Representation of conspecific vocalizations in amygdala of awake marmosets.

Human speech and animal vocalizations are important for social communication and animal survival. Neurons in the auditory pathway are responsive to a range of sounds, from elementary sound features to complex acoustic sounds. For social communication, responses to distinct patterns of vocalization are usually highly specific to an individual conspecific call, in some species. This includes the specificity of sound patterns and embedded biological information. We conducted single-unit recordings in the amygdala of awake marmosets and presented calls used in marmoset communication, calls of other species and calls from specific marmoset individuals. We found that some neurons (47/262) in the amygdala distinguished 'Phee' calls from vocalizations of other animals and other types of marmoset vocalizations. Interestingly, a subset of Phee-responsive neurons (22/47) also exhibited selectivity to one out of the three Phees from two different 'caller' marmosets. Our findings suggest that, while it has traditionally been considered the key structure in the limbic system, the amygdala also represents a critical stage of socially relevant auditory perceptual processing.

Comparing perioperative outcomes following off-pump multi-vessel minimally invasive via a single left intercostal space incision with median sternotomy coronary artery bypass grafting: A single-center retrospective cohort study.

BACKGROUND: The perioperative outcomes following off-pump multi-vessel minimally invasive surgery (MICS) coronary artery bypass grafting (CABG) via a single left intercostal space incision has not been well evaluated. METHOD: From July 2019 to January 2022, a total of 444 patients with multi-vessel coronary artery disease (CAD) were enrolled and divided into MICS (n = 179) and sternotomy CABG (n = 265). Perioperative outcomes were compared between these two groups, including intraoperative blood loss, postoperative first 24 h drainage, ventilation duration, length of stay (LOS) in ICU and total LOS in hospital. Intraoperative blood flow of graft vessels were measured by transit-time flow measurement after vascular anastomosis and mean flow (MF) and pulsatile index (PI) were compared. RESULTS: There were no significant differences in preoperative profiles between these two groups except younger and lower proportion of female in MICS. No significant difference in the number of graft vessels was observed between MICS (3.18 ± 0.74) and sternotomy CABG (3.28 ± 0.86). Compared to sternotomy CABG, patients with MICS showed longer operation duration [(4.33 ± 0.86) h versus (5.10 ± 1.09) h], fewer intraoperative blood loss [700 (600, 900) mL versus 500 (200, 700) mL], fewer postoperative first 24 h drainage [400 (250, 500) mL versus 300 (200, 400) mL], shorter postoperative ventilation duration [16.5 (12.5, 19.0) h versus 15.0 (12.0, 17.0) h], LOS in ICU [20.0 (16.0, 23.0) h versus 18.0 (15.0, 20.0) h] and total LOS in hospital [(14.5 ± 3.9) d versus (12.6 ± 2.7) d] (all p < .001). MI and PI of graft vessels were similar and no significant differences in major perioperative complications and mortality were observed between MICS and sternotomy CABG (all p > .05). CONCLUSION: Off-pump multi-vessel MICS may be an alternative treatment for patients with multi-vessel CAD with better perioperative outcomes than sternotomy CABG.

Hand-Rearing Method for Infant Marmosets.

The common marmoset (Callithrix jacchus) is a small and highly social New World monkey with high reproduction rates, which has been proven to be a compelling non-human primate model for biomedical and neuroscience research. Some females give birth to triplets; however, the parents cannot raise all of them. To save these infants, we have developed a hand-rearing method for raising newborn marmosets. In this protocol, we describe the formula of the food, the time for feeding, the configuration of the temperature and humidity, as well as the adaptation of the hand-reared infants to the colony environment. This hand-rearing method significantly increases the survival rate of marmoset infants (without hand-rearing: 45%; with hand-rearing: 86%) and provides the opportunity to study the development of marmoset infants with similar genetic backgrounds raised in different postnatal environments. As the method is practical and easy to use, we anticipate that it could also be applied to other labs working with common marmosets.

Deconstruction of Vermal Cerebellum in Ramp Locomotion in Mice.

The cerebellum is involved in encoding balance, posture, speed, and gravity during locomotion. However, most studies are carried out on flat surfaces, and little is known about cerebellar activity during free ambulation on slopes. Here, it has been imaged the neuronal activity of cerebellar molecular interneurons (MLIs) and Purkinje cells (PCs) using a miniaturized microscope while a mouse is walking on a slope. It has been found that the neuronal activity of vermal MLIs specifically enhanced during uphill and downhill locomotion. In addition, a subset of MLIs is activated during entire uphill or downhill positions on the slope and is modulated by the slope inclines. In contrast, PCs showed counter-balanced neuronal activity to MLIs, which reduced activity at the ramp peak. So, PCs may represent the ramp environment at the population level. In addition, chemogenetic inactivation of lobule V of the vermis impaired uphill locomotion. These results revealed a novel micro-circuit in the vermal cerebellum that regulates ambulatory behavior in 3D terrains.

Effect of a High Estrogen Level in Early Pregnancy on the Development and Behavior of Marmoset Offspring.

The use of assisted reproductive technology (ART) has risen steadily worldwide over the past 3 decades and helps many infertile families. However, ART treatments lead to an abnormal internal environment in the uterus, which may increase the risks of health problems for the offspring. Higher maternal estradiol (E2) is a notable feature in women who use ART treatments, and this has been suggested as a key factor for the risk of diseases in the offspring. In the current study, we have established a marmoset model with a high E2 level in early pregnancy to examine its potential risk to the development and behavior of the offspring. In comparison with the normal group, babies of the high E2 group exhibited lower average survival rates and birth weights. However, those who survived in the high E2 group demonstrated normal vocal production with rich call repertoires, normal speed during locomotion, and normal behaviors in the home cage. In contrast to the normal group, surviving babies of the high E2 group spent more time sleeping during development without signs of sleep disorders. In summary, our study revealed that high estrogen in early pregnancy may cause low survival rates and birth weights of the offspring, though the surviving infants did not show obvious behavioral deficiencies during development. The current study is a valuable and highly important non-human primate study for evaluating the safety of ART treatments. However, it is worth noting that some results did not reach the significant level, which may be due to the small sample size caused by animal shortage stemming from the COVID-19 epidemic.

DeepBhvTracking: A Novel Behavior Tracking Method for Laboratory Animals Based on Deep Learning.

Behavioral measurement and evaluation are broadly used to understand brain functions in neuroscience, especially for investigations of movement disorders, social deficits, and mental diseases. Numerous commercial software and open-source programs have been developed for tracking the movement of laboratory animals, allowing animal behavior to be analyzed digitally. In vivo optical imaging and electrophysiological recording in freely behaving animals are now widely used to understand neural functions in circuits. However, it is always a challenge to accurately track the movement of an animal under certain complex conditions due to uneven environment illumination, variations in animal models, and interference from recording devices and experimenters. To overcome these challenges, we have developed a strategy to track the movement of an animal by combining a deep learning technique, the You Only Look Once (YOLO) algorithm, with a background subtraction algorithm, a method we label DeepBhvTracking. In our method, we first train the detector using manually labeled images and a pretrained deep-learning neural network combined with YOLO, then generate bounding boxes of the targets using the trained detector, and finally track the center of the targets by calculating their centroid in the bounding box using background subtraction. Using DeepBhvTracking, the movement of animals can be tracked accurately in complex environments and can be used in different behavior paradigms and for different animal models. Therefore, DeepBhvTracking can be broadly used in studies of neuroscience, medicine, and machine learning algorithms.

Clinical characteristics and risk factors for fatal outcome of patients receiving Sun's procedure after previous cardiac surgery.

BACKGROUND: Cardiac reoperation has always been a difficult problem in clinical practice. Because of the difficulty of operation, the incidence of complications and mortality rate is high. Secondary aortic surgery, especially the reoperation involving arch, has higher risk and is more difficult for patients with renal failure. Sun's operation (total arch replacement + stent elephant nose) has achieved good results in the treatment of diseases involving aortic arch, and occupies an important position in the treatment of patients with secondary arch lesions after cardiac surgery. METHODS: A total of 395 patients with a history of cardiac surgery were recorded in our center from January 1, 2009 to December 31, 2017, among whom 118 (30.1%) patients underwent aortic reoperation via the original incision using Sun's aortic procedure owing to postoperative great vessel disease. We analyzed the clinical data and survival time, and used Cox regression to analyze the risk factors for 30-day mortality as well as long term mortality. RESULTS: The interval between the last operation and the present operation was 0.08-19 years. Sixteen patients died within 30 days after operation and the average mortality rate was 13.6%. During the follow-up period, 28 patients died, with the mortality rate of 23.7%. As of December 31, 2017, the longest survival time was 9.36 years, and the survival time of 70 patients was more than 3.05 years. The main risk factor associated with the 30-day survival was cardiopulmonary bypass (CPB) time. The longer the CPB time was, the greater the risk of death was. The main risk factors associated with the long-term survival were CPB time and 24-h bleeding volume. The longer the CPB time was, the more the 24-h bleeding volume was, the higher long-term mortality rate was. CONCLUSION: The second Sun's operation, as a surgical treatment after cardiac surgery, showed a high survival rate, with long survival time and good curative effect. CPB is the main risk factor for the 30-day survival state after operation, and CPB time and 24-h bleeding volume are the main risk factors for the long-term survival state after operation.

Discovery and Evaluation of Pyrazolo[3,4-d]pyridazinone as a Potent and Orally Active Irreversible BTK Inhibitor.

The identification and lead optimization of a series of pyrazolo[3,4-d]pyridazinone derivatives are described as a novel class of potent irreversible BTK inhibitors, resulting in the discovery of compound 8. Compound 8 exhibited high potency against BTK kinase and acceptable PK profile. Furthermore, compound 8 demonstrated significant in vivo efficacy in a mouse-collagen-induced arthritis (CIA) model.

Design, synthesis and biological evaluation of vincamine derivatives as potential pancreatic ß-cells protective agents for the treatment of type 2 diabetes mellitus.

A series of vincamine derivatives were designed, synthesized and evaluated as pancreatic ß-cells protective agents for type 2 diabetes mellitus. Most of the compounds displayed potent pancreatic ß-cells protective activities and five derivatives were found to exhibit 20-50-fold higher activities than vincamine. Especially for compounds Vin-C01 and Vin-F03, exhibited a remarkable EC50 value of 0.22 µM and 0.27 µM, respectively. Their pancreatic ß-cells protective activities increased approximately 2 times than vincamine. In cell viability assay, compounds Vin-C01 and Vin-F03 could effectively promote ß-cell survival and protect ß-cells from STZ-induced apoptosis. Further cellular mechanism of action studies demonstrated that their potent ß-cells protective activities were achieved by regulating IRS2/PI3K/Akt signaling pathway. The present study evidently showed that compounds Vin-C01 and Vin-F03 were two more potent pancreatic ß-cells protective agents compared to vincamine and might serve as promising lead candidates for the treatment of type 2 diabetes mellitus.

Nest site selection for five common birds and their coexistence in an urban habitat.

Many species of birds gradually adapt to urbanization and colonize cities successfully. However, their nest site selection and competitive relationship in an urban community remain little known. Understanding the impact of urbanization on birds and the competitive relationship has important implications for the conservation and management of wildlife in urban ecosystems. Here, we undertook a systematic study to quantify nests in all species of birds in an urbanizing area of Nanchang, China. A total of 363 nests were detected in surveys including 340 nests of 16 bird species and 23 unidentified species nests. We mainly analyzed 5 dominant breeding birds with a sample size of >10 during the two breeding seasons (From April to July in 2016 and 2017), which included the light-vented bulbul, Chinese blackbird, scaly-breasted munia, spotted dove and grey-capped greenfinch. Most birds (93.66%) nested in the tree of artificial green belts, which seems to be the best breeding habitat for urban birds. Our results suggested that birds' breeding success relies on the trade-off between the benefit and the expense of specific stresses from habitats. The nest site selection of birds is also affected by the life habit of urban predators. Furthermore, competition among species can influence their distributions and utilization of environmental resources when birds nest in cities. We confirmed that the niche differentiation of five bird species in an urban environment makes them coexist successfully by utilizing various resources.

Efficacy of Total Aortic Arch Replacement Combined with Frozen Elephant Trunk in Aortic Reoperation.

BACKGROUND The aim of this study was to estimate the long-term efficacy of total aortic arch replacement combined with the frozen elephant trunk (TAR+FET) technique for aortic disease following a prior cardiac surgery procedure. MATERIAL AND METHODS We performed TAR+FET for 118 patients for major vessel disease following a prior cardiac procedure with median sternotomy incision. All patients were divided into 5 groups: in group A, the prior major procedure was aortic valve replacement (AVR); in group B, the prior major procedure was isolated ascending aorta replacement; in group C, the prior major procedure was aortic root replacement; in group D, the prior major procedure was aortic arch replacement or intervention; and in group E, the prior major procedure was 'other' cardiac operative procedure. The long-term follow-up visit results were estimated using the Kaplan-Meier method. RESULTS The 30-day mortality rate after the operation was 13.6% (16/118) - 2 died in group A, 1 in group B, 8 in group C, 4 in group D, and 1 in group E. Follow-up visits were completed in 99% of patients. The mean follow-up time was 47.6±36.3 months and 12 patients had died by follow-up, so the total long-term survival rate was 76.3%. One-year survival rates of the 5 groups were 85% (group A), 93.8% (group B), 82.3% (group C), 50% (group D), and 50% (group E), respectively. Five-year survival rates of the 5 groups were 85%, 93.8%, 80.6%, 50%, and 50%, respectively. CONCLUSIONS The TAR+FET technique is feasible and efficacious for aortic reoperation in patients who previously underwent cardiac surgery since the short-term mortality in patients with recurrent aortic arch disease after cardiac surgery is not high.

Design, synthesis and biological evaluation of LX2343 derivatives as neuroprotective agents for the treatment of Alzheimer's disease.

A series of LX2343 derivatives were designed, synthesized and evaluated as neuroprotective agents for Alzheimer's disease (AD) in vitro. Most of the compounds displayed potent neuroprotective activities. Especially for compound A6, exhibited a remarkable EC50 value of 0.22 µM. Further investigation demonstrated that compound A6 can significantly reduce Aß production and increase Aß clearance, and alleviate Tau hyperphosphorylation. Most importantly, compound A6 could ameliorate learning and memory impairments in APP/PS1 transgenic mice. The present study evidently showed that compound A6 is a potent neuroprotective agent and might serve as a promising lead candidate for the treatment of Alzheimer's disease.

Tumor-targeting efficacy of a BF211 prodrug through hydrolysis by fibroblast activation protein-α.

BF211, a bufalin (BF) derivative, exhibits stronger anti-cancer activity than BF but with potential cardiotoxicity. Fibroblast activation protein-α (FAPα) is a membrane-bound protease specifically expressed by carcinoma-associated fibroblasts, thus has been used for the selective delivery of anticancer agents. In this study, we used a FAPα-based prodrug strategy to synthesize a dipeptide (Z-Gly-Pro)-conjugated BF211 prodrug named BF211-03. BF211-03 was hydrolyzed by recombinant human FAPα (rhFAPα) and cleaved by homogenates of human colon cancer HCT-116 or human gastric cancer MGC-803 xenografts. In contrast, BF211-03 showed good stability in plasma and in the homogenates of FAPα-negative normal tissues, such as heart and kidney. In HCT-116 and MGC-803 cells with low levels of FAPα expression, BF211-03 displayed a lower in vitro cytotoxicity than BF211 with approximately 30 to 40-fold larger IC50 values, whereas in human breast cancer MDA-MB-435 cells with high levels of FAPα expression, the IC50 value difference between BF211-03 and BF211 was small (approximately 4-fold). Although the cytotoxicity of BF211-03 against tumor cells was dramatically decreased by the chemical decoration, it was restored after cleavage of BF211-03 by rhFAPα or tumor homogenate. In HCT-116 tumor-bearing nude mice, doubling the dose of BF211-03, compared with BF211, caused less weight loss, but showing similar inhibitive effects on tumor growth. Our results suggest that BF211-03 is converted to active BF211 in tumor tissues and exhibits anti-tumor activities in tumor-bearing nude mice. FAPα-targeted BF211-03 displays tumor selectivity and may be useful as a targeting agent to improve the safety profile of cytotoxic natural products for use in cancer therapy.

Self-Powered Pulse Sensor for Antidiastole of Cardiovascular Disease.

Cardiovascular diseases are the leading cause of death globally; fortunately, 90% of cardiovascular diseases are preventable by long-term monitoring of physiological signals. Stable, ultralow power consumption, and high-sensitivity sensors are significant for miniaturized wearable physiological signal monitoring systems. Here, this study proposes a flexible self-powered ultrasensitive pulse sensor (SUPS) based on triboelectric active sensor with excellent output performance (1.52 V), high peak signal-noise ratio (45 dB), long-term performance (107 cycles), and low cost price. Attributed to the crucial features of acquiring easy-processed pulse waveform, which is consistent with second derivative of signal from conventional pulse sensor, SUPS can be integrated with a bluetooth chip to provide accurate, wireless, and real-time monitoring of pulse signals of cardiovascular system on a smart phone/PC. Antidiastole of coronary heart disease, atrial septal defect, and atrial fibrillation are made, and the arrhythmia (atrial fibrillation) is indicative diagnosed from health, by characteristic exponent analysis of pulse signals accessed from volunteer patients. This SUPS is expected to be applied in self-powered, wearable intelligent mobile diagnosis of cardiovascular disease in the future.

Palladium-Catalyzed Formylation of Aryl Iodides with HCOOH as CO Source.

A facile and practical method for the synthesis of aromatic aldehydes by palladium-catalyzed reductive carbonylation starting from aryl iodides and HCOOH is described. Compared to the known formylation procedure, HCOOH serves not only as the most convenient and environmental-friendly C1 source but also as the reviving agent in the reductive elimination process of a Pd-catalyst. Furthermore, this procedure is also applied successfully to the modification of natural products, such as vindoline, tabersonin, and vincamine, to obtain the corresponding products in good yields.

LX2343 alleviates cognitive impairments in AD model rats by inhibiting oxidative stress-induced neuronal apoptosis and tauopathy.

Alzheimer's disease (AD) is a progressive neurodegenerative disease leading to the irreversible loss of brain neurons and cognitive abilities, and the vicious interplay between oxidative stress (OS) and tauopathy is believed to be one of the major players in AD development. Here, we demonstrated the capability of the small molecule N-(1,3-benzodioxol-5-yl)-2-[5-chloro-2-methoxy(phenylsulfonyl)anilino]acetamide (LX2343) to ameliorate the cognitive dysfunction of AD model rats by inhibiting OS-induced neuronal apoptosis and tauopathy. Streptozotocin (STZ) was used to induce OS in neuronal cells in vitro and in AD model rats that were made by intracerebroventricular injection of STZ (3 mg/kg, bilaterally), and Morris water maze test was used to evaluate the cognitive dysfunction in ICV-STZ rats. Treatment with LX2343 (5-20 µmol/L) significantly attenuated STZ-induced apoptosis in SH-SY5Y cells and mouse primary cortical neurons by alleviating OS and inhibiting the JNK/p38 and pro-apoptotic pathways. LX2343 was able to restore the integrity of mitochondrial function and morphology, increase ATP biosynthesis, and reduce ROS accumulation in the neuronal cells. In addition, LX2343 was found to be a non-ATP competitive GSK-3ß inhibitor with IC50 of 1.84±0.07 µmol/L, and it potently inhibited tau hyperphosphorylation in the neuronal cells. In ICV-STZ rats, administration of LX2343 (7, 21 mg·kg-1·d-1, ip, for 5 weeks) efficiently improved their cognitive deficits. LX2343 ameliorates the cognitive dysfunction in the AD model rats by suppressing OS-induced neuronal apoptosis and tauopathy, thus highlighting the potential of LX2343 for the treatment of AD.

Small molecule LX2343 ameliorates cognitive deficits in AD model mice by targeting both amyloid ß production and clearance.

AIM: Streptozotocin (STZ) is widely used to induce oxidative damage and to impair glucose metabolism, apoptosis, and tau/Aß pathology, eventually leading to cognitive deficits in both in vitro and in vivo models of Alzheimer's disease (AD). In this study, we constructed a cell-based platform using STZ to induce stress conditions mimicking the complicated pathologies of AD in vitro, and evaluated the anti-amyloid effects of a small molecule, N-(1,3-benzodioxol-5-yl)-2-[5-chloro-2-methoxy(phenylsulfonyl)anilino]acetamide (LX2343) in the amelioration of cognitive deficits in AD model mice. METHODS: Cell-based assays for screening anti-amyloid compounds were established by assessing Aß accumulation in HEK293-APPsw and CHO-APP cells, and Aß clearance in primary astrocytes and SH-SY5Y cells after the cells were treated with STZ in the presence of the test compounds. Autophagic flux was observed using confocal laser scanning microscopy. APP/PS1 transgenic mice were administered LX2343 (10 mg·kg-1·d-1, ip) for 100 d. After LX2343 administration, cognitive ability of the mice was evaluated using Morris water maze test, and senile plaques in the brains were detected using Thioflavine S staining. ELISA assay was used to evaluate Aß and sAPPß levels, while Western blot analysis was used to measure the signaling proteins in both cell and animal brains. RESULTS: LX2343 (5-20 µmol/L) dose-dependently decreased Aß accumulation in HEK293-APPsw and CHO-APP cells, and promoted Aß clearance in SH-SY5Y cells and primary astrocytes. The anti-amyloid effects of LX2343 were attributed to suppressing JNK-mediated APPThr668 phosphorylation, thus inhibiting APP cleavage on one hand, and inhibiting BACE1 enzymatic activity with an IC50 value of 11.43±0.36 µmol/L, on the other hand. Furthermore, LX2343 acted as a non-ATP competitive PI3K inhibitor to negatively regulate AKT/mTOR signaling, thus promoting autophagy, and increasing Aß clearance. Administration of LX2343 in APP/PS1 transgenic mice significantly ameliorated cognitive deficits and markedly ameliorated the Aß pathology in their brains. CONCLUSION: LX2343 ameliorates cognitive dysfunction in APP/PS1 transgenic mice via both Aß production inhibition and clearance promotion, which highlights the potential of LX2343 in the treatment of AD.