bluuebunny/crossref_metadata_2025 huggingface dataset:
Cadherins: molecular codes for axon guidance and synapse formation
Authors: Ranscht Barbara
Published: July 2002

The formation of the myriad of neuronal connections within the vertebrate nervous system relies on expression of molecular tags that match extending axon populations with synaptic target sites. Recent work suggests that cadherins, a group of calcium‐dependent cell adhesion molecules, are candidates to serve such a role. The diversity of the cadherin family in the nervous system allows for a multitude of interactions to specify neuronal connections. Specific cadherin types demarcate subpopulations of developing axons that interconnect within neuronal circuits. Expression of different cadherin species at select synapse populations raises exciting prospects for this molecule class in controlling adhesive interactions during synaptogenesis and plasticity. Regulation of cadherin‐mediated adhesive strength is an attractive mechanism to explain the different cadherin functions in axon growth and at synapses.
Prolactin concurrently activates Src‐PLD and JAK/Stat signaling pathways to induce proliferation while promoting differentiation in embryonic astrocytes
Authors: Mangoura Dimitra , Pelletiere Chris , Leung Soyan , Sakellaridis Nikos , Wang De Xin
Published: July 2002

In normal development, embryonic astrocytes progress through their cell lineage by acquiring differentiation, by apoptosis, and by proliferation. In this study, we show that embryonic astrocytes may maintain and make gains in differentiation as they simultaneously progress through one cell cycle when induced by prolactin (PRL). Prolactin induced the majority of astrocytes to incorporate bromodeoxyuridine (BrdU) with a four‐fold increase over controls after 18 h of exposure. Investigating possible mitogenic signaling pathways we show for the first time that prolactin is coupled to a sustained phospholipase D (PLD) activation, with an efficacy similar to the phorbol ester and astrocytic mitogen 12‐tetradecanoylphorbol‐13‐acetate (TPA). Both cyclosporine and suramin abolished this activation. Staurosporine and calphostin C also inhibited the PRL effect by 50%, consistent with involvement of protein kinase C‐(PKC)‐α, the major PKC isoform in astrocytes. Genistein and PP1 blocked the activation indicating additional regulation by cytosolic tyrosine kinases. This profile of PLD activation was suggestive of a PLD I isoform and a mitogenic response. Upon completion of the cell cycle, analysis of glia fibrillary acidic protein (GFAP) and vimentin abundance, and glutamine synthetase (GS) activity showed that astrocytes had gained in expression of differentiation markers. Moreover, the intensity of GFAP immunofluorescence was greater per cell, as was the length of the cell processes. In exploring the signaling for prolactin‐induced differentiation we found that prolactin activated the tyrosine kinase Janus kinase (JAK) 2 and significantly stimulated tyrosine, phosphorylation of the prolactin receptor. Stat 1 and 3 were also activated presumably downstream to JAK2 activation. A rapid translocation of the cytosolic Stats over the nucleus was seen in nearly every astrocyte corresponding well with the gains in GFAP per cell. The Stats translocation did not depend on MEK‐ERK inhibition by PD98059, inhibition of p38 by 1 μm SB203580, or Src kinase family inhibition by PP1. Our results demonstrate the ability of PRL to concurrently induce activation of PLD, a mitogenic signaling pathway in astrocytes, and prolonged stimulation of Stat1, compatible with the increased GFAP upregulation and cell differentiation. Considered together this data may provide an explanation on the fast gain in both numbers and differentiation in the astrocytic population during development (HD 09402, CRF).
Involvement of astrocytes in purine‐mediated reparative processes in the brain
Authors: Ciccarelli R. , Ballerini P. , Sabatino G. , Rathbone M.P. , D'Onofrio M. , Caciagli F. , Di Iorio P.
Published: July 2002

Astrocytes are involved in multiple brain functions in physiological conditions, participating in neuronal development, synaptic activity and homeostatic control of the extracellular environment. They also actively participate in the processes triggered by brain injuries, aimed at limiting and repairing brain damages. Purines may play a significant role in the pathophysiology of numerous acute and chronic disorders of the central nervous system (CNS). Astrocytes are the main source of cerebral purines. They release either adenine‐based purines, e.g. adenosine and adenosine triphosphate, or guanine‐based purines, e.g. guanosine and guanosine triphosphate, in physiological conditions and release even more of these purines in pathological conditions. Astrocytes express several receptor subtypes of P1 and P2 types for adenine‐based purines. Receptors for guanine‐based purines are being characterised. Specific ecto‐enzymes such as nucleotidases, adenosine deaminase and, likely, purine nucleoside phosphorylase, metabolise both adenine‐ and guanine‐based purines after release from astrocytes. This regulates the effects of nucleotides and nucleosides by reducing their interaction with specific membrane binding sites. Adenine‐based nucleotides stimulate astrocyte proliferation by a P2‐mediated increase in intracellular [Ca2+] and isoprenylated proteins. Adenosine also, via A2 receptors, may stimulate astrocyte proliferation, but mostly, via A1 and/or A3 receptors, inhibits astrocyte proliferation, thus controlling the excessive reactive astrogliosis triggered by P2 receptors. The activation of A1 receptors also stimulates astrocytes to produce trophic factors, such as nerve growth factor, S100β protein and transforming growth factor β, which contribute to protect neurons against injuries. Guanosine stimulates the output of adenine‐based purines from astrocytes and in addition it directly triggers these cells to proliferate and to produce large amount of neuroprotective factors. These data indicate that adenine‐ and guanine‐based purines released in large amounts from injured or dying cells of CNS may act as signals to initiate brain repair mechanisms widely involving astrocytes.
Muscle activity‐resistant acetylcholine receptor accumulation is induced in places of former motor endplates in ectopically innervated regenerating rat muscles
Authors: Gašperšič Rok , Koritnik Blaž , Eržen Ida , Sketelj Janez
Published: July 2002

Expression of acetylcholine receptors (AChRs) in the extrajunctional muscle regions, but not in the neuromuscular junctions, is repressed by propagated electric activity in muscle fibers. During regeneration, subsynaptic‐like specializations accumulating AChRs are induced in new myotubes by agrin attached to the synaptic basal lamina at the places of former motor endplates even in the absence of innervation. We examined whether AChRs still accumulated at these places when the regenerating muscles were ectopically innervated and the former synaptic places became extrajunctional. Rat soleus muscles were injured by bupivacaine and ischemia to produce complete myofiber degeneration. The soleus muscle nerve was permanently severed and the muscle was ectopically innervated by the peroneal nerve a few millimeters away from the former junctional region. After 4 weeks of regeneration, the muscles contracted upon nerve stimulation, showed little atrophy and the cross‐section areas of their fibers were completely above the range in non‐innervated regenerating muscles, indicating successful innervation. Subsynaptic‐like specializations in the former junctional region still accumulated AChRs (and acetylcholinesterase) although no motor nerve endings were observed in their vicinity and the cross‐section area of their fibers clearly demonstrated that they were ectopically innervated. We conclude that the expression of AChRs at the places of the former neuromuscular junctions in the ectopically innervated regenerated soleus muscles is activity‐independent.
Dopaminergic and gabaergic interneurons of the olfactory bulb are derived from the neonatal subventricular zone
Authors: Betarbet Ranjita , Zigova Tanja , Bakay Roy A.E. , Luskin Marla B.
Published: July 2002

Earlier studies in our laboratory have demonstrated that a discrete region of the anterior part of the neonatal subventricular zone (SVZa) contains exclusively neuronal progenitor cells. The descendants of the SVZa progenitor cells are destined for the granule cell and glomerular layers of the olfactory bulb, where they differentiate into granule and periglomerular cells, the interneurons of the olfactory bulb, respectively. In the present set of experiments we examined the neurotransmitter phenotype of the SVZa‐derived cells. In order to label SVZa‐derived cells, the cell proliferation marker bromodeoxyuridine (BrdU) was injected into the SVZa of postnatal day 2 (P2) rats. After 3 weeks, by which time most of the SVZ‐aderived cells have migrated to their final destination in the bulb, the animals were perfused and their brains processed for immunohistochemistry. To identify the neurotransmitter phenotype of the SVZa‐derived cells, sagittal sections of the forebrain, including the olfactory bulb, were double‐labeled with an antibody to BrdU in conjunction with an antibody to γ‐amino‐butyric acid (GABA) or tyrosine hydroxylase (TH), the rate limiting enzyme in the synthesis of dopamine. Using simultaneous indirect immunofluorescence to detect the presence of single‐ and double‐labeled cells, we found that 59% and 51% of the BrdU‐positive cells were immunoreactive for GABA in the granule cell and glomerular layers, respectively. In addition, 10% of the BrdU‐positive periglomerular cells were immunoreactive for TH. The presence of double‐labeled (BrdU‐positive/GABA‐positive and BrdU‐positive/TH‐positive) cells in the olfactory bulb, demonstrates that the SVZa is a source of the GABAergic and dopaminergic interneurons of the olfactory bulb during postnatal development.
Muscarinic and purinergic Ca2+ mobilizations in the neural retina of early embryonic chick
Authors: Sakaki Yoko , Fukuda Yutaka , Yamashita Masayuki
Published: July 2002

Acetylcholine and adenosine triphosphate (ATP) raise intracellular Ca2+ concentration via muscarinic receptors and P2U purinoceptors by releasing Ca2+ from intracellular Ca2+ stores in the neural retina of early embryonic chick. The signal transduction mechanisms for the muscarinic and purinergic Ca2+ responses with fura‐2 fluorescence measurements were studied. Li+ (1 mM), which inhibits phosphatidylinositol metabolism, enhanced both the Ca2+ rises to carbamylcholine (CCh, 30 μM), a muscarinic agonist, and ATP (200 μM). Thapsigargin (250 nM), an inhibitor of Ca2+‐ATPase of inositol trisphosphate (IP3)‐sensitive Ca2+ stores, abolished both the Ca2+ rises to CCh (100 μM) and ATP (500 μM). U‐73122 (2 μM), an inhibitor of phospholipase Cb, suppressed the Ca2+ rise to ATP (500 μM), but its analog U‐73343 (2 μM) did not suppress it. In contrast, both U‐73122 and U‐73343 suppressed the Ca2+ rise to CCh (100 μM). Pertussis toxin (250 ng/ml) suppressed the ATP‐induced Ca2+ rise at least partly, whereas no inhibition was observed on the CCh‐induced Ca2+ rise. Cross‐talk occurred between the muscarinic and purinergic Ca2+ mobilizations but they were not occlusive. This study suggests that the muscarinic and purinergic Ca2+ mobilizations utilize IP3‐sensitive Ca2+ stores, but different signal transduction pathways are involved in between the muscarinic and purinergic Ca2+ responses.
Effect of experimental hyperphenylalaninemia on the postnatal rat brain
Authors: Ushakova Alina A. , Gubkina Helena A. , Kachur Victoria A. , Lepekhin Eugene A.
Published: July 2002

The molecular mechanism of the disturbance to brain development caused by phenylketonuria remains mostly unknown. We have studied three molecular markers that reflect the development of neurons, glia and the extracellular matrix of the postnatal rat brain in an animal model of hyperphenylalaninemia, in order to elucidate the possible mechanism by which increased phenylalanine influences brain development. The contents of NCAM, GFAP and hyaluronate‐binding activity were compared in cerebellum and telencephalon of normal rats and those subjected to high phenylalanine. No statistically significant changeswere found in telencephalon when experimental animals were compared to controls. In the hyperphenylalaninemic cerebellum, the developmental dynamic of NCAM content (represented by two peaks at about postnatal days 5 and 22 during normal development) is dramatically altered. The GFAP content in the cerebellum of treated rats exceeded those in controls significantly during late developmental stages (postnatal days 28–35). Hyaluronate‐binding activity in the extracellular protein fraction from treated rat cerebellum was increased compared to normal rat at the early stages of development only (postnatal day 7). These results suggest that high serum phenylalanine may lead to permanent brain dysfunction through a disturbance of a wide range of developmental events.
Morphological evidence for supporting cell to hair cell conversion in the mammalian utricular macula
Authors: Li Lin , Forge Andrew
Published: July 2002

The possible origin of the immature hair cells that appear in the utricular maculae of guinea pigs following gentamicin‐induced hair cell death was investigated. Guinea pigs were continuously infused with bromodeoxyuridine, to label proliferating cells and their progeny, for 2 weeks after inducing damage to the inner ear on one side with gentamicin. The opposite ear in each animal served as control. Serial sections were cut through the entire utricular maculae of both ears of each animal and the number of labelled cells in the epithelium and underlying connective tissue was counted. Label was present in cells in the sensory epithelium in the utricles from the drug exposed ears but not in the controls. The nuclei of cells in the underlying connective tissue were also labelled in both ears. Some of the labelled nuclei in the epithelium were at the level normally occupied by hair cells, but most were at the level of supporting cell nuclei. However, the total number of labelled nuclei in the sensory epithelium was small; the maximum was 12 in one animal. The number of labelled nuclei in the connective tissue of the treated ears was significantly greater than the number in the untreated ear. This confirms that cell proliferation is stimulated in the mature mammalian utricular macula after hair cell loss, but the extent to which it occurs appears to be insufficient to explain the recovery in hair cell numbers which is observed. Detailed thin section studies of the utricular maculae of gentamicin‐treated animals over a prolonged post‐treatment period were also performed. In utricles which had suffered damage, there were cells which, like supporting cells but unlike hair cells, were resting on basement membrane, but which possessed at their apical ends organized bundles of microvilli similar to immature hair cell stereocilia. Other cells with more obvious stereocilia remained in contact with the basement membrane via and a small foot process. In still other cells, where a stereociliary bundle was obvious and almost mature in appearance, there was a foot process extending towards the basement membrane but not quite in contact, suggesting it had just detached. All these cells were contacted by nerve endings and specialization of the membranes were apparent at the site of cell‐neurone contact. The morphological characteristics of these cells are consistent with phenotypic conversion of supporting cells into hair cells and this may account for some of the hair cell production in the mature mammalian vestibular sensory epithelia after hair cell death.
Viral‐mediated gene transfer in the cochlea
Authors: Weiss Melissa A. , Frisancho Juan C. , Roessler Blake J. , Raphael Yehoash
Published: July 2002

Gene transfer is an exciting new tool in medical therapy and scientific investigation, but only very recently has it begun to be developed in the auditory system. This paper describes in vivo and ex vivo experiments using an adenoviral vector (Ad. RSVntlacZ), which is a replication‐deficient virus based on a human adenoviral (serotype 5) genomic backbone. The in vivo experiments demonstrate successful gene transfer into multiple types of cochlear cells. We observed a relatively efficient transduction, several weeks of sustained transgene expression and an absence of major lethal cytotoxicity in spiral ganglion and epithelial cells of the cochlea in adult animals. The ex vivo experiments were performed using fibroblasts transduced in vitro with Ad. RSVntlacZ. Two weeks after inoculation of the fibroblasts into the perilymph, we observed transplanted fibroblasts, which were adherent to the lining of the perilymphatic spaces, and were expressing the lacZ transgene. We speculate that, as the genetic basis of degenerative cochlear diseases is characterized on a mutational level, transgene expression will allow us to test hypotheses regarding the effects of specific genes on cochlear cell biology. Gene transfer will not only increase our understanding of the pathophysiology of hearing loss, but also may provide gene therapy for disease.
Time course of nerve‐fiber regeneration in the noise‐damaged mammalian cochlea
Authors: Lawner Brian E. , Harding Gary W. , Bohne Barbara A.
Published: July 2002

The time course of events which are essential for nerve‐fiber regeneration in the mammalian cochlea was determined using a group of chinchillas that had been exposed for 3.5 hr to an octave band of noise with a center frequency of 4 kHz and a sound pressure level of 108 dB. The animals recovered from 40 min (0 days) to 100 days at which times their inner ears were fixed and the organs of Corti prepared for phase‐contrast and bright‐field microscopy as plastic‐embedded flat preparations. Selected areas identified in the flat preparations were semi‐thick and thin sectioned at radial or tangential angles for examination by bright‐field and transmission electron microscopy. The following time‐ordered events appeared critical for nerve‐fiber regeneration: (1) The area of the basilar membrane in which regeneration had a possibility of occurring showed signs of severe injury. Outer hair cells degenerated first followed by outer pillars, inner pillars, inner hair cells and other supporting cells; (2) Myelinated nerve fibers in the osseous spiral lamina became fragmented, starting at the distal ends of the fibers. This degeneration gradually extended back to Rosenthal's canal; (3) Fibrous processes, originating from Schwann‐like cells in the osseous spiral lamina, extended laterally on the basilar membrane; (4) Schwann cells lined up medial to the habenulae perforata in the areas of severest damage, apparently ready to migrate through the habenulae onto the basilar membrane; (5) Schwann‐cell nuclei appeared on the basilar membrane beneath the developing layer of squamous epithelium which was in the process of replacing the degenerated portion of the organ of Corti; (6) Regenerated nerve fibers with thin myelin sheaths or a simple investment of Schwann cell cytoplasm appeared in areas of total loss of the organ of Corti; and (7) The myelin sheaths on the regenerated nerve fibers gradually became thicker.
Cholinergic immunolesions by 192IgG‐saporin—a useful tool to simulate pathogenic aspects of alzheimer's disease
Authors: Roßner Steffen
Published: July 2002

Alzheimer's disease, the most common cause of senile dementia, is characterized by intracellular formation of neurofibrillary tangles, extracellular deposits of beta amyloid as well as cerebrovascular amyloid accumulation and a profound loss of cholinergic neurons within the nucleus basalis Meynert with alterations in cortical neurotransmitter receptor densities. The use of the cholinergic immunotoxin 192IgG‐saporin allows for the first time study of the impact of cortical cholinergic deafferentation on cortical neurotransmission, learning, and memory without direct effects on other neuronal sytems. This model also allows the elucidation of contributions of cholinergic mechanisms to the establishment of other pathological features of Alzheimer's disease. The findings discussed here demonstrate that cholinergic immunolesions by 192IgG‐saporin induce highly specific, permanent cortical cholinergic hypoactivity and alterations in cortical neurotransmitter densities comparable to those described for Alzheimer's disease. The induced cortical cholinergic deficit also leads to cortical/hippocampal neurotrophin accumulation and reduced amyloid precursor protein (APP) secretion, possibly reflecting the lack of stimulation of postsynaptic M1/M3 muscarinic receptors coupled to protein kinase C. This immunolesion model should prove useful to test therapeutic strategies based on stimulation of cortical cholinergic neurotransmission or amelioration of pathogenic aspects of cholinergic degeneration in the basal forebrain. Application of the model to animal species that can developβ‐amyloid plaques could provide information about the contribution of cholinergic function to amyloidogenic APP processing.
Prenatal stress: consequences of glucocorticoids on hippocampal development and function
Authors: Takahashi Lorey K.
Published: July 2002

Prenatally stressed offspring exhibit a variety of physiological and behavioral alterations. This paper highlights those alterations associated with prenatal stress‐induced elevations in glucocorticoid secretion. Three major alterations are identified that may be produced by glucocorticoid‐induced actions on the developing hippocampus. Changes include reductions in steroid receptors that bind endogenous glucocorticoids, enhanced secretion of stress hormones and increased reactivity or emotionality in stressful situations. Some of these alterations may be ameliorated by early postnatal environmental manipulations such as adoption and handling procedures. These latter results suggest that prenatal stress‐induced effects of glucocorticoids extend into the early postnatal period to produce long‐term hippocampal and behavioral alterations. Support for this hypothesis is based on studies demonstrating that the hippocampus undergoes considerable maturational changes during the early postnatal period such as establishing the regional distribution of corticosteroid receptor densities and development of hippocampal dentate gyrus cells as well as cholinergic systems. Hippocampal corticosteroid receptors are involved in the regulation of glucocorticoid negative feedback and hippocampal dentate gyrus and cholinergic development are influenced by endogenous glucocorticoids and are implicated in the development of defensive or stress‐induced behavior. The developing hippocampus appears especially vulnerable to alterations induced by prenatal stress‐induced elevations in glucocorticoids that continue to produce their effects throughout the early postnatal period.
Quantitative study of plasticity in the auditory nuclei of chick under conditions of prenatal sound attenuation and overstimulation with species specific and music sound stimuli
Authors: Wadhwa Shashi , Anand Phalguni , Bhowmick Deepika
Published: July 2002

Morphological effects of prenatal sound attenuation and sound overstimulation by species specific and music sounds on the brainstem auditory nuclei of chick have been evaluated quantitatively. Changes in length, volume, neuron number, size of neuronal nuclei and glial numbers of second and third order auditory nuclei, n. magnocellularis (NM) and n. laminaris (NL), were determined from thionine‐stained serial sections of control and experimental groups on posthatch day 1 using stereological methods.

Significant increase in volume of both auditory nuclei attributable to increase in length of nucleus, number and size of neurons, number of glia as well as neuropil was observed in response to both species specific and music overstimulation given during the critical period of development. The enhanced development of auditory nuclei in response to enriched environment prenatally indicates a positive effect of activity on neurons which may have clinical implications in addition to providing explanation for preference to auditory cues in the postnatal life.

Reduction in neuron number with a small increase in proportion of cell nuclei of large size as well as an increase in glial numbers was seen in both NM and NL of the prenatally sound attenuated chicks. The increase in size of some neuronal nuclei may probably be evidence of enhanced synthesis of proteins involved in cell death or an attempt at recovery.

The dissociated response of neurons and glia under sound attenuated and auditory stimulated conditions suggests that they are independently regulated by activity‐dependent signals with glia also being under influence of other signals for a role in removal of dead cell debris.
Increased SPARC expression promotes U87 glioblastoma invasion in vitro
Authors: Golembieski W.A. , Ge S. , Nelson K. , Mikkelsen T. , Rempel S.A.
Published: July 2002

Our recent studies have focused on identifying invasion‐promoting genes that are expressed early in brain tumor progression. We identified and characterized SPARC (secreted protein acidic and rich in cysteine) as a potential candidate. To determine whether increased SPARC expression functionally promotes brain tumor invasion, SPARC was transfected into U87MG glioblastoma cells using the tetracycline‐off gene expression system. The parental cell line (U87MG), the parental transactivator‐transfected clone (U87T2) and three selected U87T2–SPARC‐transfected clones (A2bi, A2b2 and C2a4) were characterized for endogenous and transfected SPARC expression. In comparison to the parental or U87T2 cell lines, the SPARC‐transfected clones demonstrated: (1) morphological changes, (2) increased SPARC transcript and protein abundances that were down‐regulated by the tetracycline analog doxycycline, (3) perinuclear localization of the transfected SPARC (consistent with reported localization of SPARC in normal cells in culture) and (4) altered adhesion and increased invasion as assessed by the spheroid confrontation assay. These data indicate that increased SPARC expression contributes to U87 glioblastoma tumor invasion in vitro and that these cell lines will serve as useful reagents to investigate the mechanism(s) by which SPARC promotes this phenotype in vitro and in vivo.
Matrix metalloproteinases and their biological function in human gliomas
Authors: Chintala Shravan K. , Tonn Jorg C. , Rao Jasti S.
Published: July 2002

Gliomas, a type of devastating primary brain tumors, are distinct from other solid, nonneural primary neoplasms, in that they display extensive infiltrative invasive behavior but seldom metastasize to distant organs. This invasiveness into the surrounding normal brain tissue makes gliomas a major challenge for clinical intervention. Total surgical resection of gliomas is not possible, and recurrence of tumor growth is common; mean survival time is 8–12 months. Although substantial progress has been made recently toward understanding the behavior of gliomas, the mechanisms that facilitate invasion are still poorly documented. Clues to the invasion process have been ascertained through clarification of the key roles played by the extracellular matrix (ECM), cell‐adhesion molecules and matrix degrading proteases. Serine proteases and metalloproteinases have been implicated in glioma tumor cell‐invasion. Matrix metalloproteinases (MMPs) in particular can degrade almost all known ECM components and seem to play important roles in mediating glioblastoma tumor cell invasion. This review focuses on recent developments concerning the role of MMPs in the invasiveness of human gliomas.
Social separation in infant Cebus apella: patterns of behavioral and cortisol response
Authors: Byrne Gayle , Suomi Stephen J.
Published: July 2002

34 infant tufted capuchins (Cebus apella) were separated from their social groups for a 2‐hour period and videotaped in isolation at the ages of 6 months and 1 year. Baseline and 2‐hour blood samples were measured for levels of serum cortisol. Compared to homecage baseline levels, passivity, locomotion and vocalizations increased during separation, while self‐directed behavior and environmental exploration decreased. Both behavioral and cortisol responses to separation showed individual stability over the 6 month period, although both responses were somewhat attenuated at the later age. There was little correlation between cortisol and behavior during separations. Females vocalized more than did males during separations and showed greater cortisol increases at 6 months of age. The pattern of behavioral response seen in the 2 hours following separation appeared to be more passive than the typical 'protest' response described in many nonhuman primates, and may reflect either the physical circumstances of the separation or a characteristic of species with relaxed social bonds and considerable allomothering available to infants.
Retrovirus producer cells encoding antisense VEGF prolong survival of rats with intracranial GS9L gliomas
Authors: Sasaki M. , Wizigmann‐Voos S. , Risau W. , Plate K.H.
Published: July 2002

With increasing size tumors are continually dependent on a functional blood vessel system to guarantee the supply with oxygen and nutrients. Vascular endothelial growth factor (VEGF) is a key mediator not only of developmental but also of hypoxia‐mediated and tumor‐induced angiogenesis. Gene therapy using antisense VEGF with the aim to inhibit tumor angiogenesis may be a successful strategy for the treatment of highly vascular and invasive malignant gliomas. We investigated whether retrovirus producer cells encoding antisense VEGF can be used for in vivo gene transfer. The full length mouse VEGF164 cDNA was cloned in a sense and antisense direction into the retroviral expression vector pLEN. pLEN–VEGF (sense) and pLEN–FGEV (antisense) expression vectors were used to transfect the packaging cell line GP+E86 and to establish ecotropic virus producer cell lines. GP+E86:LEN–FGEV (#5) cells showed high expression of antisense VEGF mRNA, whereas GP+E86:LEN–VEGF (#8) showed high expression of sense VEGF mRNA and active VEGF protein. Co‐implantation of GS‐9L cells with retrovirus producing cells containing the antisense VEGF construct into the brains of syngeneic rats showed a statistically significant inhibition of tumor growth and prolongation of survival time, while co‐implantation of retrovirus producer cells containing the sense VEGF expression vector resulted in an increasing tumor growth and reduced survival time of the rats compared to control animals. Histological analysis of the tumors co‐implanted with GP+E86:LEN–FGEV (#5) cells showed the suppression of angiogenesis, high degree of necrosis and no evidence of a significant immune response. Expression of antisense VEGF mRNA in these tumors was confirmed by in situ hybridization analysis. This is the first report demonstrating the potential utility of virus producer cells as in vivo gene transfer vehicles for antisense VEGF gene therapy of malignant gliomas.
Size, time‐varying beta, and conditional heteroscedasticity in UK stock returns
Authors: Reyes Mario G.
Published: July 2002

The purpose of this study is to examine the relationship between firm size and time‐varying betas of UK stocks. We extend the Schwert and Seguin (1990)(Journal of Finance 45, 1120–1155) methodology by explicitly modeling conditional heteroscedasticity in the market model residual returns. Our results show that the time‐varying coefficient is not statistically significant for both small and large firm stock indexes. We also find that accounting for GARCH effects in the Schwert‐Seguin market model yields beta estimates that are markedly differently from those when conditional heteroscedasticity is ignored. Event studies that ignore conditional heteroscedasticity may bias the abnormal returns of small and large firms, thereby leading to a different conclusion regarding the significance of an information event.
The bridge helix of Cas12a imparts selectivity in cis‐DNA cleavage and regulates trans‐DNA cleavage
Authors: Parameshwaran Hari Priya , Babu Kesavan , Tran Christine , Guan Kevin , Allen Aleique , Kathiresan Venkatesan , Qin Peter Z. , Rajan Rakhi
Published: February 2021

Cas12a is an RNA‐guided DNA endonuclease of the type V‐A CRISPR‐Cas system that has evolved convergently with the type II Cas9 protein. We previously showed that proline substitutions in the bridge helix (BH) impart target DNA cleavage selectivity in Streptococcus pyogenes (Spy) Cas9. Here, we examined a BH variant of Cas12a from Francisella novicida (FnoCas12aKD2P) to test mechanistic conservation. Our results show that for RNA‐guided DNA cleavage (cis‐activity), FnoCas12aKD2P accumulates nicked products while cleaving supercoiled DNA substrates with mismatches, with certain mismatch positions being more detrimental for linearization. FnoCas12aKD2P also possess reduced trans‐single‐stranded DNA cleavage activity. These results implicate the BH in substrate selectivity in both cis‐ and trans‐cleavages and show its conserved role in target discrimination among Cas nucleases.
Inorganic Lead‐Free Cs2AuBiCl6 Perovskite Absorber and Cu2O Hole Transport Material Based Single‐Junction Solar Cells with 22.18% Power Conversion Efficiency
Authors: Kale Abhijeet J. , Chaurasiya Rajneesh , Dixit Ambesh
Published: February 2021

Cs2AuBiCl6 is considered to be a potential lead‐free double perovskite alternative for perovskite solar cells. Its electronic and optical properties are investigated using density functional theory. The electronic properties of Cs2AuBiCl6 material ensure a bandgap of 1.40 eV (without considering SOC) and 1.12 eV (with SOC) using mBJ exchange‐correlation functional, close to the optimal bandgap for solar cell application as per the Shockley–Queisser limit. Optical properties suggest a high absorption coefficient ≈105 cm−1 with low reflectance, making it the optimal absorber material. Furthermore, the photovoltaic performance of Cs2AuBiCl6 based single‐junction transparent conducting oxide (TCO)/IDL1/Cs2AuBiCl6/IDL2/Cu2O solar cell is investigated using SCAPS‐1D device simulation program. The impact of electron affinity, thickness, carrier concentration, defect density, and interface defect density is examined using interface defect layer (IDL) on the photovoltaic performance. The maximum photoconversion efficiency (PCE) of ≈22.18% is noticed for optimized material's parameters. These studies on TCO/IDL1/Cs2AuBiCl6/IDL2/Cu2O solar cell will provide guidelines for designing and developing an efficient lead‐free perovskite‐based solar cell as an alternative to conventional halide perovskite materials based solar cell.
Mixed Matrix Membranes for Sustainable Electrical Energy‐Saving Applications
Authors: Harami Hossein Riasat , Amirkhani Farid , Abedsoltan Hossein , Younas Mohammad , Rezakazemi Mashallah , Sheikh Mahdi , Shirazian Saeed
Published: February 2021

This work presents a technical investigation and review of the development of mixed matrix membranes (MMMs) employed in different applications to save electrical energy. The MMMs design has been recently adjusted and improved to restore more energy bulks. The important factors to control the performance of the MMMs are the penetrant type, membrane matrix, and polymer‐filler interface interactions. This study reviews the current methods to deal with dielectric MMMs and smart nanomembranes for energy saving. These methods include ferroelectric membrane fabrication, dielectric permittivity, conductive dopants, construction of nanocomposites with modified surfaces, and the usage of combined effects. Most chemists and scientists have dedicated all their efforts to develop the attributes of dielectric materials at various electric fields and to find their relationship with chemical construction, composite morphology, and particle density.
Impact of Protein Fouling on the Charge Injection Capacity, Impedance, and Effective Electrode Area of Platinum Electrodes for Bionic Devices
Authors: Harris Alexander R. , Carter Paul , Cowan Robert , Wallace Gordon G.
Published: February 2021

The impact of protein fouling on platinum electrodes was assessed by electrochemical methods. Protein fouling affected the electrode potential and charge transfer through the electrode‐solution interface. Adsorbed proteins partially blocked the electrode, with no charge passing through blocked regions. The electrochemical theory and methodology for investigating partially blocked electrodes is fully presented, applied to protein adsorption, and the implications for bionics applications are discussed. The partially blocked electrode had a reduced admittance, and increased impedance and polarization resistance consistent with a smaller effective electrode area. The charge storage capacity and charge injection capacity decreased after protein adsorption. The effective electrode area was assessed by impedance and cyclic voltammetry. The diffusion profile towards the partially blocked electrode was mixed between linear and radial diffusion.
Clinical and organizational risk factors for mortality during deterioration events among pediatric oncology patients in Latin America: A multicenter prospective cohort
Authors: Agulnik Asya , Cárdenas Adolfo , Carrillo Angela K. , Bulsara Purva , Garza Marcela , Alfonso Carreras Yvania , Alvarado Manuel , Calderón Patricia , Díaz Rosdali , de León Claudia , del Real Claudia , Huitz Tania , Martínez Angélica , Miralda Scheybi , Montalvo Erika , Negrín Octavia , Osuna Alejandra , Perez Fermin Clara Krystal , Pineda Estuardo , Soberanis Dora , Juárez Tobias Maria Susana , Lu Zhaohua , Rodriguez‐Galindo Carlos ,   EVAT Study Group
Published: February 2021

Background

Hospitalized pediatric hematology‐oncology (PHO) patients have frequent clinical deterioration events (CDE) requiring intensive care unit (ICU) admission, particularly in resource‐limited settings. The objective of this study was to describe CDEs in hospitalized PHO patients in Latin America and to identify event‐level and center‐level risk factors for mortality.

Methods

In 2017, the authors implemented a prospective registry of CDEs, defined as unplanned transfers to a higher level of care, use of ICU‐level interventions on the floor, or nonpalliative floor deaths, in 16 PHO centers in 10 countries. PHO hospital admissions and hospital inpatient days were also reported. This study analyzes the first year of registry data (June 2017 to May 2018).

Results

Among 16 centers, 553 CDEs were reported in PHO patients during 11,536 admissions and 119,414 inpatient days (4.63 per 1000 inpatient days). Event mortality was 29% (1.33 per 1000 inpatient days) but ranged widely across centers (11%‐79% or 0.36‐5.80 per 1000 inpatient days). Significant risk factors for event mortality included requiring any ICU‐level intervention on the floor and not being transferred to a higher level of care. Events with organ dysfunction, a higher severity of illness, and a requirement for ICU intervention had higher mortality. In center‐level analysis, hospitals with a higher volume of PHO patients, less floor use of ICU intervention, lower severity of illness on transfer, and lower rates of floor cardiopulmonary arrest had lower event mortality.

Conclusions

Hospitalized PHO patients who experience CDEs in resource‐limited settings frequently require floor‐based ICU interventions and have high mortality. Modifiable hospital practices around the escalation of care for these high‐risk patients may contribute to poor outcomes. Earlier recognition of critical illness and timely ICU transfer may improve survival in hospitalized children with cancer.
Methods for Rapid Protein Depletion in C. elegans using Auxin‐Inducible Degradation
Authors: Divekar Nikita S. , Horton Hannah E. , Wignall Sarah M.
Published: February 2021

Numerous methods have been developed in model systems to deplete or inactivate proteins to elucidate their functional roles. In Caenorhabditis elegans, a common method for protein depletion is RNA interference (RNAi), in which mRNA is targeted for degradation. C. elegans is also a powerful genetic organism, amenable to large‐scale genetic screens and CRISPR‐mediated genome editing. However, these approaches largely lead to constitutive inhibition, which can make it difficult to study proteins essential for development or to dissect dynamic cellular processes. Thus, there have been recent efforts to develop methods to rapidly inactivate or deplete proteins to overcome these barriers. One such method that is proving to be exceptionally powerful is auxin‐inducible degradation. In order to apply this approach in C. elegans, a 44–amino acid degron tag is added to the protein of interest, and the Arabidopsis ubiquitin ligase TIR1 is expressed in target tissues. When the plant hormone auxin is added, it mediates an interaction between TIR1 and the degron‐tagged protein of interest, which triggers ubiquitination of the protein and its rapid degradation via the proteasome. Here, we have outlined multiple methods for inducing auxin‐mediated depletion of target proteins in C. elegans, highlighting the versatility and power of this method. © 2021 Wiley Periodicals LLC.

This article was corrected on 19 July 2022. See the end of the full text for details.

Basic Protocol 1: Long‐term auxin‐mediated depletion on plates

Support Protocol: Preparation of NGM and NGM‐auxin plates

Basic Protocol 2: Rapid auxin‐mediated depletion via soaking

Basic Protocol 3: Acute auxin‐mediated depletion in isolated embryos

Basic Protocol 4: Assessing auxin‐mediated depletion
Macrosystems revisited: challenges and successes in a new subdiscipline of ecology
Authors: Dodds Walter K , Rose Kevin C , Fei Songlin , Chandra Sudeep
Published: February 2021

Macrosystems biology research has expanded and evolved over the past decade as the scientific community grapples with ecological issues at regional to continental scales relevant to human interactions within the biosphere. Macrosystems biology builds on established fields of study like population and community ecology, biogeography, and global biogeochemistry, and has the potential to develop into a unique and important subdiscipline. If we achieve this outcome, macrosystems research will likely have increasing relevance to ecological science and its practical application, and could potentially transform large‐scale ecological understanding. Both previous studies and the articles included in this Special Issue document the development of a broad spectrum of macrosystems approaches, how ecological researchers have accommodated the sociological aspects of collaboration among diverse individuals and groups, and how new methods are being applied to deal with the large and diverse types of data used by macrosystems biologists.
Training macrosystems scientists requires both interpersonal and technical skills
Authors: Farrell Kaitlin J , Weathers Kathleen C , Sparks Sarah H , Brentrup Jennifer A , Carey Cayelan C , Dietze Michael C , Foster John R , Grayson Kristine L , Matthes Jaclyn H , SanClements Michael D
Published: February 2021

Macrosystems science strives to integrate patterns and processes that span regional to continental scales. The scope of such research often necessitates the involvement of large interdisciplinary and/or multi‐institutional teams composed of scientists across a range of career stages, a diversity that requires researchers to hone both technical and interpersonal skills. We surveyed participants in macrosystems projects funded by the US National Science Foundation to assess the perceived importance of different skills needed in their research, as well as the types of training they received. Survey results revealed a mismatch between the skills participants perceive as important and the training they received, particularly for interpersonal and management skills. We highlight lessons learned from macrosystems training case studies, explore avenues for further improvement of undergraduate and graduate education, and discuss other training opportunities for macrosystems scientists. Given the trend toward interdisciplinary research beyond the macrosystems community, these insights are broadly applicable for scientists involved in diverse, collaborative projects.
Do foreign lenders' national cultures affect loan pricing?
Authors: Pappas Kostas , Xu Alice Liang
Published: February 2021

We examine the role of foreign lenders' national cultures in the pricing of syndicated loans. Using Schwartz's cultural dimensions, embeddedness, and mastery, we find that foreign lenders domiciled in countries with higher embeddedness and mastery scores offer lower interest rates. These findings are robust to a battery of robustness tests and incremental to the effects of formal institutions. We also document that greater information asymmetry and foreign lenders' bargaining powers strengthen the impact of the foreign lenders' cultural values on loan pricing. An additional analysis shows that the intensity of loan covenants is also negatively related to the embeddedness and mastery scores of the foreign lenders' countries of domicile. Our findings suggest that cross‐border debt contracting decisions are not only determined by objective judgments about risk and return but also depend on the subjective assertion of values and beliefs guided by informal institutions, such as cultural norms. Cultural values can nurture and shape economic incentives and perceptions of sophisticated professional bankers in increasingly globalized market settings, even when the financial stakes are substantial.
Pulmonary mucosa‐associated lymphoid tissue lymphoma: CT findings and pathological basis
Authors: Bi Wanli , Zhao Shuo , Wu Chongchong , Gao Jie , Zhao Shaohong , Yang Shifeng , Deng Yan , Nie Pei , Yu Xinxin , Deng Hui , Zang Xuelei , Ma Xidong , Han Jun , Asuquo Idorenyin , Wang Ximing , Xue Xinying
Published: February 2021

Background

Pulmonary mucosa‐associated lymphoid tissue lymphoma (MALToma) is the most frequent subset of primary pulmonary lymphoma. This study aimed to identify radiologic characteristics of pulmonary MALToma based on computed tomography (CT) observations and pathologic features, and further investigate its prognosis.

Methods

Sixty‐six patients (55.4 ± 10.9 years; 51.5% male) diagnosed as pulmonary MALToma by pathology were retrospectively enrolled. According to distributions and features of lesions shown on CT, patients were divided into three patterns, including single nodular/mass, multiple nodular/mass, and pneumonia‐like consolidative.

Results

Variety of the location and extent of the lymphomatous infiltration accounted for different characteristics demonstrated at CT. The pneumonia‐like consolidative pattern was the most frequent pattern observed in 42 patients (63.6%), followed by single nodular/mass (21.2%) and multiple nodular/mass (15.2%). CT features included air bronchogram (72.7%), well‐marginated halo sign (53.0%), coarse spiculate with different lengths (72.7%), angiogram sign (77.1% of 35 patients), peribronchovascular thickening (48.5%), irregular cavitation (16.7%) and pulmonary cyst (7.6%). The estimated 5‐year cumulative overall survival rate of pulmonary MALToma was 100.0%.

Conclusions

Pulmonary MALToma demonstrates several characteristics at CT. Identification of the significant pulmonary abnormalities of this indolent disease entity might be helpful for early diagnosis and optimal treatment.