Efficacy, immunogenicity, and safety of a monovalent mRNA vaccine, ABO1020, in adults: A randomized, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: ABO1020 is a monovalent COVID-19 mRNA vaccine. Results from a phase 1 trial showed ABO1020 was safe and well tolerated, and phase 3 trials to evaluate the efficacy, immunogenicity, and safety of ABO1020 in healthy adults are urgently needed. METHODS: We conducted a multinational, randomized, placebo-controlled, double-blind, phase 3 trial among healthy adults (ClinicalTrials.gov: NCT05636319). Participants were randomly assigned (1:1) to receive either 2 doses of ABO1020 (15 µg per dose) or placebo, administered 28 days apart. The primary endpoint was the vaccine efficacy in preventing symptomatic COVID-19 cases that occurred at least 14 days post-full vaccination. The second endpoint included the neutralizing antibody titers against Omicron BA.5 and XBB and safety assessments. FINDINGS: A total of 14,138 participants were randomly assigned to receive either vaccine or placebo (7,069 participants in each group). A total of 366 symptomatic COVID-19 cases were confirmed 14 days after the second dose among 93 participants in the ABO1020 group and 273 participants in the placebo group, yielding a vaccine efficacy of 66.18% (95% confidence interval: 57.21-73.27, p < 0.0001). A single dose or two doses of ABO1020 elicited potent neutralizing antibodies against both BA.5 and XBB.1.5. The safety profile of ABO1020 was characterized by transient, mild-to-moderate fever, pain at the injection site, and headache. CONCLUSION: ABO1020 was well tolerated and conferred 66.18% protection against symptomatic COVID-19 in adults. FUNDING: National Key Research and Development Project of China, Innovation Fund for Medical Sciences from the CAMS, National Natural Science Foundation of China.

Conversion therapy of a giant hepatocellular carcinoma with portal vein thrombus and inferior vena cava thrombus: A case report and review of literature.

BACKGROUND: The prognosis of hepatocellular carcinoma (HCC) combined with portal and hepatic vein cancerous thrombosis is poor, for unresectable patients the combination of targeted therapy and immune therapy was the first-line recommended treatment for advanced HCC, with a median survival time of only about 2.7-6 months. In this case report, we present the case of a patient with portal and hepatic vein cancerous thrombosis who achieved pathologic complete response after conversion therapy. CASE SUMMARY: In our center, a patient with giant HCC combined with portal vein tumor thrombus and hepatic vein tumor thrombus was treated with transcatheter arterial chemoembolization (TACE), radiotherapy, targeted therapy and immunotherapy, and was continuously given icaritin soft capsules for oral regulation. After 7 months of conversion therapy, the patient's tumor shrank and the tumor thrombus subsided significantly. The pathology of surgical resection was in complete remission, and there was no progression in the postoperative follow-up for 7 months, which provided a basis for the future strategy of combined conversion therapy. CONCLUSION: In this case, atezolizumab, bevacizumab, icaritin soft capsules combined with radiotherapy and TACE had a good effect. For patients with hepatocellular carcinoma combined with hepatic vein/inferior vena cava tumor thrombus, adopting a high-intensity, multimodal proactive strategy under the guidance of multidisciplinary team (MDT) is an important attempt to break through the current treatment dilemma.

[Systematic evaluation of the incidence of the knee donor area after autobone cartilage mosaic xentoplasty].

OBJECTIVE: To provide an overview of the incidence of knee donor -site morbidity after autologous osteochondral mosaicplasty. METHODS: A comprehensive search was conducted in PubMed, EMbase, Wanfang Medical Network, and CNKI databases from January 2010 to April 20, 2021. Relevant literature was selected based on predefined inclusion and exclusion criteria, and data were evaluated and extracted. The correlation between the number and size of transplanted osteochondral columns and donor-site morbidity was analyzed. RESULTS: A total of 13 literatures were included, comprising a total of 661 patients. Statistical analysis revealed an incidence of knee donor-site morbidity at 8.6% (57/661), with knee pain being the most common complaint, accounting for 4.2%(28/661). There was no significant correlation between the number of osteochondral columns and postoperative donor-site incidence (P=0.424, N=10), nor between the diameter size of osteochondral columns and postoperative donor-site incidence(P=0.699, N=7). CONCLUSION: Autologous osteochondral mosaicplasty is associated with a considerable incidence of knee donor-site morbidity, with knee pain being the most frequent complaint. There is no apparent correlation between donor-site incidence and the number and size of transplanted osteochondral columns. Donors should be informed about the potential risks.

Dissection of insular cortex layer 5 reveals two sublayers with opposing modulatory roles in appetitive drinking behavior.

The insular cortex (insula) is known to play a modulatory role in feeding and drinking. Previous studies have revealed anterior-posterior differences of subcortical projections and roles for the insula, yet the anatomical and functional heterogeneity among the cortical layers remains poorly understood. Here, we show that layer 5 of the mouse dysgranular insula has two distinct neuronal subpopulations along the entire anterior-posterior axis: The L5a population, expressing NECAB1, projects bilaterally to the lateral and capsular divisions of the central amygdala, and the L5b population, expressing CTIP2, projects ipsilaterally to the parasubthalamic nucleus and the medial division of the central amygdala. Optogenetically activating L5a and L5b neuronal populations in thirsty male mice led to suppressed and facilitated water spout licking, respectively, without avoidance against or preference for the spout paired with the opto-stimulation. Our results suggest sublayer-specific bidirectional modulatory roles of insula layer 5 in the motivational aspect of appetitive behavior.

Neurochemical properties for defining subdivisions of the mouse medial geniculate body.

The medial geniculate body (MGB) exhibits anatomical and physiological properties that underlie its role in the auditory system. Anatomical properties, including myelo- and cyto-architecture, are used to identify MGB subdivisions. Recently, neurochemical properties, including calcium-binding proteins, have also been employed to define the MGB subdivisions. Because these properties do not show clear boundaries in the MGB and do not involve anatomical connectivity, whether the MGB subdivisions can be defined based on anatomical and neurochemical properties remains unclear. In this study, 11 different neurochemical markers were employed for defining the MGB subdivisions. In terms of anatomical connectivity, immunoreactivities for vesicular transporter demonstrated glutamatergic, GABAergic and glycinergic afferents and provided clues about the boundaries of the MGB subdivisions. On the other hand, the distribution of novel neurochemical markers of the MGB demonstrated distinct boundaries of the MGB subdivisions and resulted in the discovery of a putative homolog of the rabbit internal division of the MGB. Additionally, corticotropin-releasing factor was expressed in the larger neurons in the medial division of the MGB (MGm), particularly in the caudal MGm. Lastly, the analysis of anatomical details by measuring the size and density of vesicular transporters revealed heterogeneity among the MGB subdivisions. Our results demonstrate that the MGB is composed of five subdivisions based on their anatomical and neurochemical properties.

Temporal profiles of neuronal responses to repeated tone stimuli in the mouse primary auditory cortex.

How the auditory system processes temporal information of sound has been investigated extensively using repeated stimuli. Recent studies on how the response of neurons in the primary auditory cortex (A1) changes with the progression of stimulus repetition, have reported response temporal profiles of two categories: "adaptation", i.e., gradual decrease, and "facilitation", i.e., gradual increase. To explore the existence of profiles of other categories and to examine the tone-frequency-dependence of the profile category in single neurons, here we studied the response of mouse A1 neurons to four or five tone-trains; each train comprised 10 identical tone pips, with 0.5-s inter-tone-intervals, and the four or five trains differed only in tone frequency. The response to each tone in a train was evaluated using the peak of the ON response, and how the peak response changed with the tone number in the train, i.e., the response temporal profile, was examined. We confirmed the existence of profiles of both "adaptation" and "facilitation" categories; "adaptation" could be further subcategorized into "slow adaptation" and "fast adaptation" profiles, with the latter being encountered more frequently. Moreover, two new categories of non-monotonic profiles were identified: an "adaptation with recovery" profile and a "facilitation followed by adaptation" profile. Examination of single neurons with trains of different tone frequencies revealed that some A1 neurons exhibited profiles of the same category to tone trains of different tone frequencies, whereas others exhibited profiles of different categories, depending on the tone frequency. These results demonstrate the variety in the response temporal profiles of mouse A1 neurons, which may benefit the encoding of individual tones in a train.

Pharmacokinetics and Bioequivalence of Two Formulations of Rosuvastatin Following Single-dose Administration in Healthy Chinese Subjects Under Fasted and Fed Conditions.

The main objective of the study was to evaluate the bioequivalence of two rosuvastatin calcium tablets in healthy Chinese subjects under fasted and fed conditions. The study was carried out using a randomized, open-label, two-formulation, two-sequence, two-period, single-dose crossover design, with a washout period of 7 days. Both the fasted study and fed study enrolled 28 subjects. In each study period, the subjects were administrated a single oral dose of the test product or reference product of rosuvastatin 10 mg. Blood samples were collected from pre-dose to 72 hours after administration with 16 time points in total. Bioequivalence evaluation was performed using ln-transformed pharmacokinetic parameters of rosuvastatin, including Cmax , AUC0-t , and AUC0-∞ . In the present study, 95% confidence intervals (CIs) of test/reference geometric mean ratios (GMRs) of Cmax , AUC0-t , and AUC0-∞ under the fasted and fed conditions were all within the acceptance range of 80%-125%. Additionally, only one subject experienced one adverse event (AE). High-fat meals reduced the Cmax , AUC0-t , and AUC0-∞ , but had no significant effects on the λz, t1/2 , or Tmax of rosuvastatin. In the current study, the test product was bioequivalent to the reference product, and a single dose of rosuvastatin (10 mg) was well-tolerated. Food decreased the systemic exposure of rosuvastatin without the effects on the Tmax or elimination rate.

[Clinical effects of arthroscopy-assisted anterior cruciate ligament tibial eminence avulsion fracture compared with traditional open surgery:a Meta-analysis].

OBJECTIVE: To systematically evaluate the clinical efficacy of arthroscopy and traditional incision in the treatment of tibial avulsion fracture of anterior cruciate ligament (ACL). METHODS: From July 2010 to July 2020, clinical comparative trial about arthroscopy and traditional incision in the treatment of ACL tibial avulsion fracture was conducted by using computer-based databases, including Embase, Pubmed, Central, Cinahl, PQDT, CNKI, Weipu, Wanfang, Cochrane Library, CBM. Literature screening and data extraction were carried out according to the inclusion and exclusion criteria, and the quality of the included literature was evaluated by improved Jadad score and Ottawa Newcastle scale (NOS). The operation time, hospital stay, fracture healing time, knee range of motion, postoperative excellent and good rate, complication rate, Lysholm score, International Knee Documentation Committee (IKDC) score and Tegner score were statistically analyzed by Review Manager 5.3 software. RESULTS: Finally, 16 literatures were included, including 1 randomized controlled trial and 15 non randomized controlled trials, with a total of 822 patients (405 in arthroscopy group and 417 in traditional incision group). Meta analysis showed that the operation time [MD=-9.03, 95% CI(-14.36, -3.70), P<0.001], hospital stay [MD=-5.81, 95%CI(-9.32, -2.31), P=0.001] and fracture healing time [MD=-14.61, 95% CI(-17.93, -11.28), P<0.001] in the arthroscopy group were better than those in the traditional incision group. The incidence of complications in arthroscopy group was lower than that in traditional incision group[OR=0.15, 95%CI(0.07, 0.33), P<0.001]. The postoperative excellent and good rate[OR=4.39, 95%CI (1.96, 9.82), P<0.001], knee mobility[MD=6.78, 95%CI(2.79, 10.77), P<0.001], Lysholm score[MD=11.63, 95%CI(4.91, 18.36), P<0.001], IKDC score[MD=7.83, 95%CI(6.09, 9.57), P<0.001] and Tegner score[MD=0.60, 95%CI(0.31, 0.89), P<0.001] in the arthroscopic group were higher than those in the traditional incision group. CONCLUSION: Compared with the traditional open reduction and internal fixation, arthroscopic surgery in patients with ACL tibial avulsion fracture can shorten the operation time, hospital stay and fracture healing time, reduce the incidence of postoperative complications, and obtain good postoperative knee function. It can be recommended as one of the first choice for patients with ACL tibial avulsion fracture.

Region-dependent Millisecond Time-scale Sensitivity in Spectrotemporal Integrations in Guinea Pig Primary Auditory Cortex.

Spectrotemporal integration is a key function of our auditory system for discriminating spectrotemporally complex sounds, such as words. Response latency in the auditory cortex is known to change with the millisecond time-scale depending on acoustic parameters, such as sound frequency and intensity. The functional significance of the millisecond-range latency difference in the integration remains unclear. Actually, whether the auditory cortex has a sensitivity to the millisecond-range difference has not been systematically examined. Herein, we examined the sensitivity in the primary auditory cortex (A1) using voltage-sensitive dye imaging techniques in guinea pigs. Bandpass noise bursts in two different bands (band-noises), centered at 1 and 16 kHz, respectively, were used for the examination. Onset times of individual band-noises (spectral onset-times) were varied to virtually cancel or magnify the latency difference observed with the band-noises. Conventionally defined nonlinear effects in integration were analyzed at A1 with varying sound intensities (or response latencies) and/or spectral onset-times of the two band-noises. The nonlinear effect measured in the high-frequency region of the A1 linearly changed depending on the millisecond difference of the response onset-times, which were estimated from the spatially-local response latencies and spectral onset-times. In contrast, the low-frequency region of the A1 had no significant sensitivity to the millisecond difference. The millisecond-range latency difference may have functional significance in the spectrotemporal integration with the millisecond time-scale sensitivity at the high-frequency region of A1 but not at the low-frequency region.

Pharmacokinetics and bioequivalence study of two ciprofloxacin hydrochloride tablets in healthy Chinese subjects under fasting and fed conditions: A randomized, open-label, two-formulation, two-sequence, two-period, single-dose crossover study.

OBJECTIVE: The study mainly aimed to determine the bioequivalence of two branded ciprofloxacin hydrochloride tablets (250 mg) under fasting and fed conditions. MATERIALS AND METHODS: The study was carried out in 48 healthy Chinese subjects under fasting and fed conditions with a randomized, open-label, two-formulation, two-sequence, two-period, single-dose crossover design. In each period of the study, the subjects were assigned to receive a single oral dose of 250 mg ciprofloxacin hydrochloride. Blood samples were collected from 1 hour before dosing to 36 hours after administration with 16 timepoints in total. The bioequivalence analysis was performed after ln-transformation of the ciprofloxacin pharmacokinetic parameters including Cmax, AUC0-t, and AUC0-∞. RESULTS: A total of 48 subjects were enrolled in the fasting and fed studies, and 1 of the subjects was excluded before drug administration. In the fasting study, the 90% CIs for the test/reference geometric mean ratios (GMRs) of the ln-transformed data for Cmax, AUC0-t, and AUC0-∞ were 85.41 - 100.97%, 95.40 - 100.27%, and 95.48 - 100.30%, respectively. For the fed study, the 90% CIs for the test/reference GMRs of the ln-transformed data for Cmax, AUC0-t, and AUC0-∞ were 90.15 - 113.75%, 99.10 - 103.77%, and 99.11 - 103.80%, respectively. These values all fell within the standard acceptance range of 80 - 125%. CONCLUSION: In the study, the generic (test) product of ciprofloxacin hydrochloride 250 mg was bioequivalent to the innovator (reference) product after single-, oral-dose administration under fasting and fed conditions.

Studies of Articular Cartilage Repair from 2009 to 2018: A Bibliometric Analysis of Articles.

OBJECTIVE: To perform a bibliometric analysis of research on articular cartilage repair published in Chinese and English over the past decade. Fundamental and clinical research topics of high interest were further comparatively analyzed. METHODS: Relevant studies published from 1 January 2009 to 31 December 2018 (10 years) were retrieved from the Wanfang database (Chinese articles) and six databases, including MEDLINE, WOS, INSPEC, SCIELO, KJD, and RSCI on the website "Web of Science" (English articles), using key words: "articular cartilage" AND "injury" AND "repair". The articles were categorized according to research focuses for a comparative analysis between those published in Chinese vs English, and further grouped according to publication date (before and after 2014). A comparative analysis was performed on research focus to characterize the variation in research trends between two 5-year time spans. Moreover, articles were classified as basic and clinical research studies. RESULTS: Overall, 5762 articles were retrieved, including 2748 in domestic Chinese journals and 3014 in international English journals. A total of 4937 articles focused on the top 10 research topics, with the top 3 being stem cells (32.1%), tissue-engineered scaffold (22.8%), and molecular mechanisms (16.4%). Differences between the numbers of Chinese and English papers were observed for 3 topics: chondrocyte implantation (104 vs 316), osteochondral allograft (27 vs 86), and microfracture (127 vs 293). The following topics gained more research interest in the second 5-year time span compared with the first: microfracture, osteochondral allograft, osteochondral autograft, stem cells, and tissue-engineered scaffold. Articles with a focus on three-dimensional-printing technology have shown the fastest increase in publication numbers. Among 5613 research articles, basic research studies accounted for the majority (4429), with clinical studies described in only 1184 articles. The top 7 research topics of clinical studies were: chondrocyte implantation (28.7%), stem cells (21.9%), microfracture (19.2%), tissue scaffold (10.6%), osteochondral autograft (10.5%), osteochondral allograft (6.3%), and periosteal transplantation (2.8%). CONCLUSION: Studies focused on stem cells and tissue-engineered scaffolds led the field of damaged articular cartilage repair. International researchers studied allograft-related implantation approaches more often than Chinese researchers. Traditional surgical techniques, such as microfracture and osteochondral transplantation, gained high research interest over the past decade.

Postnatal development of subfields in the core region of the mouse auditory cortex.

The core region of the rodent auditory cortex has two subfields: the primary auditory area (A1) and the anterior auditory field (AAF). Although the postnatal development of A1 has been studied in several mammalian species, few studies have been conducted on the postnatal development of AAF. Using a voltage-sensitive-dye-based imaging method, we examined and compared the postnatal development of AAF and A1 in mice from postnatal day 11 (P11) to P40. We focused on the postnatal development of tonotopy, the relative position between A1 and AAF, and the properties of tone-evoked responses in the subfields. Tone-evoked responses in the mouse auditory cortex were first observed at P12, and tonotopy was found in both A1 and AAF at this age. Quantification of tonotopy using the cortical magnification factor (CMF; octave difference per unit cortical distance) revealed a rapid change from P12 to P14 in both A1 and AAF, and a stable level from P14. A similar time course of postnatal development was found for the distance between the 4 kHz site in A1 and AAF, the distance between the 16 kHz site in A1 and AAF, and the angle between the frequency axis of A1 and AAF. The maximum amplitude and rise time of tone-evoked signals in both A1 and AAF showed no significant change from P12 to P40, but the latency of the responses to both the 4 kHz and 16 kHz tones decreased during this period, with a more rapid decrease in the latency to 16 kHz tones in both subfields. The duration of responses evoked by 4 kHz tones in both A1 and AAF showed no significant postnatal change, but the duration of responses to 16 kHz tones decreased exponentially in both subfields. The cortical area activated by 4 kHz tones in AAF was always larger than that in A1 at all ages (P12-P40). Our results demonstrated that A1 and AAF developed in parallel postnatally, showing a rapid maturation of tonotopy, slow maturation of response latency and response duration, and a dorsal-to-ventral order (high-frequency site to low-frequency site) of functional maturation.

Dynamic changes of timing precision in timed actions during a behavioural task in guinea pigs.

Temporal precision is a determinant of performance in various motor activities. Although the accuracy and precision of timing in activities have been previously measured and quantified, temporal dynamics with flexible precision have not been considered. Here, we examined the temporal dynamics in timed motor activities (timed actions) using a guinea pig model in a behavioural task requiring an animal to control action timing to obtain a water reward. In well-trained animals, momentary variations in timing precision were extracted from the temporal distribution of the timed actions measured over daily 12-h sessions. The resampling of the observed time of action in each session demonstrated significant changes of timing precision within a session. Periods with higher timing precision appeared indiscriminately during the same session, and such periods lasted ~ 20 min on average. We conclude that the timing precision in trained actions is flexible and changes dynamically in guinea pigs. By elucidating the brain mechanisms involved in flexibility and dynamics with an animal model, future studies should establish more effective methods to actively enhance timing precision in our motor activities, such as sports.

Tsukushi is essential for the development of the inner ear.

Tsukushi (TSK)-a small, secreted, leucine-rich-repeat proteoglycan-interacts with and regulates essential cellular signaling cascades. However, its functions in the mouse inner ear are unknown. In this study, measurement of auditory brainstem responses, fluorescence microscopy, and scanning electron microscopy revealed that TSK deficiency in mice resulted in the formation of abnormal stereocilia in the inner hair cells and hearing loss but not in the loss of these cells. TSK accumulated in nonprosensory regions during early embryonic stages and in both nonprosensory and prosensory regions in late embryonic stages. In adult mice, TSK was localized in the organ of Corti, spiral ganglion cells, and the stria vascularis. Moreover, loss of TSK caused dynamic changes in the expression of key genes that drive the differentiation of the inner hair cells in prosensory regions. Finally, our results revealed that TSK interacted with Sox2 and BMP4 to control stereocilia formation in the inner hair cells. Hence, TSK appears to be an essential component of the molecular pathways that regulate inner ear development.

Differential cortical and subcortical projection targets of subfields in the core region of mouse auditory cortex.

The core region of the rodent auditory cortex has two areas: the primary auditory area (A1) and the anterior auditory field (AAF). However, the functional difference between these areas is unclear. To elucidate this issue, here we studied the projections from A1 and AAF in mice using adeno-associated virus (AAV) vectors expressing either a green fluorescent protein or a red fluorescent protein. After mapping A1 and AAF using optical imaging, we injected a distinct AAV vector into each of the two fields at a frequency-matched high-frequency location. We found that A1 and AAF projected commonly to virtually all target areas examined, but each field had its own preference for projection targets. Frontal and parietal regions were the major cortical targets: in the frontal cortex, A1 and AAF showed dominant projections to the anterior cingulate cortex Cg1 and the secondary motor cortex (M2), respectively; in the parietal cortex, A1 and AAF exhibited dense projections to the medial secondary visual cortex and the posterior parietal cortex (PPC), respectively. Although M2 and PPC received considerable input from A1 as well, A1 innervated the medial part whereas AAF innervated the lateral part of these cortical regions. A1 also projected to the orbitofrontal cortex, while AAF also projected to the primary somatosensory cortex and insular auditory cortex. As for subcortical projections, A1 and AAF projected to a common ventromedial region in the caudal striatum with a comparable strength; they also both projected to the medial geniculate body and the inferior colliculus, innervating common and distinct divisions of the nuclei. A1 also projected to visual subcortical structures, such as the superior colliculus and the lateral posterior nucleus of the thalamus, where fibres from AAF were sparse. Our results demonstrate the preference of A1 and AAF for cortical and subcortical targets, and for divisions in individual target. The preference of A1 and AAF for sensory-related structures suggest a role for A1 in providing auditory information for audio-visual association at both the cortical and subcortical level, and a distinct role of AAF in providing auditory information for association with somatomotor information in the cortex.

Mice deficient in protein tyrosine phosphatase receptor type Z (PTPRZ) show reduced responsivity to methamphetamine despite an enhanced response to novelty.

Methamphetamine (METH), a commonly abused drug, elevates extracellular dopamine (DA) levels by inducing DA efflux through the DA transporter (DAT). Emerging evidence in rodent models suggests that locomotor responses to a novel inescapable open field may predict behavioral responses to abused drugs; METH produces more potent stimulant effects in high responders to novelty than in low responders. We herein found that mice deficient in protein tyrosine phosphatase receptor type Z (Ptprz-KO) exhibited an enhanced behavioral response to novelty; however, METH-induced hyperlocomotion was significantly lower in Ptprz-KO than in wild-type mice when METH was administered at a non-toxic dose of 1 mg per kg body weight (bdw). Single-cell RT-PCR revealed that the majority of midbrain DA neurons expressed PTPRZ. No histological alterations were observed in the mesolimbic or nigrostriatal dopaminergic pathways in Ptprz-KO brains; however, a significant decrease was noted in brain DA turnover, suggesting functional alterations. In vivo microdialysis experiments revealed that METH-evoked DA release in the nucleus accumbens was significantly lower in Ptprz-KO mice than in wild-type mice. Consistent with this result, Ptprz-KO mice showed significantly fewer cell surface DAT as well as weaker DA uptake activity in striatal synaptosomes prepared 1 hr after the administration of METH than wild-type mice, while no significant differences were observed in the two groups treated with saline. These results indicate that the high response phenotype of Ptprz-KO mice to novelty may not be simply attributed to hyper-dopaminergic activity, and that deficits in PTPRZ reduce the effects of METH by reducing DAT activity.

Cue-dependent safety and fear learning in a discriminative auditory fear conditioning paradigm in the mouse.

Discrimination between sensory stimuli associated with safety and threat is crucial for behavioral decisions. Discriminative conditioning paradigms with two acoustic conditioned stimuli (one paired with shock [CS+], the other unpaired with shock [CS-]) have been widely used as an experimental model for fear learning. However, no attention has been paid to the effect of the CS- on safety in the paradigms, because the CS- served as a neutral cue or elevated the freezing level due to fear generalization although less effectively than the CS+. By using a noise and a tone as two acoustic CSs in a discriminative auditory fear conditioning (AFC) paradigm, here we demonstrate that mice learn safety for the CS- while showing fear for the CS+ with opposing emotional behaviors. We found that after learning mice exhibited a significant suppression of context-dependent freezing during the CS-, but not during the CS+, indicating learned safety without fear generalization for the CS-. In contrast, the mice showed an enhanced level of freezing during the CS+ even in a novel spatial context, indicating cued fear for the CS+. Moreover, the CS+ also induced rapid defensive behaviors, whereas the CS- disinhibited normal exploratory behaviors. On the other hand, mice showed no significant suppression of contextual fear during the CS- in a paradigm with a pair of tone CSs at different frequencies, although they clearly discriminated the two tones. These results suggest our AFC paradigm with the noise and tone CSs as a useful experimental model for cue-dependent discriminative learning of safety and threat.

A novel role of the antitumor agent tricyclodecan-9-yl-xanthogenate as an open channel blocker of KCNQ1/KCNE1.

Tricyclodecan-9-yl-xanthogenate (D609) is widely known for its antitumor and antiviral properties via the inhibition of phosphatidylcholine-specific phospholipase C and sphingomyelin synthase. Previously, we found that chronic application of D609 suppressed the K+ channel, KCNQ1/KCNE1, more drastically than expected from its actions on the enzymes, suggesting a direct action of D609 on the channel. Here, we aimed to test this possibility by studying the affinity, specificity, and mechanisms of D609 on KCNQ1/KCNE1. The effect of D609 on KCNQ1/KCNE1 was studied using an in vitro expression system and in native cells, using electrophysiological techniques. We found that D609 rapidly and reversibly inhibited KCNQ1/KCNE1 channels expressed in human embryonic kidney 293 T (HEK293T) cells, in a concentration-dependent manner with a high affinity. D609 neither suppressed endogenous K+ currents in HEK293T cells, nor inhibited the sustained and transient K+ currents of mouse neostriatal neurons, but blocked a KCNQ1/KCNE1-like current in neostriatal neurons. D609 potently blocked IKs, the cardiac KCNQ1/KCNE1 channel, in guinea pig cardiac muscle cells. The action of D609 on KCNQ1/KCNE1 depended on the usage of the channel, suggesting that D609 binds to the channel in the open state. We identified D609 as a potent and specific open channel blocker of KCNQ1/KCNE1. Because KCNQ1/KCNE1 is highly expressed in the heart, the inner ear and the pancreas, D609, when used as an antitumor or antiviral drug, may affect the function of a number of organs in vivo even when used at low concentrations.

Organization of auditory areas in the superior temporal gyrus of marmoset monkeys revealed by real-time optical imaging.

The prevailing model of the primate auditory cortex proposes a core-belt-parabelt structure. The model proposes three auditory areas in the lateral belt region; however, it may contain more, as this region has been mapped only at a limited spatial resolution. To explore this possibility, we examined the auditory areas in the lateral belt region of the marmoset using a high-resolution optical imaging technique. Based on responses to pure tones, we identified multiple areas in the superior temporal gyrus. The three areas in the core region, the primary area (A1), the rostral area (R), and the rostrotemporal area, were readily identified from their frequency gradients and positions immediately ventral to the lateral sulcus. Three belt areas were identified with frequency gradients and relative positions to A1 and R that were in agreement with previous studies: the caudolateral area, the middle lateral area, and the anterolateral area (AL). Situated between R and AL, however, we identified two additional areas. The first was located caudoventral to R with a frequency gradient in the ventrocaudal direction, which we named the medial anterolateral (MAL) area. The second was a small area with no obvious tonotopy (NT), positioned between the MAL and AL areas. Both the MAL and NT areas responded to a wide range of frequencies (at least 2-24 kHz). Our results suggest that the belt region caudoventral to R is more complex than previously proposed, and we thus call for a refinement of the current primate auditory cortex model.