Inherited OKT4 epitope deficiency in a Chinese rhesus macaque.

OKT4 is an important epitope of the CD4 molecular. Amino acid mutations in the CD4V3 region result in deficiency of the OKT4 epitope in human. Here, we firstly reported a case of hereditary deficiency of OKT4 epitope in an inbred Chinese rhesus macaque family. This epitope deficiency is due to cytosine to thymine transition and homozygote at the nucleotide position 793 of CD4 coding sequences, which leads to the replace of arginine at 265th position of CD4 molecule by tryptophan. The results reveal that OKT4 epitope deficiency is a very old phenotype and may be parentally inherited, and emphasize the importance of avoiding inbreeding in primate population breeding.

SECTM1-based CAR T cells enriched with CD7-low/negative subsets exhibit efficacy in CD7-positive malignancies.

CD7 has been found to be a promising chimeric antigen receptor (CAR) T cell target in several clinical trials. However, its expression on normal T cells poses additional challenges in CD7-directed CAR therapy, such as complete fratricide, contamination with malignant cells, and immune suppression due to T-cell aplasia. By taking advantage of evolved affinity between ligand and receptor, we constructed a CD7-directed CAR with the extracellular domain of SECTM1, a natural ligand of CD7, as the recognition domain. SECTM1 CAR T cells killed the majority of T cells with high CD7 expression in vitro. However, SECTM1 CAR T cells with low or negative CD7 expression survived, expanded, and showed strong cytotoxicity to CD7+ malignant cell lines and primary leukemic blasts from patients with T-cell acute lymphoblastic leukemia and acute myelogenous leukemia in vitro. It also exhibited efficacy in inhibiting xenograft tumor growth in vivo. More exploration is needed for clinical efficacy potential to patients with CD7+ malignancies.

Abnormality of anxious behaviors and functional connectivity between the amygdala and the frontal lobe in maternally deprived monkeys.

OBJECTIVE: Anxious behaviors often occur in individuals who have experienced early adversity. Anxious behaviors can bring many hazards, such as social withdrawal, eating disorders, negative self-efficacy, self-injurious thoughts and behaviors, anxiety disorders, and even depression. Abnormal behavior are is closely related to changes in corresponding circuit functions in the brain. This study investigated the relationship between brain circuits and anxious behaviors in maternal-deprived rhesus monkey animal model, which mimic early adversity in human. METHODS: Twenty-five rhesus monkeys (Macaca mulatta) were grouped by two different rearing conditions: 11 normal control and mother-reared (MR) monkeys and 14 maternally deprived and peer-reared (MD) monkeys. After obtaining images of the brain areas with significant differences in maternal separation and normal control macaque function, the relationship between functional junction intensity and stereotypical behaviors was determined by correlation analysis. RESULTS: The correlation analysis revealed that stereotypical behaviors were negatively correlated with the coupling between the left lateral amygdala subregion and the left inferior frontal gyrus in both MD and MR macaques. CONCLUSION: This study suggests that early adversity-induced anxious behaviors are associated with changes in the strength of the amygdala-prefrontal connection. The normalization of the regions involved in the functional connection might reverse the behavioral abnormality. It provides a solid foundation for effective intervention in human early adversity. SIGNIFICANCE STATEMENT: This study suggests that early adversity-induced anxious behaviors are associated with changes in the strength of the amygdala-prefrontal connection. The higher the amygdala-prefrontal connection strength, the less stereotyped behaviors exhibited by monkeys experiencing early adversity. Thus, in the future, changing the strength of the amygdala-prefrontal connection may reverse the behavioral abnormalities of individuals who experience early adversity. This study provides a solid foundation for effective intervention in humans' early adversity.

Influence of Annealing Treatment on Microstructure and Properties of Ni-Rich NiTi Alloy Coating Prepared by Laser Cladding.

NiTi alloys are widely known for their shape memory effect and super-elasticity. In this study, the laser cladding method was applied to prepare Ni-rich NiTi alloy coatings on 316L stainless steel substrate. The microstructure, phase composition, element distribution and phase transformation behavior of the coatings were investigated in as-fabricated and annealing-treated states. The results indicated that the recrystallized microstructure obtained and the content of Ni3Ti and Ti2Ni phases increased significantly with a rising annealing temperature. Annealing treatment also induced a decrease in the phase-transition enthalpy and a rise in the transformation temperature, even though no obvious martensite transformation was observed. This was suppressed due to the Fe element diffused from the substrate and was probably retarded by the mounting metallic compounds formed during annealing as well. The mechanical properties have also improved obviously; coatings annealed under 850 °C exhibited the highest microhardness of 839 HV, and the wear resistance of the coatings after annealing was enhanced with an 11% average wear mass loss reduction.

Aging induces severe SIV infection accompanied by an increase in follicular CD8+ T cells with overactive STAT3 signaling.

The number of elderly people living with HIV is increasing globally, and the condition of this population is relatively complicated due to the dual effects of aging and HIV infection. However, the impact of HIV infection combined with aging on the immune homeostasis of secondary lymphoid organs remains unclear. Here, we used the simian immunodeficiency virus mac239 (SIVmac239) strain to infect six young and six old Chinese rhesus macaques (ChRMs) and compared the infection characteristics of the two groups in the chronic stage through multiplex immunofluorescence staining of lymph nodes. The results showed that the SIV production and CD4/CD8 ratio inversion in old ChRMs were more severe than those in young ChRMs in both the peripheral blood and the lymph nodes, especially when a large number of CD8+ T cells infiltrated the follicles and germinal centers. STAT3 in these follicular CXCR5+CD8+ T cells was highly activated, with high expression of granzyme B, which might be caused by the severe inflammatory milieu in the follicles of old ChRMs. This study indicates that aging may be a cofactor involved in SIV-induced immune disorders in secondary lymphoid tissues, affecting the effective antiviral activity of highly enriched follicular CXCR5+CD8+ cells.

Study on the Effect of Ni Addition on the Microstructure and Properties of NiTi Alloy Coating on AISI 316 L Prepared by Laser Cladding.

This paper investigated 55 NiTi commercial alloy powder and 55 NiTi with 5% pure Ni mixed powder (55 NiTi + 5 Ni) coatings fabricated by laser cladding to study the effect of extra Ni addition on the microstructure and properties of the coating. The XRD and EDS results show that the major phases in the coatings were NiTi and Ni3Ti. Besides that, a second phase like Ni4Ti3, Fe2Ti, and NiTi2 was also detected, among which, NiTi2 was only found in 55 NiTi coating. The proportion of the phase composition in the coating was calculated via the software Image-Pro Plus. The hardness of the cladding layer reaches 770-830 HV, which was almost four times harder than the substrate, and the hardness of 55 NiTi + 5 Ni coating was around 8% higher than that of 55 NiTi coating. The wear resistance of the 55 NiTi + 5 Ni coating was also better; the wear mass loss decreased by about 13% and with a smaller friction coefficient compared with the 55 NiTi coating. These results are attributed to the solid solution strengthening effect caused by Ni addition and the second phase strengthening effect caused by the content increase of the Ni3Ti phase in the cladding layer.

Effects of neurofeedback on the activities of motor-related areas by using motor execution and imagery.

Previous studies have reported that real-time functional magnetic resonance imaging (fMRI) neurofeedback using motor imagery can modulate the activity of several motor-related areas. However, the differences in these modulatory effects on distinct motor-related target regions using the same experimental protocol remain unelucidated. This study aimed to compare neurofeedback effects on the primary motor area (M1) and the ventral premotor cortex (PMv). Of the included participants, 15 received blood oxygenation level-dependent (BOLD) signals from their left M1, and the other 15 received signals from their left PMv. Both groups were instructed to try to increase the neurofeedback score (NF-Score), which reflected the averaged activation level of the target region, by executing or imagining a right-hand clenching movement. The result revealed that during imagery condition, the left M1 was deactivated in the PMv-group but not in the M1-group, whereas the left PMv was activated in the PMv-group but not in the M1-group. Our finding indicates that neurofeedback from distinct motor-related regions has different effects on brain activity regulation.

CircGRIA1 shows an age-related increase in male macaque brain and regulates synaptic plasticity and synaptogenesis.

Circular RNAs (circRNAs) are abundant in mammalian brain and some show age-dependent expression patterns. Here, we report that circGRIA1, a conserved circRNA isoform derived from the genomic loci of α-mino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor subunit Gria1, shows an age-related and male-specific increase in expression in the rhesus macaque prefrontal cortex and hippocampus. We show circGRIA1 is predominantly localized to the nucleus, and find an age-related increase in its association with the promoter region of Gria1 gene, suggesting it has a regulatory role in Gria1 transcription. In vitro and in vivo manipulation of circGRIA1 negatively regulates Gria1 mRNA and protein levels. Knockdown of circGRIA1 results in an age-related improvement of synaptogenesis, and GluR1 activity-dependent synaptic plasticity in the hippocampal neurons in males. Our findings underscore the importance of circRNA regulation and offer an insight into the biology of brain aging.

Infection with novel coronavirus (SARS-CoV-2) causes pneumonia in Rhesus macaques.

The 2019 novel coronavirus (SARS-CoV-2) outbreak is a major challenge for public health. SARS-CoV-2 infection in human has a broad clinical spectrum ranging from mild to severe cases, with a mortality rate of ~6.4% worldwide (based on World Health Organization daily situation report). However, the dynamics of viral infection, replication and shedding are poorly understood. Here, we show that Rhesus macaques are susceptible to the infection by SARS-CoV-2. After intratracheal inoculation, the first peak of viral RNA was observed in oropharyngeal swabs one day post infection (1 d.p.i.), mainly from the input of the inoculation, while the second peak occurred at 5 d.p.i., which reflected on-site replication in the respiratory tract. Histopathological observation shows that SARS-CoV-2 infection can cause interstitial pneumonia in animals, characterized by hyperemia and edema, and infiltration of monocytes and lymphocytes in alveoli. We also identified SARS-CoV-2 RNA in respiratory tract tissues, including trachea, bronchus and lung; and viruses were also re-isolated from oropharyngeal swabs, bronchus and lung, respectively. Furthermore, we demonstrated that neutralizing antibodies generated from the primary infection could protect the Rhesus macaques from a second-round challenge by SARS-CoV-2. The non-human primate model that we established here provides a valuable platform to study SARS-CoV-2 pathogenesis and to evaluate candidate vaccines and therapeutics.

[Three-dimensional reconstruction of human kidney based on UroMedix-3D system and its application in kidney surgery].

OBJECTIVE: To explore the feasibility of rapid and accurate three-dimensional (3D) image reconstruction using Uromedix-3D software for urological surgery. METHODS: The original renal thin-slice enhancement CT data were obtained from patients with kidney lesions treated in our hospital between December, 2015 and October, 2018. The self-developed Uromedix- 3D system was used to reconstruct the normal kidney structures, blood vessels, collecting systems and the lesions. The spatial anatomic relationships of the structures were measured and digitized for surgical planning. RESULTS: 3D reconstruction of the kidneys was performed in a total of 173 cases, and the mean time for reconstruction was 31.24±2.012 min. Of these cases, 147 (84.9%) had renal tumors, and 2 had renal tumors with tumor thrombus. In addition to renal tumors, the Uromedix-3D system was also used for reconstructing other lesions including UPJO, kidney stones and retroperitoneal masses. Renal artery reconstruction was performed in 170 cases, which allowed observation of the precise terminal branches (up to 7th grade arterial branch) of the artery; 109 (64%) cases showed the 5th grade arterial branch or above. Renal artery variations were detected in 37 cases, including accessory renal artery (24 cases) and multiple renal arteries (13 cases). The renal veins were reconstructed in 164 cases, and second grade or above (up to the 4th grade) vein branches were observed in 138 (84%) cases. CONCLUSIONS: Uromedix-3D system can accurately and efficiently reconstruct the 3D structure of human kidneys and the renal lesions based on enhanced CT data. The reconstructed 3D model allows objective assessment of the spatial anatomical relationship of the lesions to provide assistance in surgical planning.

Common Neural System for Sentence and Picture Comprehension Across Languages: A Chinese-Japanese Bilingual Study.

While common semantic representations for individual words across languages have been identified, a common meaning system at sentence-level has not been determined. In this study, fMRI was used to investigate whether an across-language sentence comprehension system exists. Chinese-Japanese bilingual participants (n = 32) were asked to determine whether two consecutive stimuli were related (coherent) or not (incoherent) to the same event. Stimuli were displayed with three different modalities (Chinese written sentences, Japanese written sentences, and pictures). The behavioral results showed no significant difference in accuracy and response times among the three modalities. Multi-voxel pattern analysis (MVPA) of fMRI data was used to classify the semantic relationship (coherent or incoherent) across the stimulus modalities. The classifier was first trained to determine coherency within Chinese sentences and then tested with Japanese sentences, and vice versa. A whole-brain searchlight analysis revealed significant above-chance classification accuracy across Chinese and Japanese sentences in the supramarginal gyrus (BA 40), extending into the angular gyrus (BA 39) as well as the opercular (BA 44) and triangular (BA 45) parts of the inferior frontal gyrus in the left hemisphere (cluster-level FWE corrected p < 0.05). Significant above-chance classification accuracy was also found across Japanese sentences and pictures in the supramarginal (BA 40) and angular gyrus (BA 39). These results indicate that a common meaning system for sentence processing across languages and modalities exists, and it involves the left inferior parietal gyrus.

Direct sunlight exposure reduces hair cortisol levels in rhesus monkeys (Macaca mulatta).

Major depressive disorder (MDD), commonly known as depression, is a mental disease characterized by a core symptom of low mood. It lasts at least two weeks (Badamasi et al., 2019; Wang et al., 2019) and is frequently accompanied by low self-esteem, loss of interest in routinely enjoyable activities, low energy, and unexplained pain (Huey et al., 2018; Park et al., 2012; Post & Warden, 2018; Rice et al., 2019; Xiao et al., 2018). Approximately 2%-8% of adults with MDD commit suicide (Richards & O'Hara, 2014; Strakowski & Nelson, 2015), and around half of suicidal individuals suffer depression or other mood disorders (Bachmann, 2018).

Chronic Glucocorticoid Exposure Induces Depression-Like Phenotype in Rhesus Macaque (Macaca Mulatta).

It has long been observed in humans that the occurrence of depressive symptoms is often accompanied by the dysfunction of hypothalamic-pituitary-adrenal (HPA) axis. The rodent experiments also showed that chronic corticosterone exposure could induce depression-like phenotype. However, rodents are phylogenetically distant from humans. In contrast, non-human primates bear stronger similarities with humans, suggesting research on primates would provide an important complement. For the first time, we investigated the effects of chronic glucocorticoid exposure on rhesus macaques. Seven male macaques were selected and randomized to glucocorticoid or vehicle groups, which were subjected to either prednisolone acetate or saline injections, respectively. The depression-like behaviors were assessed weekly, and the body weights, HPA axis reactivity, sucrose solution consumption and monoaminergic neurotransmitters were further compared between these two groups. The glucocorticoid group was not found to display more depression-like behaviors than the vehicle group until 7 weeks after treatment. Chronic glucocorticoid exposure significantly decreased the levels of cortisol determined from blood (a biomarker for acute HPA axis reactivity) but increased the hair cortisol concentrations (a reliable indicator of chronic HPA axis reactivity) compared with controls. The glucocorticoid group was also found to consume less sucrose solution than controls, a good manifestation of anhedonia. This could be possibly explained by lower dopamine (DA) levels in cerebrospinal fluid induced by chronic glucocorticoid treatment. The results presented here indicate that chronic glucocorticoid exposure could disturb both the acute and chronic HPA axis reactivity, which eventually disturbed the neurotransmitter system and led monkeys to display depression-like phenotype.

[Three-dimensional spatial measurement versus conventional CT planning in laparoscopic partial nephrectomy for renal tumors].

OBJECTIVE: To analyze the advantages of spatial measurement of anatomical parameters in a 3D model in surgical planning for laparoscopic partial nephrectomy (LPN). METHODS: From February, 2016 to October, 2017, 37 patients diagnosed with T1 renal mass underwent LPN based on 3D reconstruction after enhanced CT scanning using the Uromedix-3D system (group A), and another 38 patients received LPN with conventional CT planning (group B). The anatomical parameters were measured in the reconstructed 3D model and the demographic data, surgical outcome and postoperative data were compared between the two groups. RESULTS: In group A, the average time for 3D model reconstruction was (29.3∓9.7) min; the length, width and depth of the renal defect in 3D model were 3.2∓1.1 cm, 2.6∓0.9 cm and 1.7∓0.7 cm, respectively; The distance of the tumor from the collecting system was 3.8∓2.2 mm; The mean R.E.N.A.L score of the patients was 7∓1.5, and 3 patients had accessory renal artery and 2 had early branching of the renal artery. LPNs were completed via the retroperitoneal approach in all the 75 patients without conversion to open or total nephrectomy. Group A and group B showed significant differences in warm ischemic time (26.7∓6.4 vs 31.9∓7.0 min), tumor-excision time (8.4∓2.6 vs 10.4∓2.8 min), renal defect suture time (18.3∓3.9 vs 21.5∓3.4 min), 24-h volume of retroperitoneal drainage (88.6∓40.2 vs 134.3∓58.3 mL) and 48-h volume of retroperitoneal drainage (127.9∓54.5 vs 198.1∓86.3 mL), but not in the demographic data, operation time, intraoperative blood loss or postoperative hospital stay. CONCLUSIONS: 3D reconstruction of the renal masses can be completed efficiently and accurately using this system. Compared with conventional CT-based measurement, 3D spatial measurement of the anatomical structures helps to increase the precision in the performance of LPN and reduce the warm ischemia time.

Alterations of Gray Matter Volume and White Matter Integrity in Maternal Deprivation Monkeys.

Maternal deprivation (MD) in rhesus monkeys has been demonstrated to be an effective model to mimic early adversity in humans because of the close phylogenetic similarity affinity. Although behavioral and hormonal abnormalities have been observed in MD monkeys, the neurobiological underpinning of the long-term deleterious effect of MD on monkeys is still unclear. In this study, we assessed emotional changes and socio-behavioral abnormalities induced by long-term MD and assessed structural alterations of gray matter volume (GMV) and white matter integrity (WMI) in 15 MD rhesus monkeys and in 15 age-, gender-matched normal controls (NC) using voxel-based morphology and voxel-based analysis methods. We found increased stereotypical behavioral durations and decreased social grooming durations in MD monkeys. Reduced GMV in the primary visual cortex (V1) and increased fractional anisotropy (FA) in the left posterior superior temporal sulcus (pSTS) was also found in MD monkeys. Moreover, the mean FA values in pSTS showed positive correlation with the stereotypical behavioral durations in MD monkeys and negative correlation with social grooming durations in NC monkeys. Our findings indicated that the deleterious effects of MD on rhesus monkeys resulted in structural abnormalities in the visual cortex and premature myelination in the pSTS. These findings provide new insights into understanding the impact of maternal deprivation on the neurological basis of brain development.

[Small RNA interference-mediated ADP-ribosylation factor 6 silencing inhibits proliferation, migration and invasion of human prostate cancer PC-3 cells].

OBJECTIVE: To investigate the effects of silencing ADP-ribosylation factor 6 (Arf6) on the proliferation, migration, and invasion of prostate cancer cell line PC-3 and the possible molecular mechanisms. METHODS: Three Arf6-specific small interfering RNA (siRNA) were transfected into cultured prostate cancer cell line PC-3. Arf6 expression was examined by real-time PCR and Western blotting. MTT assay, wound healing assay, and Transwell migration and invasion assay were used to observe the effect of Arf6 silencing on the proliferation, migration, and invasion ability of PC-3 cells. The levels of phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2), ERK1/2, p-AKT, AKT and Rac1 were detected by Western blotting. RESULTS: Transfection of siRNA-3 resulted in significantly decreased Arf6 mRNA and protein expression with inhibition rates of (91.88±3.13)% and (86.37±0.57)%, respectively. Arf6 silencing by siRNA-3 markedly suppressed the proliferation, migration and invasion of PC-3 cells and reduced the expression levels of p-ERK1/2 and Rac1. CONCLUSION: Silencing of Arf6 efficiently inhibits the proliferation, migration, and invasion of PC-3 cells in vitro, and the underlying mechanisms may involve the down-regulation of p-ERK1/2 and Rac1.

Social correlates of the dominance rank and long-term cortisol levels in adolescent and adult male rhesus macaques (Macaca mulatta).

A common pattern in dominance hierarchies is that some ranks result in higher levels of psychosocial stress than others. Such stress can lead to negative health outcomes, possibly through altered levels of stress hormones. The dominance rank-stress physiology relationship is known to vary between species; sometimes dominants show higher levels of glucocorticoid stress hormones, whereas in other cases subordinates show higher levels. It is less clear how this relationship varies between groups of different ages or cultures. In this study, we used long-term cortisol measurement methods to compare the effect of rank on cortisol levels in adult and adolescent male rhesus macaques. In the adult groups, subordinates had significantly higher cortisol levels. In the adolescents, no significant correlation between cortisol and status was found. Further analysis demonstrated that the adult hierarchy was stricter than that of the adolescents. Adult subordinates received extreme aggression more frequently than dominants, and this class of behavior was positively correlated with cortisol; by contrast, adolescents showed neither trend. Together, these findings provide evidence for a cortisol-rank relationship determined by social factors, namely, despotism of the group, and highlight the importance of group-specific social analysis when comparing or combining results obtained from different groups of animals.