Memory formation and retrieval of neuronal silencing in the auditory cortex

Sensory stimuli not only activate specific populations of cortical neurons but can also silence other populations. However, it remains unclear whether neuronal silencing per se leads to memory formation and behavioral expression. Here we show that mice can report optogenetic inactivation of auditory neuron ensembles by exhibiting fear responses or seeking a reward. Mice receiving pairings of footshock and silencing of a neuronal ensemble exhibited a fear response selectively to the subsequent silencing of the same ensemble. The valence of the neuronal silencing was preserved for at least 30 d and was susceptible to extinction training. When we silenced an ensemble in one side of auditory cortex for conditioning, silencing of an ensemble in another side induced no fear response. We also found that mice can find a reward based on the presence or absence of the silencing. Neuronal silencing was stored as working memory. Taken together, we propose that neuronal silencing without explicit activation in the cerebral cortex is enough to elicit a cognitive behavior.Cortical neurons exhibit spontaneous activity without explicit external stimuli (1–3), which may not only increase, but also be suppressed, by sensory stimuli (4, 5). For example, auditory stimuli suppress a subset of auditory cortical neurons in a frequency-dependent manner (5). Synaptic inhibition in the cerebral cortex is fundamental for neuronal modulation (6), including gain control (7), response selectivity (8, 9), and synchronized activities (10, 11). Inhibition-based modulations may contribute to stimulus-driven behaviors and associative memories of sensory stimuli (12); however, it remains unclear whether neuronal silencing (i.e., a transient reduction in firing rates from their spontaneous level) by itself can serve as a memory trace and bring about behavioral expressions. In this study, we tested this possibility by optogenetically silencing auditory cortical neurons.     

Age-related learning deficits can be reversible in honeybees Apis mellifera

Many animals are characterized by declining brain function at advanced ages, including honeybees (Apis mellifera). Variation in honeybee social development, moreover, results in individual differences in the progression of aging that may be accelerated, delayed, and sometimes reversed by changes in behavior. Here, we combine manipulations of social development with a measurement of sensory sensitivity, Pavlovian (associative) learning, and a proteomic technique to study the brain of aged honeybees. First, we confirm that sensory sensitivity can remain intact during aging, and that age-associated learning deficits are specific to bees that forage, a behavior typically expressed after a period of nursing activity. These initial data go beyond previous findings by showing how foragers age in social groups of different age compositions and sizes. Thereafter, we establish that learning ability can recover in aged foragers that revert to nursing tasks. Finally, we use liquid chromatography coupled to tandem mass spectrometry (LC-MS(2)) to describe proteomic differences between central brains, from reverted former foragers that varied in recovery of learning performance, and from nurse bees that varied in learning ability but never foraged. We find that recovery is positively associated with levels of stress response/cellular maintenance proteins in the central brain, while variation in learning before aging is negatively associated with the amounts of metabolic enzymes in the brain tissue. Our work provides the strongest evidence, thus far, for reversibility of learning deficits in aged honeybees, and indicates that recovery-related brain plasticity is connected to cellular stress resilience, maintenance and repair processes.     

Glucocorticoids interact with the hippocampal endocannabinoid system in impairing retrieval of contextual fear memory

There is extensive evidence that glucocorticoid hormones impair the retrieval of memory of emotionally arousing experiences. Although it is known that glucocorticoid effects on memory retrieval impairment depend on rapid interactions with arousal-induced noradrenergic activity, the exact mechanism underlying this presumably nongenomically mediated glucocorticoid action remains to be elucidated. Here, we show that the hippocampal endocannabinoid system, a rapidly activated retrograde messenger system, is involved in mediating glucocorticoid effects on retrieval of contextual fear memory. Systemic administration of corticosterone (0.3-3 mg/kg) to male Sprague-Dawley rats 1 h before retention testing impaired the retrieval of contextual fear memory without impairing the retrieval of auditory fear memory or directly affecting the expression of freezing behavior. Importantly, a blockade of hippocampal CB1 receptors with AM251 prevented the impairing effect of corticosterone on retrieval of contextual fear memory, whereas the same impairing dose of corticosterone increased hippocampal levels of the endocannabinoid 2-arachidonoylglycerol. We also found that antagonism of hippocampal β-adrenoceptor activity with local infusions of propranolol blocked the memory retrieval impairment induced by the CB receptor agonist WIN55,212-2. Thus, these findings strongly suggest that the endocannabinoid system plays an intermediary role in regulating rapid glucocorticoid effects on noradrenergic activity in impairing memory retrieval of emotionally arousing experiences.     

Hippocampal molecular mechanisms involved in the enhancement of fear extinction caused by exposure to novelty

Exposure to a novel environment enhances the extinction of contextual fear. This has been explained by tagging of the hippocampal synapses used in extinction, followed by capture of proteins from the synapses that process novelty. The effect is blocked by the inhibition of hippocampal protein synthesis following the novelty or the extinction. Here, we show that it can also be blocked by the postextinction or postnovelty intrahippocampal infusion of the NMDA receptor antagonist 2-amino-5-phosphono pentanoic acid; the inhibitor of calcium/calmodulin-dependent protein kinase II (CaMKII), autocamtide-2–related inhibitory peptide; or the blocker of L-voltage–dependent calcium channels (L-VDCCs), nifedipine. Inhibition of proteasomal protein degradation by β-lactacystin has no effect of its own on extinction or on the influence of novelty thereon but blocks the inhibitory effects of all the other substances except that of rapamycin on extinction, suggesting that their action depends on concomitant synaptic protein turnover. Thus, the tagging-and-capture mechanism through which novelty enhances fear extinction involves more molecular processes than hitherto thought: NMDA receptors, L-VDCCs, CaMKII, and synaptic protein turnover.Frey and Morris (1, 2) and their collaborators (3–7) proposed a mechanism whereby relatively “weak” hippocampal long-term potentiation (LTP) or long-term depression (LTD) lasting only a few minutes can nevertheless “tag” the synapses involved with proteins synthesized ad hoc, so that other plasticity-related proteins (PRPs) produced at other sets of synapses by other LTPs or LTDs can be captured by the tagged synapses and strengthen their activity to “long” LTPs or LTDs lasting hours or days (8). LTDs and LTPs can “cross”-tag each other; that is, LTDs can enhance both LTDs and LTPs, and vice versa (6, 8). Because many learned behaviors rely on hippocampal LTP or LTD (7–9), among them the processing of novelty (9, 10) and the making of extinction (11–13), interactions between consecutive learnings can also be explained by the “tagging-and-capture” hypothesis (9, 10, 13), whose application to behavior became known as “behavioral tagging and capture” (5, 7, 9, 13). Typically, exposure to a novel environment [e.g., a nonanxiogenic 50 × 50 × 40-cm open field (OF) (5, 7, 9, 10, 14)] is interpolated before testing for another task, which becomes enhanced (4–10, 13). The usual reaction to novelty is orienting and exploration (14), followed by habituation of this response (14–16). Habituation is perhaps the simplest form of learning, and it consists of inhibition of the orienting/exploratory response (14, 16).We recently showed that the brief exposure of rats to a novel environment (the OF) within a limited time window enhances the extinction of contextual fear conditioning (CFC) through a mechanism of synaptic tagging and capture (13), which is a previously unidentified example of behavioral tagging of inhibitory learning. Fear extinction is most probably due to LTD in the hippocampus (11, 12), although the possibility that it may also involve LTP is not discarded (13). The enhancement of extinction by novelty probably relies on the habituation to the novel environment, which is also probably due to LTD (15, 16). The enhancement of extinction by the exposure to novelty depends on hippocampal gene expression and ribosomal protein synthesis following extinction training and on both ribosomal and nonribosomal protein synthesis caused by the novel experience (13). Nonribosomal protein synthesis that can be blocked by rapamycin is believed to be dendritic (13, 17), so it would be strategically located for tagging-and-capture processes, but it has not been studied in synaptic tagging to date (3–8) or in other forms of behavioral tagging (7–10). As occurs with the interactions between LTPs and/or LTDs (4), the enhancement of extinction by novelty relies on hippocampal but not amygdalar processes (13).Recent findings indicate that several hippocampal processes related to learning and memory, such as the reconsolidation of spatial learning, are highly dependent on NMDA glutamate receptors, calcium/calmodulin protein kinase II (CaMKII), and long-term voltage channel blockers (L-VDCCs), which, in turn, rely on the proteasomal degradation of proteins (18). Here, we study the effects of an NMDA blocker, 2-amino-5-phosphono pentanoic acid (AP5); the L-VDCC blocker nifedipine (Nife); a CaMKII inhibitor, the autocamtide-2–related inhibitory peptide (AIP); and the irreversible proteasome blocker β-lactacystin (12, 13) on the interaction between novelty and extinction (11). As will be seen, we found that both the setting up of tags by extinction and the presumable production of PRPs by the processing of novelty are dependent on NMDA receptors, CaMKII, and L-VDCCs. This endorses and expands the hypothesis that the novelty–extinction interaction relies on synaptic tagging and capture (13).     

Disruption of the expression of the proprotein convertase PC7 reduces BDNF production and affects learning and memory in mice

PC7 belongs to the proprotein convertase family, whose members are implicated in the cleavage of secretory precursors. The in vivo function of PC7 is unknown. Herein, we find that the precursor proBDNF is processed into mature BDNF in COS-1 cells coexpressing proBDNF with either PC7 or Furin. Conversely, the processing of proBDNF into BDNF is markedly reduced in the absence of either Furin or PC7 in mouse primary hepatocytes. In vivo we observe that BDNF and PC7 mRNAs are colocalized in mouse hippocampus and amygdala and that mature BDNF protein levels are reduced in these brain areas in PC7 KO mice but not in the hippocampus of PC1/3 KO mice. Various behavioral tests reveal that in PC7 KO mice spatial memory is intact and plasticity of responding is mildly abnormal. Episodic and emotional memories are severely impaired, but both are rescued with the tyrosine receptor kinase B agonist 7,8-dihydroxyflavone. Altogether, these results support an in vivo role for PC7 in the regulation of certain types of cognitive performance, in part via proBDNF processing. Because polymorphic variants of human PC7 are being characterized, it will be important in future studies to determine their effects on additional physiological and behavioral processes.Nine secretory proprotein convertases (PCs) play major roles in regulating multiple cellular and extracellular processes both in health and disease states (reviewed in refs. 1 and 2). The convertases PC1/3, PC2, Furin, PC4, PC5/6, PACE4, and PC7 cleave their substrates after single or pairs of basic amino acids, SKI-1/S1P processes protein precursors after nonbasic residues, and PCSK9 has no known substrates other than itself (1). Studies that have analyzed tissue expression, levels, regulation, ontogeny, phenotypes of model animals lacking one or more PCs, and human/mouse natural mutations are starting to provide clues as to the specific roles of these enzymes in cells and whole-animal physiological and pathological processes.The type I membrane-bound PC7 is the most ancient member of the mammalian basic amino acid-specific PC family, and it exhibits the closest homology to yeast kexin (3). Human PC7 is synthesized as an N-glycosylated zymogen (proPC7) that, like most other PCs, undergoes autocatalytic cleavage in the endoplasmic reticulum at RAKR₁₄₁↓SV. Mature PC7 can reach the cell surface by an unconventional route from the endoplasmic reticulum (4), but it also accumulates in the trans Golgi network (TGN) and can cycle between the cell surface and TGN via endosomes, in part by virtue of a Pro-Leu-Cys₇₂₆ motif in its cytosolic tail (5). The tail also contains two cysteine residues, Cys₆₉₉ and Cys₇₀₄, which are palmitoylated (3, 4, 6), that may assist in this process. Confocal and electron microscopy studies have revealed that PC7 localizes to vesicles located immediately beneath the plasma membrane (4, 7). No soluble shed forms of PC7 have been detected. Enzymatic activity assays using only the soluble luminal/extracellular domain of PC7 (sol.PC7) and fluorogenic substrates have indicated that this Ca²⁺-dependent enzyme exhibits a neutral pH optimum and a cleavage specificity similar to that of Furin, cleaving within the general motif (R/K)-2X_n-R↓ where n = 0–2 (8, 9).Only the membrane-bound PC7 induces the processing of proepidermal growth factor into a ∼115-kDa transmembrane form (10). PC7 is abundant in neurons (11) but is also expressed in microglia (12). It has been shown that PC7 exerts an important function in MHC class I-mediated antigen presentation (7), befitting its high expression within the immune system (3). Finally, PC7 is unique because it is able to shed the human transferrin receptor 1 (TfR1) into a soluble form by cleavage at KTECER₁₀₀↓LA within endosomes (13).The physiological importance of the PCs is illustrated by the early death or major phenotypes observed in mice lacking one or more convertase (1, 14). Although generated several years ago, deletion of PC7 is the only PC KO mouse for which no overt phenotype(s) has been described (15). In contrast, PC7 knockdown in Xenopus is embryonic lethal. These embryos lack eyes and brain and exhibit abnormal anterior neural development (16). Unless this knockdown is due to an off-target effect, amphibian PC7 seems to fulfill essential neuronal functions that, in mammals, may be either nonessential or redundantly assumed by other PCs. Notably, the regulation of the PC7 gene (PCSK7) has not been examined (3, 17).In the present work we describe behavioral alterations in mice lacking PC7. Our results show that PC7 KO mice have lower levels of BDNF in the hippocampus and amygdala than WT mice and exhibit learning and memory impairments. Reduced BDNF levels are likely responsible for some of these deficits, because they are rescued by an agonist to the BDNF receptor tyrosine receptor kinase B (TrkB). Therefore, PC7 seems to play unique roles in the CNS, at least in part, through regulating levels of BDNF.     

Trisomy of the G protein-coupled K+ channel gene, Kcnj6, affects reward mechanisms, cognitive functions, and synaptic plasticity in mice

G protein-activated inwardly rectifying K+ channels (GIRK) generate slow inhibitory postsynaptic potentials in the brain via G(i/o) protein-coupled receptors. GIRK2, a GIRK subunit, is widely abundant in the brain and has been implicated in various functions and pathologies, such as learning and memory, reward, motor coordination, and Down syndrome. Down syndrome, the most prevalent cause of mental retardation, results from the presence of an extra maternal chromosome 21 (trisomy 21), which comprises the Kcnj6 gene (GIRK2). The present study examined the behaviors and cellular physiology properties in mice harboring a single trisomy of the Kcnj6 gene. Kcnj6 triploid mice exhibit deficits in hippocampal-dependent learning and memory, altered responses to rewards, hampered depotentiation, a form of excitatory synaptic plasticity, and have accentuated long-term synaptic depression. Collectively the findings suggest that triplication of Kcnj6 gene may play an active role in some of the abnormal neurological phenotypes found in Down syndrome.     

Differential roles of the dopamine 1-class receptors,D1R and D5R,in hippocampal dependent memory

Activation of the hippocampal dopamine 1-class receptors (D1R and D5R) are implicated in contextual fear conditioning (CFC). However, the specific role of the D1R versus D5R in hippocampal dependent CFC has not been investigated. Generation of D1R- and D5R-specific in situ hybridization probes showed that D1R and D5R mRNA expression was greatest in the dentate gyrus (DG) of the hippocampus. To identify the role of each receptor in CFC we generated spatially restricted KO mice that lack either the D1R or D5R in DG granule cells. DG D1R KOs displayed significant fear memory deficits, whereas DG D5R KOs did not. Furthermore, D1R KOs but not D5R KOs, exhibited generalized fear between two similar but different contexts. In the familiar home cage context, c-Fos expression was relatively low in the DG of control mice, and it increased upon exposure to a novel context. This level of c-Fos expression in the DG did not further increase when a footshock was delivered in the novel context. In DG D1R KOs, DG c-Fos levels in the home cage was higher than that of the control mice, but it did not further increase upon exposure to a novel context and remained at the same level upon a shock delivery. In contrast, the levels of DG c-Fos expression was unaffected by the deletion of DG D5R neither in the home cage nor upon a shock delivery. These results suggest that DG D1Rs, but not D5Rs, contribute to the formation of distinct contextual representations of novel environments.The hippocampus is crucial for aversive Pavlovian conditioning, such as contextual fear conditioning (CFC) (1, 2). In CFC, the conditioned stimulus (context) is paired with the unconditioned stimulus (footshock), and after pairing, the context serves as a cue to predict a potential footshock (3, 4). Although the role of dopamine has been studied in the context of reward learning (5), evidence suggests that midbrain dopaminergic neurons are also important for aversive Pavlovian conditioning (6–9). In line with this evidence, hippocampal encoding of novel and contextual information is linked to dopamine release via excitation of dopamine neurons of the midbrain (5, 10, 11). Additionally, delivery of aversive stimuli, such as a footshock, results in increased dopaminergic neuron activity (12). Moreover, inactivation of hippocampal D1Rs and D5Rs attenuates contextual fear memory (13). Thus, it follows that delivery of an aversive stimulus activates midbrain dopamine neurons that project to the hippocampus, which is crucial for encoding novel contextual cues (12, 14, 15). Activation of hippocampal D1Rs and D5Rs may then strengthen the encoding of novel contextual information during CFC.The precise role of subregion-specific D1R or D5R activation in hippocampal-dependent learning and memory is unknown. This is in part due to the inability to discriminate between and spatially restrict D1R from D5R function (16–18), which is an important caveat because each receptor is involved in modulating distinct neuronal processes (19–22). Indeed, there is a lack of consensus of D1R and D5R expression patterns in the rodent hippocampus (23–27). Moreover, pharmacological findings are at odds with D1R and D5R global KO studies, which show that neither D1Rs nor D5Rs are required for fear conditioning (16, 17). Therefore, to reconcile these disparate findings and to test the necessity of D1R and D5R activation for CFC, it is necessary to functionally isolate and spatially restrict hippocampal D1R and D5R activity.In this study, we found that D1Rs and D5Rs exhibit overlapping expression in dentate gyrus (DG) granule cells. DG D1R activation is necessary to increase c-Fos expression in the DG and CA3 to enhance novel contextual encoding. Moreover, DG D1R activation decreases generalization of the conditioned fear response to novel contexts. However, we found no role for DG D5Rs in modulating DG c-Fos expression or contextual fear learning and memory. In using our subregion-specific KO mice, we show that the hippocampal dopamine signal plays a definitive role in CFC.     

Smoking in the absence of nicotine: behavioral, subjective and physiological effects over 11 days

AIMS: Sensorimotor stimuli associated with tobacco smoking influence smoking behavior; however, current research has focused almost exclusively on the effects of brief, laboratory-based exposure to smoking-related stimuli. The purpose of this experiment was to characterize the effects of smoking stimuli delivered in the absence of nicotine over an extended (11-day) exposure. DESIGN, SETTING AND PARTICIPANTS: Thirty adult regular smokers participated in an in-patient study. After assessing preferred brand smoking, participants were assigned randomly to one of three groups corresponding to subsequent smoking conditions: nicotine-containing cigarettes, de-nicotinized cigarettes or no smoking. MEASUREMENTS: Measures of smoking reinforcement, subjective effects, physiological effects, withdrawal/craving and puff topography were taken repeatedly during both periods of free access and controlled assessments during abstinence. FINDINGS: Daily de-nicotinized cigarette use declined immediately by 1.7 cigarettes/day compared to the preferred brand baseline and declined by another 3.5 cigarettes over time; participants smoking de-nicotinized cigarettes also demonstrated a 31% decline in the number of puffs earned on a progressive ratio, a measure of the motivation to smoke, during the study. Subjective ratings of smoking were largely negative throughout the study in the de-nicotinized group, while the nicotine-containing condition reported increasingly positive subjective effects with repeated exposure. Acute craving suppression following smoking remained evident throughout the study regardless of nicotine content. CONCLUSIONS: These effects highlight the importance of non-nicotine sensorimotor stimuli as determinants of the maintenance of smoking behavior and suggests that extinction of conditioned reinforcement in the absence of nicotine progresses slowly.     

Prognosis of ulcerative colitis differs between patients with complete and partial mucosal healing,which can be predicted from the platelet count

AIM: To determine the difference in clinical outcome between ulcerative colitis (UC) patients with Mayo endoscopic subscore (MES) 0 and those with MES 1.METHODS: UC patients with sustained clinical remission of 6 mo or more at the time of colonoscopy were examined for clinical outcomes and the hazard ratios of clinical relapse according to MES. Parameters, including blood tests, to identify predictive factors for MES 0 and slight endoscopic recurrence in clinically stable patients were assessed. Moreover, a receiver operating characteristic curve was generated, and the area under the curve was calculated to indicate the utility of the parameters for the division between complete and partial mucosal healing. All P values were two-sided and considered significant when less than 0.05.RESULTS: A total of 183 patients with clinical remission were examined. Patients with MES 0 (complete mucosal healing: n = 80, 44%) were much less likely to relapse than those with MES 1 (partial mucosal healing: n = 89, 48%) (P < 0.0001, log-rank test), and the hazard ratio of risk of relapse in patients with MES 1 vs MES 0 was 8.17 (95%CI: 4.19-17.96, P < 0.0001). The platelet count (PLT) < 26 × 10⁴/μL was an independent predictive factor for complete mucosal healing (OR = 4.1, 95%CI: 2.15-7.99). Among patients with MES 0 at the initial colonoscopy, patients of whom colonoscopy findings shifted to MES 1 showed significant increases in PLT compared to those who maintained MES 0 (3.8 × 10⁴/μL vs -0.6 × 10⁴/μL, P < 0.0001).CONCLUSION: The relapse rate differed greatly between patients with complete and partial mucosal healing. A shift from complete to partial healing in clinically stable UC patients can be predicted by monitoring PLT.     

Behavioral and hygienic characteristics of primary schoolchildren which can be modified to reduce the prevalence of geohelminth infections: a study in central Java, Indonesia

Five schools in central Java that enroll more than 500 students in grades one through six were chosen for a study of the prevalence of parasitic geohelminths and selected protozoan infections. The schools are located in regions that differ in geological features, density of vegetation and cultural and economic attributes. The prevalence of soil-transmitted helminths among children in the five schools ranged from 8.7% to 76.1%, and protozoan infections from 2.8% to 32.1%. The principal objective of the study was to identify physical, hygienic and behavioral characteristics of the children that increase the likelihood of becoming infected. Although most of the characteristics studied are considered to be contributing factors, few previous attempts have been made to rank them in order of importance in causing infection. The results of this study suggest that a systematic and sustained effort to teach children to (a) avoid certain types of behavior that favor infection, and (b) practice good personal hygiene, are the best approaches to significant and enduring reduction of the scourge of intestinal parasitism.     

Noonan syndrome is associated with enhanced pERK activity,the repression of which can prevent craniofacial malformations

A gain of function mutation in SHP2, a protein phosphatase encoded by PTPN11, causes Noonan syndrome (NS), which is characterized in part by developmental deficits in both the cardiac and skull fields. Previously, we found that expression of the mutated protein SHP2 Q79R in the heart led to a phenotypic presentation that mimicked some aspects of NS and that this was dependent upon activation of the ERK1/2 pathway. To understand the role that ERK1/2 signaling plays in skull development through signaling in the neural crest, we explored the consequences of Q79R expression in neural crest cells, which contribute to a subset of the bony and cartilaginous structures of the skull. Hyperactivation of ERK1/2 led to craniofacial defects that included smaller skull lengths, greater inner canthal distances, and taller frontal bone heights. In proportion to the smaller skull length, mandibular bone length was also reduced. Inhibition of ERK1/2 hyperactivity as a result of Q79R expression was achieved by injection of the MAPK/ERK kinase inhibitor U0126 during pregnancy. The drug effectively decreased the severity of the craniofacial defects and restored normal skull shape and fontanelle closure. X-ray computer-assisted microtomography analysis of the head confirmed that decreasing ERK1/2 activity led to an abrogation of the craniofacial deficits and brain shape changes that presented in the mice. These data show that normal ERK1/2 signaling in the neural crest is imperative for normal craniofacial development and offer insight into how the heart and craniofacial developmental fields might be affected in some congenital syndromic presentations.     

Autologous stem cell transplantation for follicular lymphoma is of most benefit early in the disease course and can result in durable remissions,irrespective of prior rituximab exposure

The role of autologous stem cell transplantation (ASCT) and the optimal timing of such transplants in patients with follicular lymphoma (FL) remains contentious. We present a single‐centre experience documenting the outcomes of 70 FL patients who underwent BEAM (carmustine, cytarabine, etopside, melphalan)‐conditioned ASCT between 1988 and 2009. With a median follow‐up of 6·8 years (0·1–19·2), the 7‐year overall survival (OS) and progression‐free survival (PFS) from the date of ASCT was 76% and 60%, respectively. A significant difference in OS was found when comparing the patients transplanted in first or second remission versus those transplanted in later remissions (P = 0·02) and this significance was maintained when OS was calculated from the date of diagnosis (P = 0·03). There was a plateau on the PFS curves for patients transplanted in either first or second remissions after 9·3 and 6·4 years respectively, suggesting that these groups may never relapse. No differences were seen in OS or PFS in those treated with rituximab prior to transplant versus those who were not. Our data shows that BEAM ASCT can be a highly effective treatment in patients with FL early in the disease course, and that a proportion of patients experience prolonged disease‐free survival and may be cured.     

从棘突蛋白基因重组探讨严重急性呼吸综合征冠状病毒的来源

目的：探讨SARS冠状病毒（SARS-CoV）的起源。方法：运用生物信息学的方法，比较不同SARS样冠状病毒之间的异同，着重分析蝙蝠所携带的SARS样冠状病毒（SL-CoV）跨越种属屏障传播的可能性。结果：除编码棘突蛋白（S蛋白）基因外，SARS-coV与蝙蝠SL-CoV间编码结构蛋白的基因与编码复制酶的基因相似程度均很高；而S基因的差异主要集中在S1片段，且该片段的C,C含量与SARS-CoV基因组的C,C含量明显不同。进一步分析表明，由S1片段构建的冠状病毒进化树与由S2片段构建的进化树存在拓扑结构上的不平行性。结论：人类SARS病毒可能来源于蝙蝠SL—CoV，但在S基因内发生了基因重组事件，从而导致其获得跨越种属屏障传播的能力。     

Alcohol inhibition of the NMDA receptor function, long-term potentiation, and fear learning requires striatal-enriched protein tyrosine phosphatase

Alcohol's deleterious effects on memory are well known. Acute alcohol-induced memory loss is thought to occur via inhibition of NMDA receptor (NMDAR)-dependent long-term potentiation in the hippocampus. We reported previously that ethanol inhibition of NMDAR function and long-term potentiation is correlated with a reduction in the phosphorylation of Tyr(1472) on the NR2B subunit and ethanol's inhibition of the NMDAR field excitatory postsynaptic potential was attenuated by a broad spectrum tyrosine phosphatase inhibitor. These data suggested that ethanol's inhibitory effect may involve protein tyrosine phosphatases. Here we demonstrate that the loss of striatal-enriched protein tyrosine phosphatase (STEP) renders NMDAR function, phosphorylation, and long-term potentiation, as well as fear conditioning, less sensitive to ethanol inhibition. Moreover, the ethanol inhibition was "rescued" when the active STEP protein was reintroduced into the cells. Taken together, our data suggest that STEP contributes to ethanol inhibition of NMDAR function via dephosphorylation of tyrosine sites on NR2B receptors and lend support to the hypothesis that STEP may be required for ethanol's amnesic effects.