Emergency nurses' experience in caring for unidentified patients: A qualitative study.

OBJECTIVE: To describe and analyse emergency nurses' experiences of caring for unidentified patients, and to provide a basis for constructing processes and standards of care for unidentified patients in the emergency department. METHODS: This study is a descriptive phenomenological research that utilized purposive sampling. Sixteen emergency department nurses, who cared for unidentified patients between June and September 2023, were selected for semi-structured face-to-face interviews. Data were analyzed using Colaizzi's 7-step method to identify and refine themes. RESULTS: Three themes were distilled: (1) increased workload, (2) increased mental stress at work, and (3) material needs and external environmental support. CONCLUSION: Emergency nurses have more complex negative emotional experiences when dealing with unidentified patients and want more external support to cope with such patients. Hospital administrators should pay full attention to nurses' caregiving experiences and provide positive interventions.

Patients' response during the co-circulation of multiple respiratory diseases in China-based on the self-regulation common-sense model.

Background: Following the COVID-19 pandemic, another large-scale respiratory epidemic has emerged in China, causing significant social impact and disruption. The article is to explore the patients' psychological and behavioral responses to the enhancement of healthcare quality. Methods: Based on the five dimensions of the Self-Regulation Common-Sense Model, we developed an interview outline to explore the process by which patients identify disease symptoms to guide action plans and coping strategies. The researchers used a semi-structured interview format to simultaneously collect data online and offline. This study gathered data from 12 patients with mixed respiratory infections, comprising 58% females and 42% males; the average age was 30.67 years (SD 20.00), with 91.7% infected with two pathogens and 8.3% with three. The data analysis employed the KJ method, themes were inductively analyzed and categorized from semi-structured interview results, which were then organized into a coherent visual and logical pathway. Key results: The study identified 5 themes: (1) Autonomous Actions Prior to Seeking Medical Care; (2) Decision-Making in Seeking Hospital Care; (3) Disease Shock; (4) Public Crisis Response; (5) Information Cocoon. Conclusion: The pandemic of respiratory infectious diseases has not ceased in recent years. Following the COVID-19 pandemic, China is now facing a trend of concurrent epidemics involving multiple respiratory pathogens. This study centers on patients' health behaviors, exploring the potential relationships among various factors that affect these behaviors. The aim is to provide references and grounds for the improvement of healthcare services when such public health events reoccur.

Regulation of PP1 interaction with I-2, neurabin, and F-actin.

Reversible phosphorylation is a fundamental regulatory mechanism required for many biological processes and is coordinated by the opposing actions of protein kinases and phosphatases. Protein phosphatase 1 (PP1) is a major protein phosphatase that plays an important role in many fundamental physiological processes including synaptic transmission and memory formation. Here we investigate the regulation of PP1 by prominent signaling proteins and synaptic scaffolds including GSK3ß, inhibitor-2 (I-2), neurabin (Nrb), and actin. While GSK3ß is known to regulate PP1 via phosphorylation of the PP1-binding protein I-2, we found that GSK3ß directly regulates PP1 via inhibitory phosphorylation in neurons. Additionally, using bioluminescence resonance energy transfer (BRET), we found that GSK3ß alters PP1-I-2 interaction in living cells. The effect of GSK3ß on PP1-I-2 interaction is independent of the PP1 C-terminal tail, contrary to predictions based on previous findings from purified proteins. I-2 has been shown to form a trimeric complex with PP1 and Nrb, a major synaptic scaffold for promoting PP1 localization to the actin cytoskeleton. Utilizing BRET, we found that Nrb promotes PP1-actin interaction, however no BRET was detected between I-2 and F-actin. Finally, we found that stabilizing F-actin promotes Nrb-PP1 binding and may also lead to conformational changes between Nrb-I-2 and Nrb-F-actin complexes. Overall, our findings elaborate the dynamic regulation of PP1 complexes by GSK3ß, targeting proteins, and actin polymerization.

Nuclear Inhibitor of Protein Phosphatase 1 (NIPP1) Regulates CNS Tau Phosphorylation and Myelination During Development.

Nuclear inhibitor of protein phosphatase 1 (NIPP1) is a known regulator of gene expression and plays roles in many physiological or pathological processes such as stem cell proliferation and skin inflammation. While NIPP1 has many regulatory roles in proliferating cells, its function in the central nervous system (CNS) has not been directly investigated. In the present study, we examined NIPP1 CNS function using a conditional knockout (cKO) mouse model in which the Nipp1 gene is excised from neural precursor cells. These mice exhibited severe developmental impairments that led to premature lethality. To delineate the neurological changes occurring in these animals, we first assessed microtubule-associated protein tau, a known target of NIPP1 activity. We found that phosphorylation of tau is significantly enhanced in NIPP1 cKO mice. Consistent with this, we found altered AKT and PP1 activity in NIPP1 cKO mice, suggesting that increased tau phosphorylation likely results from a shift in kinase/phosphatase activity. Secondly, we observed tremors in the NIPP1 cKO mice which prompted us to explore the integrity of the myelin sheath, an integral structure for CNS function. We demonstrated that in NIPP1 cKO mice, there is a significant decrease in MBP protein expression in the cortex, along with deficits in both the conduction of compound action potentials (CAP) and the percentage of myelinated axons in the optic nerve. Our study suggests that NIPP1 in neural precursor cells regulates phosphorylation of tau and CNS myelination and may represent a novel therapeutic target for neurodegenerative diseases.

Protein phosphatase-1 inhibitor-2 promotes PP1γ positive regulation of synaptic transmission.

Inhibitor-2 (I-2) is a prototypic inhibitor of protein phosphatase-1 (PP1), a major serine-threonine phosphatase that regulates synaptic plasticity and learning and memory. Although I-2 is a potent inhibitor of PP1 in vitro, our previous work has elucidated that, in vivo, I-2 may act as a positive regulator of PP1. Here we show that I-2 and PP1γ, but not PP1α, positively regulate synaptic transmission in hippocampal neurons. Moreover, we demonstrated that I-2 enhanced PP1γ interaction with its major synaptic scaffold, neurabin, by Förster resonance energy transfer (FRET)/Fluorescence lifetime imaging microscopy (FLIM) studies, while having a limited effect on PP1 auto-inhibitory phosphorylation. Furthermore, our study indicates that the effect of I-2 on PP1 activity in vivo is dictated by I-2 threonine-72 phosphorylation. Our work thus demonstrates a molecular mechanism by which I-2 positively regulates PP1 function in synaptic transmission.

Superhydrophobic Surface-Constructed Membrane Contactor with Hierarchical Lotus-Leaf-Like Interfaces for Efficient SO2 Capture.

An organic-inorganic polyvinylidene fluoride/polyvinylidene fluoride-silica (PVDF/PVDF-SiO2) mixed matrix membrane contactor is fabricated via a facile and efficient hydrophobic modification method. The solubility parameters of the PVDF particle are precisely regulated, the PVDF particles are blended with SiO2 nanoparticles to form PVDF-SiO2 suspension, and then the suspension is introduced onto the surface of the PVDF substrate by an in situ spin coating strategy. The PVDF particles are partly etched and incorporated to construct the adhesive PVDF-SiO2 core-shell layer on the PVDF substrate, which results in a more stable PVDF-SiO2 coating layer on the substrate. The surface structure is precisely regulated by changing the etching morphology of PVDF particles and amount of doped PVDF and SiO2 particles, forming an integrated porous PVDF-SiO2 layer and constructing hierarchical lotus-leaf-like interfaces. The resultant PVDF/PVDF-SiO2 membrane contactors display the relatively regular distribution of pore size with ∼420 nm and excellent hydrophobic property with a water contact angle of ∼158°, which noticeably lightens wetting phenomena of membrane contactors. The SO2 absorption fluxes can reach as high as 1.26 × 10-3 mol·m-2·s-1 using 0.625 M of ethanolamine (EA) as liquid absorbent. The high stability of the SO2 absorption flux test indicates the excellent interface compatibility between the PVDF-SiO2 coating layer and the PVDF substrate. The versatile organic-inorganic layer exhibits super hydrophobic property, which prevents wetting of membrane pores. In addition, the membrane mass transfer resistance (H/Km) and membrane phase transfer coefficient (Km) are explored.

Magnesium Acts as a Second Messenger in the Regulation of NMDA Receptor-Mediated CREB Signaling in Neurons.

Extracellular magnesium ion ([Mg2+]) is a well-known voltage-dependent blocker of NMDA receptors, which plays a critical role in the regulation of neuronal plasticity, learning, and memory. It is generally believed that NMDA receptor activation involves in Mg2+ being removed into extracellular compartment from the channel pore. On the other hand, Mg2+ is one of the most abundant intracellular cations, and involved in numerous cellular functions. However, we do not know if extracellular magnesium ions can influx into neurons to affect intracellular signaling pathways. In our current study, we found that extracellular [Mg2+] elevation enhanced CREB activation by NMDA receptor signaling in both mixed sex rat cultured neurons and brain slices. Moreover, we found that extracellular [Mg2+] led to CREB activation by NMDA application, albeit in a delayed manner, even in the absence of extracellular calcium, suggesting a potential independent role of magnesium in CREB activation. Consistent with this, we found that NMDA application leads to an NMDAR-dependent increase in intracellular-free [Mg2+] in cultured neurons in the absence of extracellular calcium. Chelating this magnesium influx or inhibiting P38 mitogen-activated protein kinase (p38 MAPK) blocked the delayed pCREB by NMDA. Finally, we found that NMDAR signaling in the absence of extracellular calcium activates p38 MAPK. Our studies thus indicate that magnesium influx, dependent on NMDA receptor opening, can transduce a signaling pathway to activate CREB in neurons.

BACE1 deletion in the adult mouse reverses preformed amyloid deposition and improves cognitive functions.

BACE1 initiates the generation of the ß-amyloid peptide, which likely causes Alzheimer's disease (AD) when accumulated abnormally. BACE1 inhibitory drugs are currently being developed to treat AD patients. To mimic BACE1 inhibition in adults, we generated BACE1 conditional knockout (BACE1fl/fl) mice and bred BACE1fl/fl mice with ubiquitin-CreER mice to induce deletion of BACE1 after passing early developmental stages. Strikingly, sequential and increased deletion of BACE1 in an adult AD mouse model (5xFAD) was capable of completely reversing amyloid deposition. This reversal in amyloid deposition also resulted in significant improvement in gliosis and neuritic dystrophy. Moreover, synaptic functions, as determined by long-term potentiation and contextual fear conditioning experiments, were significantly improved, correlating with the reversal of amyloid plaques. Our results demonstrate that sustained and increasing BACE1 inhibition in adults can reverse amyloid deposition in an AD mouse model, and this observation will help to provide guidance for the proper use of BACE1 inhibitors in human patients.

BACE1 Deficiency Causes Abnormal Neuronal Clustering in the Dentate Gyrus.

BACE1 is validated as Alzheimer's ß-secretase and a therapeutic target for Alzheimer's disease. In examining BACE1-null mice, we discovered that BACE1 deficiency develops abnormal clusters of immature neurons, forming doublecortin-positive neuroblasts, in the developing dentate gyrus, mainly in the subpial zone (SPZ). Such clusters were rarely observed in wild-type SPZ and not reported in other mouse models. To understand their origins and fates, we examined how neuroblasts in BACE1-null SPZ mature and migrate during early postnatal development. We show that such neuroblasts are destined to form Prox1-positive granule cells in the dentate granule cell layer, and mainly mature to form excitatory neurons, but not inhibitory neurons. Mechanistically, higher levels of reelin potentially contribute to abnormal neurogenesis and timely migration in BACE1-null SPZ. Altogether, we demonstrate that BACE1 is a critical regulator in forming the dentate granule cell layer through timely maturation and migration of SPZ neuroblasts.

BACE1 regulates the proliferation and cellular functions of Schwann cells.

BACE1 is an indispensable enzyme for generating ß-amyloid peptides, which are excessively accumulated in brains of Alzheimer's patients. However, BACE1 is also required for proper myelination of peripheral nerves, as BACE1-null mice display hypomyelination. To determine the precise effects of BACE1 on myelination, here we have uncovered a role of BACE1 in the control of Schwann cell proliferation during development. We demonstrate that BACE1 regulates the cleavage of Jagged-1 and Delta-1, two membrane-bound ligands of Notch. BACE1 deficiency induces elevated Jag-Notch signaling activity, which in turn facilitates proliferation of Schwann cells. This increase in proliferation leads to shortened internodes and decreased Schmidt-Lanterman incisures. Functionally, evoked compound action potentials in BACE1-null nerves were significantly smaller and slower, with a clear decrease in excitability. BACE1-null nerves failed to effectively use lactate as an alternative energy source under conditions of increased physiological activity. Correlatively, BACE1-null mice showed reduced performance on rotarod tests. Collectively, our data suggest that BACE1 deficiency enhances proliferation of Schwann cell due to the elevated Jag1/Delta1-Notch signaling, but fails to myelinate axons efficiently due to impaired the neuregulin1-ErbB signaling, which has been documented.

Neurological dysfunctions associated with altered BACE1-dependent Neuregulin-1 signaling.

Inhibition of BACE1 is being pursued as a therapeutic target to treat patients suffering from Alzheimer's disease because BACE1 is the sole ß-secretase that generates ß-amyloid peptide. Knowledge regarding other cellular functions of BACE1 is therefore critical for the safe use of BACE1 inhibitors in human patients. Neuregulin-1 (Nrg1) is a BACE1 substrate and BACE1 cleavage of Nrg1 is critical for signaling functions in myelination, remyelination, synaptic plasticity, normal psychiatric behaviors, and maintenance of muscle spindles. This review summarizes the most recent discoveries associated with BACE1-dependent Nrg1 signaling in these areas. This body of knowledge will help to provide guidance for preventing unwanted Nrg1-based side effects following BACE1 inhibition in humans. To initiate its signaling cascade, membrane anchored Neuregulin (Nrg), mainly type I and III ß1 Nrg1 isoforms and Nrg3, requires ectodomain shedding. BACE1 is one of such indispensable sheddases to release the functional Nrg signaling fragment. The dependence of Nrg on the cleavage by BACE1 is best manifested by disrupting the critical role of Nrg in the control of axonal myelination, schizophrenic behaviors as well as the formation and maintenance of muscle spindles.

Protein Phosphatase-1 Inhibitor-2 Is a Novel Memory Suppressor.

Reversible phosphorylation, a fundamental regulatory mechanism required for many biological processes including memory formation, is coordinated by the opposing actions of protein kinases and phosphatases. Type I protein phosphatase (PP1), in particular, has been shown to constrain learning and memory formation. However, how PP1 might be regulated in memory is still not clear. Our previous work has elucidated that PP1 inhibitor-2 (I-2) is an endogenous regulator of PP1 in hippocampal and cortical neurons (Hou et al., 2013). Contrary to expectation, our studies of contextual fear conditioning and novel object recognition in I-2 heterozygous mice suggest that I-2 is a memory suppressor. In addition, lentiviral knock-down of I-2 in the rat dorsal hippocampus facilitated memory for tasks dependent on the hippocampus. Our data indicate that I-2 suppresses memory formation, probably via negatively regulating the phosphorylation of cAMP/calcium response element-binding protein (CREB) at serine 133 and CREB-mediated gene expression in dorsal hippocampus. Surprisingly, the data from both biochemical and behavioral studies suggest that I-2, despite its assumed action as a PP1 inhibitor, is a positive regulator of PP1 function in memory formation. SIGNIFICANCE STATEMENT: We found that inhibitor-2 acts as a memory suppressor through its positive functional influence on type I protein phosphatase (PP1), likely resulting in negative regulation of cAMP/calcium response element-binding protein (CREB) and CREB-activated gene expression. Our studies thus provide an interesting example of a molecule with an in vivo function that is opposite to its in vitro function. PP1 plays critical roles in many essential physiological functions such as cell mitosis and glucose metabolism in addition to its known role in memory formation. PP1 pharmacological inhibitors would thus not be able to serve as good therapeutic reagents because of its many targets. However, identification of PP1 inhibitor-2 as a critical contributor to suppression of memory formation by PP1 may provide a novel therapeutic target for memory-related diseases.

The Rac1 inhibitor NSC23766 suppresses CREB signaling by targeting NMDA receptor function.

NMDA receptor signaling plays a complex role in CREB activation and CREB-mediated gene transcription, depending on the subcellular location of NMDA receptors, as well as how strongly they are activated. However, it is not known whether Rac1, the prototype of Rac GTPase, plays a role in neuronal CREB activation induced by NMDA receptor signaling. Here, we report that NSC23766, a widely used specific Rac1 inhibitor, inhibits basal CREB phosphorylation at S133 (pCREB) and antagonizes changes in pCREB levels induced by NMDA bath application in rat cortical neurons. Unexpectedly, we found that NSC23766 affects the levels of neuronal pCREB in a Rac1-independent manner. Instead, our results indicate that NSC23766 can directly regulate NMDA receptors as indicated by their strong effects on both exogenous and synaptically evoked NMDA receptor-mediated currents in mouse and rat neurons, respectively. Our findings strongly suggest that Rac1 does not affect pCREB signaling in cortical neurons and reveal that NSC23766 could be a novel NMDA receptor antagonist.

Potassium channel Kv2.1 is regulated through protein phosphatase-1 in response to increases in synaptic activity.

The functional stability of neurons in the face of large variations in both activity and efficacy of synaptic connections suggests that neurons possess intrinsic negative feedback mechanisms to balance and tune excitability. While NMDA receptors have been established to play an important role in glutamate receptor-dependent plasticity through protein dephosphorylation, the effects of synaptic activation on intrinsic excitability are less well characterized. We show that increases in synaptic activity result in dephosphorylation of the potassium channel subunit Kv2.1. This dephosphorylation is induced through NMDA receptors and is executed through protein phosphatase-1 (PP1), an enzyme previously established to play a key role in regulating ligand gated ion channels in synaptic plasticity. Dephosphorylation of Kv2.1 by PP1 in response to synaptic activity results in substantial shifts in the inactivation curve of IK, resulting in a reduction in intrinsic excitability, facilitating negative feedback to neuronal excitability.

End-completely-regular and end-inverse lexicographic products of graphs.

A graph X is said to be End-completely-regular (resp., End-inverse) if its endomorphism monoid End(X) is completely regular (resp., inverse). In this paper, we will show that if X[Y] is End-completely-regular (resp., End-inverse), then both X and Y are End-completely-regular (resp., End-inverse). We give several approaches to construct new End-completely-regular graphs by means of the lexicographic products of two graphs with certain conditions. In particular, we determine the End-completely-regular and End-inverse lexicographic products of bipartite graphs.

Synaptic activity bidirectionally regulates a novel sequence-specific S-Q phosphoproteome in neurons.

Protein phosphorylation plays a critical role in neuronal transcription, translation, cell viability, and synaptic plasticity. In neurons, phospho-enzymes and specific substrates directly link glutamate release and post-synaptic depolarization to these cellular functions; however, many of these enzymes and their protein substrates remain uncharacterized or unidentified. In this article, we identify a novel, synaptically driven neuronal phosphoproteome characterized by a specific motif of serine/threonine-glutamine ([S/T]-Q, abbreviated as SQ). These SQ-containing substrates are predominantly localized to dendrites, synapses, the soma; and activation of this SQ phosphoproteome by bicuculline application is induced via calcium influx through L-type calcium channels. On the other hand, acute application of NMDA can inactivate this SQ phosphoproteome. We demonstrate that the SQ motif kinase Ataxia-telangiectasia mutated can also localize to dendrites and dendritic spines, in addition to other subcellular compartments, and is activated by bicuculline application. Pharmacology studies indicate that Ataxia-telangiectasia mutated and its sister kinase ataxia telangiectasia mutated and Rad3-related up-regulate these neuronal SQ substrates. Phosphoproteomics identified over 150 SQ-containing substrates whose phosphorylation is bidirectionally regulated by synaptic activity.

Molecular mechanisms of homeostatic synaptic downscaling.

Homeostatic synaptic downscaling is a negative feedback response to chronic elevated network activity to reduce the firing rate of neurons. This form of synaptic plasticity decreases the strength of individual synapses to the same proportion, or in a multiplicative manner. Because of this, synaptic downscaling has been hypothesized to counter the potential run-away excitation due to Hebbian type of long term potentiation (LTP), while preserving relative synaptic weight encoded in individual synapses and thus memory information. In this article, we will review the current knowledge on the signaling and molecular mechanisms of synaptic downscaling. Specifically, we focus on three general areas. First the functional roles of several immediate early genes such as Plk2, Homer1a, Arc and Narp are discussed. Secondly, we examine the current knowledge on the regulation of synaptic protein levels by ubiquitination and transcriptional repression in synaptic downscaling. Thirdly, we review the dynamics of signaling molecules such as kinases and phosphatases critical for synaptic downscaling, and their regulation of synaptic scaffolding proteins. Finally we briefly discuss the heterogeneity of homeostatic synaptic downscaling mechanisms. This article is part of the Special Issue entitled 'Homeostatic Synaptic Plasticity'.

Synaptic NMDA receptor stimulation activates PP1 by inhibiting its phosphorylation by Cdk5.

The serine/threonine protein phosphatase protein phosphatase 1 (PP1) is known to play an important role in learning and memory by mediating local and downstream aspects of synaptic signaling, but how PP1 activity is controlled in different forms of synaptic plasticity remains unknown. We find that synaptic N-methyl-D-aspartate (NMDA) receptor stimulation in neurons leads to activation of PP1 through a mechanism involving inhibitory phosphorylation at Thr320 by Cdk5. Synaptic stimulation led to proteasome-dependent degradation of the Cdk5 regulator p35, inactivation of Cdk5, and increased auto-dephosphorylation of Thr320 of PP1. We also found that neither inhibitor-1 nor calcineurin were involved in the control of PP1 activity in response to synaptic NMDA receptor stimulation. Rather, the PP1 regulatory protein, inhibitor-2, formed a complex with PP1 that was controlled by synaptic stimulation. Finally, we found that inhibitor-2 was critical for the induction of long-term depression in primary neurons. Our work fills a major gap regarding the regulation of PP1 in synaptic plasticity.

An essential role for inhibitor-2 regulation of protein phosphatase-1 in synaptic scaling.

Protein phosphatase-1 (PP1) activity is important for many calcium-dependent neuronal functions including Hebbian synaptic plasticity and learning and memory. PP1 activity is necessary for the induction of long-term depression, whereas downregulation of PP1 activity is required for the normal induction of long-term potentiation. However, how PP1 is activated is not clear. Moreover, it is not known whether PP1 plays a role in homeostatic synaptic scaling, another form of synaptic plasticity which functions to reset the neuronal firing rate in response to chronic neuronal activity perturbations. In this study, we found that PP1 inhibitor-2 (I-2) is phosphorylated at serine 43 (S43) in rat and mouse cortical neurons in response to bicuculine application. Expression of I-2 phosphorylation-blocking mutant I-2 (S43A) blocked the dephosphorylation of GluA2 at serine 880, AMPA receptor trafficking, and synaptic downscaling induced by bicuculline application. Our data suggest that the phosphorylation of I-2 at S43 appears to be mediated by L-type calcium channels and calcium/calmodulin-dependent myosin light-chain kinase. Our work thus reveals a novel calcium-induced PP1 activation pathway critical for homeostatic synaptic plasticity.

Lithium regulates hippocampal neurogenesis by ERK pathway and facilitates recovery of spatial learning and memory in rats after transient global cerebral ischemia.

Recent studies have demonstrated that lithium has a neuroprotective effect against brain ischemia. Whether this effect is mediated by hippocampal neurogenesis remains unknown. The ERK (extracellular signal-regulated kinase) pathway plays an essential role in regulating neurogenesis. The present study was undertaken to investigate whether lithium regulates hippocampal neurogenesis by the ERK pathway and improves spatial learning and memory deficits in rats after ischemia. Rats were daily injected with lithium (1 mmol/kg) and 2 weeks later subjected to 15-min ischemia induced by four-vessel occlusion method. 5-bromo-2'-deoxyuridine (Brdu; 50mg/kg) was administrated twice daily at postischemic day 6, or for 3 days from postischemic day 6 to 8. We found that lithium increased the ERK1/2 activation after ischemia by western blotting analysis. There was a significant increase in Brdu-positive cells in the hippocampal dentate gyrus after lithium treatment, compared with ischemia group at postischemic days 7 and 21; furthermore, the survival rate of Brdu-positive cells was elevated by lithium. Inhibition of the ERK1/2 activation by U0126 diminished these effects of lithium. The percentages of Brdu-positive cells that expressed a neuronal marker or an astrocytic marker were not significantly influenced by lithium. Moreover, lithium improved the impaired spatial learning and memory ability in Morris water maze, and U0126 attenuated the behavioral improvement by lithium. These results suggest that lithium up-regulates the generation and survival of new-born cells in the hippocampus by the ERK pathway and improves the behavioral disorder in rats after transient global cerebral ischemia.