Fasting-induced RNF152 resensitizes gallbladder cancer cells to gemcitabine by inhibiting mTORC1-mediated glycolysis.

Abnormal mTORC1 activation by the lysosomal Ragulator complex has been implicated in cancer and glycolytic metabolism associated with drug resistance. Fasting upregulates RNF152 and mediates the metabolic status of cells. We report that RNF152 regulates mTORC1 signaling by targeting a Ragulator subunit, p18, and attenuates gemcitabine resistance in gallbladder cancer (GBC). We detected levels of RNF152 and p18 in tissues and undertook mechanistic studies using activators, inhibitors, and lentivirus transfections. RNF152 levels were significantly lower in GBC than in adjacent non-cancer tissues. Fasting impairs glycolysis, induces gemcitabine sensitivity, and upregulates RNF152 expression. RNF152 overexpression increases the sensitivity of GBC cells to gemcitabine, whereas silencing RNF152 has the opposite effect. Fasting-induced RNF152 ubiquitinates p18, resulting in proteasomal degradation. RNF152 deficiency increases the lysosomal localization of p18 and increases mTORC1 activity, to promote glycolysis and decrease gemcitabine sensitivity. RNF152 suppresses mTORC1 activity to inhibit glycolysis and enhance gemcitabine sensitivity in GBC.

Chronic but not acute nicotine treatment ameliorates acute inflammation-induced working memory impairment by increasing CRTC1 and HCN2 in adult male mice.

BACKGROUND: Systemic inflammation in which lipopolysaccharide (LPS) is released into circulation can cause cognitive dysfunction and we have previously shown that LPS impaired working memory (WM) which refers to the ability to guide incoming behavior by retrieving recently acquired information. However, the mechanism is not very clear, and currently, there is no approved strategy to improve inflammation-induced WM deficit. Notably, epidemiological studies have demonstrated a lower occurrence rate of inflammatory-related diseases in smoking patients, suggesting that inflammation-induced WM impairment may be improved by nicotine treatment. Here, our object is to investigate the effect and potential mechanisms of acute and chronic nicotine treatment on LPS-produced WM deficiency. METHODS: Delayed alternation T-maze task (DAT) was applied for evaluating WM which includes both the short-term information storage and the ability to correct errors in adult male mice. Immunofluorescence staining and immunoblotting were used for assessing the levels and distribution of CREB-regulated transcription coactivator 1 (CRTC1) and hyperpolarization-activated cation channels 2 (HCN2) in the medial prefrontal cortex (mPFC) and hippocampus. Quantitative PCR and ELISA were employed for analyzing the mRNA and protein levels of TNF-α and IL-1ß. RESULTS: Our results revealed that administration of LPS (i.p.) at a dose of 0.5 mg/kg significantly produced WM impairment in the DAT task accompanied by an increase in IL-1ß and TNF-α expression in the mPFC. Moreover, intra-mPFC infusion of IL-1Ra, an IL-1 antagonist, markedly alleviated LPS-induced WM deficiency. More important, chronic (2 weeks) but not acute nicotine (0.2 mg/kg, subcutaneous) treatment significantly alleviated LPS-induced WM deficiency by upregulating CRTC1 and HCN2. Of note, intra-mPFC infusion of HCN blocker ZD7288 produced significant WM deficiency. CONCLUSIONS: In summary, in this study, we show that chronic nicotine treatment ameliorates acute inflammation-induced working memory deficiency by increasing CRTC1 and HCN2 in adult male mice.

Laminar Distribution of Cannabinoid Receptor 1 in the Prefrontal Cortex of Nonhuman Primates.

Cannabis is an annual herb of the genus Cannabis, with a history of medical use going back thousands of years. However, its abuse causes many side-effects, including confusion of consciousness, alienation, and mental disorders such as schizophrenia and depression. Research conducted on rodents suggests that there are two types of cannabinoid receptors-cannabinoid receptor 1 (CB1R) and cannabinoid receptor 2 (CB2R). CB1R is found mostly in the central nervous system, particularly in the prefrontal cortex (PFC), and alterations in its expression in the PFC have been strongly linked to mental disorders. Within the layers of the PFC, Brodmann area 46 is associated with the processing of complex cognitive information. However, it remains unclear whether CB1R is expressed in the PFC 46 area of non-human primate. In this work, we applied western blotting along with immunofluorescent histochemical staining to investigate the distribution pattern of CB1R in the PFC of nonhuman primate, Our findings reveal that CB1R is highly expressed in the monkey PFC, especially in area 46. Furthermore, CB1R exhibits a layered distribution pattern within area 46 of the PFC, with the inner granular layer displaying the highest expression levels. Additionally, CB1R+PV+ cells are widely distributed in lay II-VI of area 46, with layer IV showing notable prevalence. In conclusion, CB1R is distributed in the PV interneurons in area 46 of the prefrontal cortex, particularly in layer IV, suggesting that cannabis may modulate PFC activities via regulating interneuron in the PFC. And cannabis-induced side effects may be caused by abnormal expression of CB1R.

Behavioral assessment scale of consciousness for nonhuman primates: A Delphi study.

OBJECTIVE: Nonhuman primates (NHPs) are suitable for being model animals in the study of consciousness and loss of consciousness (LoC) with a similar brain structure and function to humans. However, there is no effective consciousness assessment scale for them. This study aimed to develop a behavioral assessment scale of consciousness for NHPs. METHODS: We constructed an initial indicator framework based on the clinical consciousness disorder assessment scales and the physiological characteristics, consciousness, and arousal behavior of NHPs. A two-round online Delphi method was conducted by a multidisciplinary expert panel to construct a behavioral assessment scale of consciousness for NHPs. The indicators and descriptions were revised according to the experts' feedback and then sent out for repeated consultations along with a summary of the results of the previous round of consultations. The accepted competencies of indicators were established with mean scores in two scoring criteria (importance and feasibility) ≥4.0, agreement rate with a rating of importance or essential ≥70.0%, and a coefficient of variation ≤0.25, as well as discussions of the research group. RESULTS: Consensus was achieved after the second round of consultations, which was completed by 28 experts who specialized in rehabilitation, neuroscience, psychology, neurosurgery, and neurology. A new behavioral assessment scale of consciousness for NHPs, including 37 items organized hierarchically within seven dimensions including visual function, auditory function, motor function, orofacial movements, arousal, brainstem reflexes, and respiration, was developed in this study. CONCLUSIONS: This study has successfully developed a behavioral assessment scale for measuring the conscious state of NHPs or NHP models with LoC. This tool is expected to facilitate future research into the underlying mechanisms of consciousness by providing a detailed and comprehensive means of measurement.

Microglia are involved in regulating histamine-dependent and non-dependent itch transmissions with distinguished signal pathways.

Although itch and pain have many similarities, they are completely different in perceptual experience and behavioral response. In recent years, we have a deep understanding of the neural pathways of itch sensation transmission. However, there are few reports on the role of non-neuronal cells in itch. Microglia are known to play a key role in chronic neuropathic pain and acute inflammatory pain. It is still unknown whether microglia are also involved in regulating the transmission of itch sensation. In the present study, we used several kinds of transgenic mice to specifically deplete CX3CR1+ microglia and peripheral macrophages together (whole depletion), or selectively deplete microglia alone (central depletion). We observed that the acute itch responses to histamine, compound 48/80 and chloroquine were all significantly reduced in mice with either whole or central depletion. Spinal c-fos mRNA assay and further studies revealed that histamine and compound 48/80, but not chloroquine elicited primary itch signal transmission from DRG to spinal Npr1- and somatostatin-positive neurons relied on microglial CX3CL1-CX3CR1 pathway. Our results suggested that microglia were involved in multiple types of acute chemical itch transmission, while the underlying mechanisms for histamine-dependent and non-dependent itch transmission were different that the former required the CX3CL1-CX3CR1 signal pathway.

CRTC1 is a potential target to delay aging-induced cognitive deficit by protecting the integrity of the blood-brain barrier via inhibiting inflammation.

Aging can cause attenuation in the functioning of multiple organs, and blood-brain barrier (BBB) breakdown could promote the occurrence of disorders of the central nervous system during aging. Since inflammation is considered to be an important factor underlying BBB injury during aging, vascular endothelial cell senescence serves as a critical pathological basis for the destruction of BBB integrity. In the current review, we have first introduced the concepts related to aging-induced cognitive deficit and BBB integrity damage. Thereafter, we reviewed the potential relationship between disruption of BBB integrity and cognition deficit and the role of inflammation, vascular endothelial cell senescence, and BBB injury. We have also briefly introduced the function of CREB-regulated transcription co-activator 1 (CRTC1) in cognition and aging-induced CRTC1 changes as well as the critical roles of CRTC1/cyclooxygenase-2 (COX-2) in regulating inflammation, endothelial cell senescence, and BBB injury. Finally, the underlying mechanisms have been summarized and we propose that CRTC1 could be a promising target to delay aging-induced cognitive deficit by protecting the integrity of BBB through promoting inhibition of inflammation-mediated endothelial cell senescence.

Transcranial Direct Current Stimulation Improves Some Neurophysiological Parameters but not Clinical Outcomes after Severe Traumatic Brain Injury.

BACKGROUND: Disorders of consciousness (DOC) are one of the clinical hallmarks of severe traumatic brain injury (TBI). DOC impair patient life quality and increase the burden on their families and society. METHODS: A double-blind, randomized, controlled clinical trial was conducted to determine the efficacy of routine rehabilitation combined with transcranial direct current stimulation (tDCS) in DOC patients after TBI. A total of 78 DOC patients were randomly divided after TBI into two groups: participants in the treatment group received routine rehabilitation combined with an active tDCS protocol. In contrast, participants in the control group received routine rehabilitation combined with a sham tDCS protocol. An anode was placed over the left dorsolateral prefrontal cortex and a cathode was placed over the right supraorbital area. The stimulation intensity was 2 mA. Both tDCS protocols lasted for eight consecutive weeks (20 minutes per day, six days per week). Patients were followed up for a further eight weeks. Glasgow Outcome Scale (GOS), Glasgow Coma Scale (GCS), brainstem auditory evoked potentials, somatosensory evoked potentials and electroencephalogram were measured at weeks zero, two, four, six, eight and sixteen from the start of tDCS. RESULTS: Neither the GOS nor GCS scores differed significantly between the two groups, while brainstem auditory evoked potentials, somatosensory evoked potentials and electroencephalogram scores did. CONCLUSIONS: This study found that tDCS improves some neurophysiological parameters but not clinical outcomes of DOC patients after TBI. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR1800014808 (The version is V.1.0). Registered on February 7, 2018. http://www.chictr.org.cn/showproj.aspx?proj=25003.

Muscimol-induced inactivation of the ventral prefrontal cortex impairs counting performance in rhesus monkeys.

Numbers are one of the three basic concepts of human abstract thinking. When human beings count, they often point to things, one by one, and read numbers in a positive integer column. The prefrontal cortex plays a wide range of roles in executive functions, including active maintenance and achievement of goals, adaptive coding and exertion of general intelligence, and completion of time complexity events. Nonhuman animals do not use number names, such as "one, two, three," or numerals, such as "1, 2, 3" to "count" in the same way as humans do. Our previous study established an animal model of counting in monkeys. Here, we used this model to determine whether the prefrontal cortex participates in counting in monkeys. Two 5-year-old female rhesus monkeys (macaques), weighing 5.0 kg and 5.5 kg, were selected to train in a counting task, counting from 1 to 5. When their counting task performance stabilized, we performed surgery on the prefrontal cortex to implant drug delivery tubes. After allowing the monkeys' physical condition and counting performance to recover, we injected either muscimol or normal saline into their dorsal and ventral prefrontal cortex. Thereafter, we observed their counting task performance and analyzed the error types and reaction time during the counting task. The monkeys' performance in the counting task decreased significantly after muscimol injection into the ventral prefrontal cortex; however, it was not affected after saline injection into the ventral prefrontal cortex, or after muscimol or saline injection into the dorsal prefrontal cortex. The ventral prefrontal cortex of the monkey is necessary for counting performance.

The Evaluation Indexes Suitable for Nonhuman Primates can be Extracted from Clinical Consciousness Disorder Assessment Scales: A Hypothesis.

BACKGROUND: Currently, case studies or clinical trials in different patient populations remain the main resource underlying the understanding of disorder of consciousness (DoC). This provides a low efficacy for the derivation of data and the implementation of associated controlled experimental designs. Preclinical models provide precise controls, reduced variability, rich data output and limited ethical complexity. Nonhuman primates are suitable model animals for disorders of consciousness due to their brain structure being very similar to that of humans. Behavioral tests remain the primary standard for assessing the consciousness status of humans. However, there is currently no behavioral assessment scale available for evaluation of the state of consciousness disorder in nonhuman primates. This presents a significant challenge for the establishment of different models of consciousness disorder. Therefore, there is considerable motivation to focus on the development of a proper tool for assessment of the state of consciousness associated with nonhuman primate models that are based on clinically common consciousness assessment scales. METHODS: It is assumed that the Delphi and level analysis methods based on clinical consciousness disorder assessment scales may provide an effective way to select and include assessment indexes for levels of consciousness in nonhuman primates. RESULTS: 8 first-level indicators with 41 second-level indexes were selected preliminary as a pool of evaluation entries of state of consciousness of nonhuman primates. CONCLUSIONS: It may be practicable to extract appropriate indicators for non-human primates from the clinical consciousness disorder assessment scales. Besides, a combination of Delphi method, behavioral analysis, electroencephalography, neuroimaging (such as positron emission tomography-computed tomography) and functional magnetic resonance imaging is necessary to test the reliability and validity of the novel scale reported here.

Prefrontal Dopaminergic Regulation of Cue-Guided Risky Decision-Making Performance in Rats.

Risky decision-making is the decision made by individuals when they know the probability of each outcome. In order to survive in unpredictable environments, it is necessary for individuals to assess the probability of events occurring to an make appropriate decisions. There are few studies on the neural basis of risky decision-making behavior guided by external cues, which is related to the relative paucity of animal behavioral paradigms. Previous studies have shown that the prefrontal cortex (PFC) plays a key role in risk-based decision-making. The PFC receives projections from the dopamine (DA) system from the ventral tegmental area of the midbrain. The mesocorticolimbic DA system regulates the judgments of reward and value in decision-making. However, the specific receptor mechanism for prefrontal DA regulation of cue-guided risky decision-making behavior remains unclear. Here we established a cue-guided risky decision-making behavioral paradigm (RDM task) to detect the behavior of rats making decisions between a small certain reward and a large uncertain reward in a self-paced manner. The D1 receptor antagonist SCH-23390 (5 mM) or agonist SKF-82958 (5 mM), and the D2 receptor antagonist thioridazine hydrochloride (5 mM) or agonist MLS-1547 (5 mM) was injected into the mPFC, respectively, to investigate how the behavior in the RDM task was changed. The results showed that: (1) rats were able to master the operation of the cue-guided RDM task in a self-paced way; (2) a majority of rats were inclined to choose risk rather than a safe option when the reward expectations were equal; and (3) risk selection was reduced upon inhibition of D1 receptors or stimulation of D2 receptors, but increased upon stimulation of D1 receptors or inhibition of D2 receptors, suggesting that the RDM performance is regulated by D1 and D2 receptors in the mPFC. The present results suggest that DA receptors in the mPFC of rats are involved in regulating cue-guided RDM behavior, with differential involvement of D1 and D2 receptors in the regulation.

Behavior of Rats in a Self-Paced Risky Decision-Making Task Based on Definite Probability.

Risky decision-making (RDM) is when individuals make choices based on the definite cognition for the probabilities of the options. Risk is embodied in the certainty of reward, and the smaller the probability is, the greater the risk will be. As simulated in human behavior paradigms, RDM scenarios in real life are often guided by external cues that inform the likelihood of receiving certain rewards. There are few studies on the neural basis of RDM behavior guided by external cues, which is related to the relative paucity of the animal behavioral paradigms. Here, we established a cue-guided RDM task to detect the behavior of rats making a decision between a small certain reward and a large uncertain reward in a naturalistic manner. The reward of the risk option could be adjusted to observe the change of choice. Our results showed that: (1) rats were able to master the operation of the cue-guided RDM task; (2) many rats were inclined to choose risk rather than the safe option when the reward expectations were equal; (3) rats were able to adjust the decision strategy in time upon a change in risk, suggesting that they have the ability to perceive risk indicated by the external cues.

Transmembrane protein 108 inhibits the proliferation and myelination of oligodendrocyte lineage cells in the corpus callosum.

BACKGROUND: Abnormal white matter is a common neurobiological change in bipolar disorder, and dysregulation of myelination in oligodendrocytes (OLs) is the cause. Transmembrane protein 108 (Tmem108), as a susceptible gene of bipolar disorder, is expressed higher in OL lineage cells than any other lineage cells in the central nervous system. Moreover, Tmem108 mutant mice exhibit mania-like behaviors, belonging to one of the signs of bipolar disorder. However, it is unknown whether Tmem108 regulates the myelination of the OLs. RESULTS: Tmem108 expression in the corpus callosum decreased with the development, and OL progenitor cell proliferation and OL myelination were enhanced in the mutant mice. Moreover, the mutant mice exhibited mania-like behavior after acute restraint stress and were susceptible to drug-induced epilepsy. CONCLUSIONS: Tmem108 inhibited OL progenitor cell proliferation and mitigated OL maturation in the corpus callosum, which may also provide a new role of Tmem108 involving bipolar disorder pathogenesis.

Effects of transcranial direct current stimulation on patients with post-stroke fatigue: a study protocol for a double-blind randomized controlled trial.

INTRODUCTION: Post-stroke fatigue (PSF) is an abnormal, persistent, and unexplained physical and psychological tiredness in patients after stroke. It is a common symptom of stroke patients with poor quality of life and bleak prognosis, and the incidence rate is up to 39% to 72%. It has been widely reported that medicine treatments achieved a lot of progress, there still needs to develop more powerful new strategies to more powerful effect. The transcranial direct-current stimulation (tDCS) shows great potential for the treatment of PSF. This study proposes to apply a double-blind randomized controlled clinical trial to explore the effect and safety of tDCS combined with routine rehabilitation for PSF. METHODS AND ANALYSIS: One hundred patients with PSF will be randomly divided into two groups. One of the groups will receive conventional rehabilitation therapy and active tDCS, whereas another group will receive conventional rehabilitation treatment and sham tDCS. Both groups will receive the intervention for 4 weeks, during which time they will undergo either active or sham tDCS 20 min a day, 6 days a week. PRIMARY OUTCOME: Fatigue Severity Scale (FSS) will be measured at baseline every weekend during the intervention period. Secondary results: Fatigue Impact Scale (FIS), Functional Assessment Chronic Illness Therapy (Fatigue) (FACIT-F), and Specialized Quality of Life Scale in Stroke (SS-QOL) will be measured at baseline and at the end of the intervention time of 4 weeks. Throughout the study, adverse events and adverse reactions will be measured during every treatment. The research study "Effects of transcranial direct current stimulation on patients with post-stroke fatigue" has been approved by the Ethics Committee of the First Affiliated Hospital of Nanchang University: Clinical Medicine Ethics Review [2015]043 in Nov 2015. DISCUSSION: This study will provide insight into the efficacy of transcranial direct-current stimulation for post-stroke fatigue. This is a double-blind randomized controlled trial whose aim is to assess the effects of tDCS on PSF. This study can provide more information about the treatment of PSF. This study has a period of follow-up, which allows for greater accuracy. It is a single-center trial, and this may be a limitation. The other limitation of this study is the relatively small number of participants; thus, the influence of chance on experimental results cannot be completely ruled out. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2000031120 . Registered on March 22, 2020. This protocol version number is V1.1.

Polygalasaponin F protects hippocampal neurons against glutamate-induced cytotoxicity.

Excess extracellular glutamate leads to excitotoxicity, which induces neuronal death through the overactivation of N-methyl-D-aspartate receptors (NMDARs). Excitotoxicity is thought to be closely related to various acute and chronic neurological disorders, such as stroke and Alzheimer's disease. Polygalasaponin F (PGSF) is a triterpenoid saponin monomer that can be isolated from Polygala japonica, and has been reported to protect cells against apoptosis. To investigate the mechanisms underlying the neuroprotective effects of PGSF against glutamate-induced cytotoxicity, PGSF-pretreated hippocampal neurons were exposed to glutamate for 24 hours. The results demonstrated that PGSF inhibited glutamate-induced hippocampal neuron death in a concentration-dependent manner and reduced glutamate-induced Ca2+ overload in the cultured neurons. In addition, PGSF partially blocked the excess activity of NMDARs, inhibited both the downregulation of NMDAR subunit NR2A expression and the upregulation of NMDAR subunit NR2B expression, and upregulated the expression of phosphorylated cyclic adenosine monophosphate-responsive element-binding protein and brain-derived neurotrophic factor. These findings suggest that PGSF protects cultured hippocampal neurons against glutamate-induced cytotoxicity by regulating NMDARs. The study was approved by the Institutional Animal Care Committee of Nanchang University (approval No. 2017-0006) on December 29, 2017.

The Candidate Schizophrenia Risk Gene Tmem108 Regulates Glucose Metabolism Homeostasis.

Background: Schizophrenia (SCZ) is a severe psychiatric disease affected by genetic factors and environmental contributors, and premorbid abnormality of glucose metabolism is one of the SCZ characteristics supposed to contribute to the disease's pathological process. Transmembrane protein 108 (Tmem108) is a susceptible gene associated with multiple psychiatric diseases, including SCZ. Moreover, Tmem108 mutant mice exhibit SCZ-like behaviors in the measurement of sensorimotor gating. However, it is unknown whether Tmem108 regulates glucose metabolism homeostasis while it involves SCZ pathophysiological process. Results: In this research, we found that Tmem108 mutant mice exhibited glucose intolerance, insulin resistance, and disturbed metabolic homeostasis. Food and oxygen consumption decreased, and urine production increased, accompanied by weak fatigue resistance in the mutant mice. Simultaneously, the glucose metabolic pathway was enhanced, and lipid metabolism decreased in the mutant mice, consistent with the elevated respiratory exchange ratio (RER). Furthermore, metformin attenuated plasma glucose levels and improved sensorimotor gating in Tmem108 mutant mice. Conclusions: Hyperglycemia occurs more often in SCZ patients than in control, implying that these two diseases share common biological mechanisms, here we demonstrate that the Tmem108 mutant may represent such a comorbid mechanism.

Neurons in Primary Motor Cortex Encode External Perturbations during an Orientation Reaching Task.

When confronting an abrupt external perturbation force during movement, subjects continuously adjust their behaviors to adapt to changes. Such adaptation is of great importance for realizing flexible motor control in varied environments, but the potential cortical neuronal mechanisms behind it have not yet been elucidated. Aiming to reveal potential neural control system compensation for external disturbances, we applied an external orientation perturbation while monkeys performed an orientation reaching task and simultaneously recorded the neural activity in the primary motor cortex (M1). We found that a subpopulation of neurons in the primary motor cortex specially created a time-locked activity in response to a "go" signal in the adaptation phase of the impending orientation perturbation and did not react to a "go" signal under the normal task condition without perturbation. Such neuronal activity was amplified as the alteration was processed and retained in the extinction phase; then, the activity gradually faded out. The increases in activity during the adaptation to the orientation perturbation may prepare the system for the impending response. Our work provides important evidence for understanding how the motor cortex responds to external perturbations and should advance research about the neurophysiological mechanisms underlying motor learning and adaptation.

Antidiabetic effect of an engineered bacterium Lactobacillus plantarum-pMG36e -GLP-1 in monkey model.

Glucagon-like peptide-1 (GLP-1) reduces postprandial hyperglycaemia, but its short half-life inhibits clinical application. The aim of the current study was to evaluate the treatment efforts of an engineered strain, Lactobacillus plantarum-pMG36e-GLP-1 (L. plantarum-pMG36e-GLP-1), that continuously expresses GLP-1 in spontaneous type 2 diabetes mellitus (T2DM) monkeys. After 7 weeks of oral supplementation with L. plantarum-pMG36e-GLP-1, the fasting blood glucose (FPG) of monkeys was significantly (p < 0.05) reduced to a normal level and only a small amount of weight was lost. The results of metagenomic sequencing showed that L. plantarum-pMG36e-GLP-1 caused a substantial (p < 0.05) reduction in the intestinal pathogen Prevotella and marked enhancement of butyrate-producing Alistipes genera. According to the functional analysis using Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathways, 19 metabolism-related pathways were significantly enriched in T2DM monkeys after treatment with L. plantarum-pMG36e-GLP-1. LC-MS faecal metabolomics analysis found 41 significant differential metabolites (11 higher and 30 lower) in monkeys after treatment pathways linked to the metabolism of cofactors and vitamins were the most relevant. The present study suggests that L. plantarum-pMG36e-GLP-1 had an impact on the gut microbial composition and faecal metabolomic profile in spontaneous T2DM monkeys and may be a novel candidate for diabetes treatment.

Rhesus Monkeys Have a Counting Ability and Can Count from One to Six.

Counting ability is one of the many aspects of animal cognition and has enjoyed great interest over the last couple of decades. The impetus for studying counting ability in nonhuman animals has likely come from more than a general interest in animal cognition, as the analysis of animal abilities amplifies our understanding of human cognition. In addition, a model animal with the ability to count could be used to replace human subjects in related studies. Here we designed a behavioral paradigm to train rhesus monkeys to count 1-to-6 visual patterns presented sequentially with long and irregular interpattern intervals on a touch screen. The monkeys were required to make a response to the sixth pattern exclusively, inhibiting response to any patterns appearing at other ordinal positions. All stimulus patterns were of the same size, color, location, and shape to prevent monkeys making the right choice due to non-number physical cues. In the long delay period, the monkey had to enumerate how many patterns had been presented sequentially and had to remember in which ordinal position the current pattern was located. Otherwise, it was impossible for them to know which pattern was the target one. The results show that all three monkeys learned to correctly choose the sixth pattern within 3 months. This study provides convincing behavioral evidence that rhesus monkeys may have the capacity to count.

Reduction in post-spinal cord injury spasticity by combination of peripheral nerve grafting and acidic fibroblast growth factor infusion in monkeys.

OBJECTIVE: Spasticity is a frequent complication after spinal cord injury (SCI), but the existing therapies provide only limited relief and are associated with adverse reactions. Therefore, we aimed to develop a novel strategy to ameliorate the spasticity induced by SCI. METHODS: This nonrandomized controlled study used a repeated measurement design. The study involved four monkeys, two of which served as controls and only underwent spinal cord hemisection surgery at the T8 spine level. The other two monkeys underwent transplantation of sural nerve segments into the injured sites and long-term infusion of acidic fibroblast growth factor (aFGF). All monkeys received postoperative exercise training and therapy. RESULTS: The combined therapy substantially reduced the spasticity in leg muscle tone, patella tendon reflex, and fanning of toes. Although all monkeys showed spontaneous recovery of function over time, the recovery in the controls reached a plateau and started to decline after 11 weeks. CONCLUSIONS: The combination of peripheral nerve grafting and aFGF infusion may serve as a complementary approach to reduce the signs of spasticity in patients with SCI.