­ate groups and the amine group of the dpya ligand are involved in an extended network of intra- and inter­molecular O—H⋯O hydrogen bonds. Moreover, π–π inter­actions between the pyridine rings of the dpya ligand contribute to the stability of the structure. Two of the five uncoordinated water molecules are half-occupied

Evolutionary Instability of Collateral Susceptibility Networks in Ciprofloxacin-Resistant Clinical Escherichia coli Strains

ABSTRACT Collateral sensitivity and resistance occur when resistance development toward one antimicrobial either potentiates or deteriorates the effect of others. Previous reports on collateral effects on susceptibility focus on newly acquired resistance determinants and propose that novel treatment guidelines informed by collateral networks may reduce the evolution, selection, and spread of antimicrobial resistance. In this study, we investigate the evolutionary stability of collateral networks in five ciprofloxacin-resistant, clinical Escherichia coli strains. After 300 generations of experimental evolution without antimicrobials, we show complete fitness restoration in four of five genetic backgrounds and demonstrate evolutionary instability in collateral networks of newly acquired resistance determinants. We show that compensatory mutations reducing efflux expression are the main drivers destabilizing initial collateral networks and identify rpoS as a putative target for compensatory evolution. Our results add another layer of complexity to future predictions and clinical application of collateral networks. IMPORTANCE Antimicrobial resistance occurs due to genetic alterations that affect different processes in bacteria. Thus, developing resistance toward one antimicrobial drug may also alter the response toward others (collateral effects). Understanding the mechanisms of such collateral effects may provide clinicians with a framework for informed antimicrobial treatment strategies, limiting the emergence of antimicrobial resistance. However, for clinical implementation, it is important that the collateral effects of resistance development are repeatable and temporarily stable. Here, we show that collateral effects caused by resistance development toward ciprofloxacin in clinical Escherichia coli strains are not temporarily stable because of compensatory mutations restoring the fitness burden of the initial resistance mutations. Consequently, this instability is complicating the general applicability and clinical implementation of collateral effects into treatment strategies

Effects of a neurokinin-1 receptor antagonist in the acute phase after thoracic spinal cord injury in a rat model

Objective: Disruption of the blood-spinal cord barrier (BSCB) with subsequent edema formation and further neuroinflammation contributes to aggravation of spinal cord injury (SCI). We aimed to observe the effect of antagonizing the binding of the neuropeptide Substance-P (SP) to its neurokinin-1 (NK1) receptor in a rodent SCI model. Methods: Female Wistar rats were subjected to a T9 laminectomy with or without (Sham) a T9 clip-contusion/compression SCI, followed by the implantation of an osmotic pump for the continuous, seven-day-long infusion of a NK1 receptor antagonist (NRA) or saline (vehicle) into the intrathecal space. The animals were assessed via MRI, and behavioral tests were performed during the experiment. 7 days after SCI, wet & dry weight and immunohistological analyses were conducted. Results: Substance-P inhibition via NRA showed limited effects on reducing edema. However, the invasion of T-lymphocytes and the number of apoptotic cells were significantly reduced with the NRA treatment. Moreover, a trend of reduced fibrinogen leakage, endothelial and microglial activation, CS-GAG deposition, and astrogliosis was found. Nevertheless, only insignificant general locomotion recovery could be observed in the BBB open field score and the Gridwalk test. In contrast, the CatWalk gait analysis showed an early onset of recovery in several parameters. Conclusion: Intrathecal administration of NRA might reinforce the integrity of the BSCB in the acute phase after SCI, potentially attenuating aspects of neurogenic inflammation, reducing edema formation, and improving functional recovery

Bis(2,2′-bipyridine-κ2 N,N′)(maleato-κ2 O 1,O 1′)nickel(II) 7.34-hydrate

The title compound, [Ni(C4H2O4)(C10H8N2)2]·7.34H2O, was obtained by crystallization from an aqueous ethano­lic reaction mixture containing nickel(II) acetate, maleic acid, bipyridine, sodium hydroxide and ammonia. The asymmetric unit contains one independent complex mol­ecule and 7.34 water mol­ecules occupying eight crystallographically independent positions. Two of these water molecules are disordered. The nickel(II) atom is coordinated in a distorted octa­hedral geometry by two O atoms from one carboxyl­ate group of the maleato ligand and by four N atoms from two 2,2′-bipyridine (bipy) ligands. The water mol­ecules, along with the O atoms of the uncoordinated carboxyl­ate group, form an extended hydro­philic three-dimensional hydrogen-bonded system with large cavities in which the hydro­phobic bipy ligands are located. One H atom of the maleate ligand is involved in a weak hydrogen bond of the C—H⋯O type. Stacking inter­actions between the pyridyl rings of the bipy ligands [centroid–centroid distance = 3.549 (15) Å] lead to the formation of pairs of complex mol­ecules

Vegetation response to invasive Tamarix control in southwestern U.S. rivers: a collaborative study including 416 sites

Most studies assessing vegetation response following control of invasive Tamarix trees along southwestern U.S. rivers have been small in scale (e.g., river reach), or at a regional scale but with poor spatial-temporal replication, and most have not included testing the effects of a now widely used biological control. We monitored plant composition following Tamarix control along hydrologic, soil, and climatic gradients in 244 treated and 172 reference sites across six U.S. states. This represents the largest comprehensive assessment to date on the vegetation response to the four most common Tamarix control treatments. Biocontrol by a defoliating beetle (treatment 1) reduced the abundance of Tamarix less than active removal by mechanically using hand and chain-saws (2), heavy machinery (3) or burning (4). Tamarix abundance also decreased with lower temperatures, higher precipitation, and follow-up treatments for Tamarix resprouting. Native cover generally increased over time in active Tamarix removal sites, however, the increases observed were small and was not consistently increased by active revegetation. Overall, native cover was correlated to permanent stream flow, lower grazing pressure, lower soil salinity and temperatures, and higher precipitation. Species diversity also increased where Tamarix was removed. However, Tamarix treatments, especially those generating the highest disturbance (burning and heavy machinery), also often promoted secondary invasions of exotic forbs. The abundance of hydrophytic species was much lower in treated than in reference sites, suggesting that management of southwestern U.S. rivers has focused too much on weed control, overlooking restoration of fluvial processes that provide habitat for hydrophytic and floodplain vegetation. These results can help inform future management of Tamarix-infested rivers to restore hydrogeomorphic processes, increase native biodiversity and reduce abundance of noxious species

Competence-oriented teaching and feedback. The school pilot program alles"könner and the research project komdif

Der Hamburger Schulversuch alles"könner ist ein Unterrichts- und Schulentwicklungsprojekt, das die Förderung der individuellen Kompetenzentwicklung der Lernenden in den Blick nimmt. Dazu werden kompetenzorientierte Lernarrangements und Aufgabenformate sowie ein System formeller und informeller Rückmeldungen entwickelt. Daneben steht die Etablierung einer Kooperationskultur innerhalb und zwischen den Schulen im Mittelpunkt, um im Hamburger Schulsystem kompetenzorientierten individualisierten Unterricht zu fördern. Eng verzahnt mit dem Schulversuch ist das wissenschaftliche Forschungsprogramm komdif, in dem Wissenschaftlerinnen und Wissenschaftler der Fachdidaktiken sowie der Pädagogischen Psychologie zusammenarbeiten, um theoriegeleitet und evidenzbasiert Modelle für die diagnosegestützte individuelle Förderung von Schülerinnen und Schülern zu entwickeln. (DIPF/Orig.)The Hamburg school pilot program alles"könner is a project for instruction and school development focusing on competence development of the individual student. Competence-based learning arrangements and task formats, as well as a system of formal and informal feedback are developed for this program. The establishment of a cooperative culture within and between schools to promote competence-guided, individualized education in Hamburg\u27s public education system is also emphasized. The pilot program komdif is a research program with participants from subject-specific fields of didactics and educational psychology working collaboratively to develop theory-guided and evidence-based models for diagnosis-based individual support of students. It is closely linked to the project alles"könner. (DIPF/Orig.

Interaction of ARC and Daxx: a novel endogenous target to preserve motor function and cell loss after focal brain ischemia in mice

The aim of this study was to explore the signaling and neuroprotective effect of transactivator of transcription (TAT) protein transduction of the apoptosis repressor with CARD (ARC) in in vitro and in vivo models of cerebral ischemia in mice. In mice, transient focal cerebral ischemia reduced endogenousARCprotein in neurons in the ischemic striatum at early reperfusion time points, and in primary neuronal cultures, RNA interference resulted in greater neuronal susceptibility to oxygen glucose deprivation (OGD).TAT.ARC protein delivery led to a dose-dependent better survival after OGD. Infarct sizes 72 h after 60 min middle cerebral artery occlusion (MCAo) were on average 30±8% (mean±SD; p=0.005; T2-weighted MRI) smaller in TAT.ARC-treated mice (1ug intraventricularly during MCAo) compared with controls. TAT.ARC-treated mice showed better performance in the pole test compared with TAT.β-Gal-treated controls. Importantly, post-stroke treatment (3 h after MCAo) was still effective in affording reduced lesion volume by 20±7% (mean±SD; p˃0.05) and better functional outcome compared with controls. Delayed treatment in mice subjected to 30 min MCAo led to sustained neuroprotection and functional behavior benefits for at least 28 d. Functionally, TAT.ARC treatment inhibited DAXX–ASK1–JNK signaling in the ischemic brain. ARC interacts with DAXX in a CARD-dependent manner to block DAXX trafficking and ASK1–JNK activation. Our work identifies for the first time ARC–DAXX binding to block ASK1–JNK activation as an ARC-specific endogenous mechanism that interferes with neuronal cell death and ischemic brain injury. Delayed delivery of TAT.ARC may present a promising target for stroke therapy