Translational validity and methodological underreporting in animal research:A systematic review and meta-analysis of the Fragile X syndrome (Fmr1 KO) rodent model

Predictive models are essential for advancing knowledge of brain disorders. High variation in study outcomes hampers progress. To address the validity of predictive models, we performed a systematic review and meta-analysis on behavioural phenotypes of the knock-out rodent model for Fragile X syndrome according to the PRISMA reporting guidelines. In addition, factors accountable for the heterogeneity between findings were analyzed. The knock-out model showed good translational validity and replicability for hyperactivity, cognitive and seizure phenotypes. Despite low replicability, translational validity was also found for social behaviour and sensory sensitivity, but not for attention, aggression and cognitive flexibility. Anxiety, acoustic startle and prepulse inhibition phenotypes, despite low replicability, were opposite to patient symptomatology. Subgroup analyses for experimental factors moderately explain the low replicability, these analyses were hindered by under-reporting of methodologies and environmental conditions. Together, the model has translational validity for most clinical phenotypes, but caution must be taken due to low effect sizes and high inter-study variability. These findings should be considered in view of other rodent models in preclinical research

ICDP workshop on the Deep Drilling in the Turkana Basin Project:Exploring the link between environmental factors and hominin evolution over the past 4 Myr

Scientific drill cores provide unique windows into the processes of the past and present. In the dynamic tectonic, environmental, climatic, and ecological setting that is eastern Africa, records recovered through scientific drilling enable us to look at change through time in unprecedented ways. Cores from the East African Rift System can provide valuable information about the context in which hominins evolved in one of the key regions of hominin evolution over the past 4 Myr. The Deep Drilling in the Turkana Basin (DDTB) project seeks to explore the impact of several types of evolution (tectonic, climatic, biological) on ecosystems and environments. This includes addressing questions regarding the region’s complex and interrelated rifting and magmatic history, as well as understanding processes of sedimentation and associated hydrothermal systems within the East African Rift System. We seek to determine the relative impacts of tectonic and climatic evolution on eastern African ecosystems. We ask, what role (if any) did climate change play in the evolution of hominins? How can our understanding of past environmental change guide our planning for a future shaped by anthropogenic climate change? To organize the scientific community’s goals for deep coring in the Turkana Basin, we hosted a 4-day ICDP supported workshop in Nairobi, Kenya in July 2022. The team focused on how a 4 Myr sedimentary core from the Turkana Basin will uniquely address key scientific research objectives related to basin evolution, paleoclimate, paleoenvironment, and modern resources. Participants also discussed how DDTB could collaborate with community partners in the Turkana Basin, particularly around the themes of access to water and education. The team concluded that collecting the proposed Pliocene to modern record is best accomplished through a 2-phase drilling project with a land-based transect of four cores spanning the interval from 4 Ma to Middle/Late Pleistocene (<0.7 Ma) and a lake-based core targeting the interval from ~1 Ma to present. The second phase, while logistically more challenging due to the lack of drilling infrastructure currently on Lake Turkana, would revolutionize our understanding of a significant interval in the evolution and migration of Homo sapiens for a time period not currently accessible from the Kenyan part of the Turkana Basin. Collectively, the DDTB project will provide exceptional tectonic and climatic data directly associated with one of the world’s richest hominin fossil localities

ICDP workshop on the Deep Drilling in the Turkana Basin Project:Exploring the link between environmental factors and hominin evolution over the past 4 Myr

Scientific drill cores provide unique windows into the processes of the past and present. In the dynamic tectonic, environmental, climatic, and ecological setting that is eastern Africa, records recovered through scientific drilling enable us to look at change through time in unprecedented ways. Cores from the East African Rift System can provide valuable information about the context in which hominins evolved in one of the key regions of hominin evolution over the past 4 Myr. The Deep Drilling in the Turkana Basin (DDTB) project seeks to explore the impact of several types of evolution (tectonic, climatic, biological) on ecosystems and environments. This includes addressing questions regarding the region’s complex and interrelated rifting and magmatic history, as well as understanding processes of sedimentation and associated hydrothermal systems within the East African Rift System. We seek to determine the relative impacts of tectonic and climatic evolution on eastern African ecosystems. We ask, what role (if any) did climate change play in the evolution of hominins? How can our understanding of past environmental change guide our planning for a future shaped by anthropogenic climate change? To organize the scientific community’s goals for deep coring in the Turkana Basin, we hosted a 4-day ICDP supported workshop in Nairobi, Kenya in July 2022. The team focused on how a 4 Myr sedimentary core from the Turkana Basin will uniquely address key scientific research objectives related to basin evolution, paleoclimate, paleoenvironment, and modern resources. Participants also discussed how DDTB could collaborate with community partners in the Turkana Basin, particularly around the themes of access to water and education. The team concluded that collecting the proposed Pliocene to modern record is best accomplished through a 2-phase drilling project with a land-based transect of four cores spanning the interval from 4 Ma to Middle/Late Pleistocene (<0.7 Ma) and a lake-based core targeting the interval from ~1 Ma to present. The second phase, while logistically more challenging due to the lack of drilling infrastructure currently on Lake Turkana, would revolutionize our understanding of a significant interval in the evolution and migration of Homo sapiens for a time period not currently accessible from the Kenyan part of the Turkana Basin. Collectively, the DDTB project will provide exceptional tectonic and climatic data directly associated with one of the world’s richest hominin fossil localities

Three-body resonances in He-6, Li-6, and Be-6, and the soft dipole mode problem of neutron halo nuclei

Using the complex scaling method, the low-lying three-body resonances of $^6$He, $^6$Li, and $^6$Be are investigated in a parameter-free microscopic three-cluster model. In $^6$He a 2$^+$, in $^6$Li a 2$^+$ and a 1$^+$, and in $^6$Be the 0$^+$ ground state and a 2$^+$ excited state is found. The other experimentally known 2$^+$ state of $^6$Li cannot be localized by our present method. We have found no indication for the existence of the predicted 1$^-$ soft dipole state in $^6$He. We argue that the sequential decay mode of $^6$He through the resonant states of its two-body subsystem can lead to peaks in the excitation function. This process can explain the experimental results in the case of $^{11}$Li, too. We propose an experimental analysis, which can decide between the soft dipole mode and the sequential decay mode.Comment: REVTEX, Submitted to Phys. Rev. C, 12 pages, 2 postscript figures are available upon request. CALTECH, MAP-16

Associations between regular cannabis use and brain resting-state functional connectivity in adolescents and adults

Background/aim: Cannabis use is highly prevalent in adolescents; however, little is known about its effects on adolescent brain function. Method: Resting-state functional magnetic resonance imaging was used in matched groups of regular cannabis users (N = 70, 35 adolescents: 16–17 years old, 35 adults: 26–29 years old) and non-regular-using controls (N = 70, 35 adolescents/35 adults). Pre-registered analyses examined the connectivity of seven major cortical and sub-cortical brain networks (default mode network, executive control network (ECN), salience network, hippocampal network and three striatal networks) using seed-based analysis methods with cross-sectional comparisons between user groups and age groups. Results: The regular cannabis use group (across both age groups), relative to controls, showed localised increases in connectivity only in the ECN analysis. All networks showed localised connectivity differences based on age group, with the adolescents generally showing weaker connectivity than adults, consistent with the developmental effects. Mean connectivity across entire network regions of interest (ROIs) was also significantly decreased in the ECN in adolescents. However, there were no significant interactions found between age group and user group in any of the seed-based or ROI analyses. There were also no associations found between cannabis use frequency and any of the derived connectivity measures. Conclusion: Regular cannabis use is associated with changes in connectivity of the ECN, which may reflect allostatic or compensatory changes in response to regular cannabis intoxication. However, these associations were not significantly different in adolescents compared to adults.</p

Associations between regular cannabis use and brain resting-state functional connectivity in adolescents and adults

BACKGROUND/AIM: Cannabis use is highly prevalent in adolescents; however, little is known about its effects on adolescent brain function. METHOD: Resting-state functional magnetic resonance imaging was used in matched groups of regular cannabis users (N = 70, 35 adolescents: 16-17 years old, 35 adults: 26-29 years old) and non-regular-using controls (N = 70, 35 adolescents/35 adults). Pre-registered analyses examined the connectivity of seven major cortical and sub-cortical brain networks (default mode network, executive control network (ECN), salience network, hippocampal network and three striatal networks) using seed-based analysis methods with cross-sectional comparisons between user groups and age groups. RESULTS: The regular cannabis use group (across both age groups), relative to controls, showed localised increases in connectivity only in the ECN analysis. All networks showed localised connectivity differences based on age group, with the adolescents generally showing weaker connectivity than adults, consistent with the developmental effects. Mean connectivity across entire network regions of interest (ROIs) was also significantly decreased in the ECN in adolescents. However, there were no significant interactions found between age group and user group in any of the seed-based or ROI analyses. There were also no associations found between cannabis use frequency and any of the derived connectivity measures. CONCLUSION: Regular cannabis use is associated with changes in connectivity of the ECN, which may reflect allostatic or compensatory changes in response to regular cannabis intoxication. However, these associations were not significantly different in adolescents compared to adults

Anhedonia, apathy, pleasure, and effort-based decision-making in adult and adolescent cannabis users and controls

BACKGROUND: Cannabis use may be linked with anhedonia and apathy. However, previous studies have shown mixed results and few have examined the association between cannabis use and specific reward sub-processes. Adolescents may be more vulnerable to harmful effects of cannabis than adults. This study investigated (1) the association between non-acute cannabis use and apathy, anhedonia, pleasure, and effort-based decision-making for reward, and (2) whether these relationships were moderated by age-group. METHODS: We used data from the 'CannTeen' study. Participants were 274 adult (26-29 years) and adolescent (16-17 years) cannabis users (1-7 days/week use in the past three months), and gender- and age-matched controls. Anhedonia was measured with the Snaith-Hamilton Pleasure Scale (n=274), and apathy was measured with the Apathy Evaluation Scale (n=215). Effort-based decision-making for reward was measured with the Physical Effort task (n=139), and subjective wanting and liking of rewards was measured with the novel Real Reward Pleasure task (n=137). RESULTS: Controls had higher levels of anhedonia than cannabis users (F1,258=5.35, p=.02, ηp2=.02). There were no other significant effects of User-Group and no significant User-Group*Age-Group interactions. Null findings were supported by post hoc Bayesian analyses. CONCLUSION: Our results suggest that cannabis use at a frequency of three to four days per week is not associated with apathy, effort-based decision-making for reward, reward wanting, or reward liking in adults or adolescents. Cannabis users had lower anhedonia than controls, albeit at a small effect size. These findings are not consistent with the hypothesis that non-acute cannabis use is associated with amotivation

Removing the Microlensing Blending-Parallax Degeneracy Using Source Variability

Microlensing event MACHO 97-SMC-1 is one of the rare microlensing events for which the source is a variable star, simply because most variable stars are systematically eliminated from microlensing studies. Using observational data for this event, we show that the intrinsic variability of a microlensed star is a powerful tool to constrain the nature of the lens by breaking the degeneracy between the microlens parallax and the blended light. We also present a statistical test for discriminating the location of the lens based on the \chi^2 contours of the vector \Lambda, the inverse of the projected velocity. We find that while SMC self lensing is somewhat favored over halo lensing, neither location can be ruled out with good confidence.Comment: 15 text pages + 2 tables + 7 figures. Published in the Astrophysical Journa

EEG-based visual deviance detection in freely behaving mice

The mouse is widely used as an experimental model to study visual processing. To probe how the visual system detects changes in the environment, functional paradigms in freely behaving mice are strongly needed. We developed and validated the first EEG-based method to investigate visual deviance detection in freely behaving mice. Mice with EEG implants were exposed to a visual deviant detection paradigm that involved changes in light intensity as standard and deviant stimuli. By subtracting the standard from the deviant evoked waveform, deviant detection was evident as bi-phasic negativity (starting around 70 ms) in the difference waveform. Additionally, deviance-associated evoked (beta/gamma) and induced (gamma) oscillatory responses were found. We showed that the results were stimulus-independent by applying a "flip-flop " design and the results showed good repeatability in an independent measurement. Together, we put forward a validated, easy-to-use paradigm to measure visual deviance processing in freely behaving mice.Functional Genomics of Muscle, Nerve and Brain Disorder

GDP/GTP exchange factor MADD drives activation and recruitment of secretory Rab GTPases to Weibel-Palade bodies.

von Willebrand factor (VWF) is an essential hemostatic protein that is synthesized and secreted by endothelial cells and stored in Weibel-Palade bodies (WPBs). The secretory Rab GTPases Rab27A, Rab3B, and Rab3D have been linked with WPB trafficking and secretion. How these Rabs are activated and recruited to WPBs remains elusive. In this study, we identified MAP kinase-activating death domain (MADD) as the guanine nucleotide exchange factor for Rab27A and both Rab3 isoforms in primary human endothelial cells. Rab activity assays revealed a reduction in Rab27A, Rab3B, and Rab3D activation upon MADD silencing. Rab activation, but not binding, was dependent on the differentially expressed in normal and neoplastic cells (DENN) domain of MADD, indicating the potential existence of 2 Rab interaction modules. Furthermore, immunofluorescent analysis showed that Rab27A, Rab3B, and Rab3D recruitment to WPBs was dramatically decreased upon MADD knockdown, revealing that MADD drives Rab membrane targeting. Artificial mistargeting of MADD using a TOMM70 tag abolished Rab27A localization to WPB membranes in a DENN domain-dependent manner, indicating that normal MADD localization in the cytosol is crucial. Activation of Rab3B and Rab3D was reduced upon Rab27A silencing, suggesting that activation of these Rabs is enhanced through previous activation of Rab27A by MADD. MADD silencing did not affect WPB morphology, but it did reduce VWF intracellular content. Furthermore, MADD-depleted cells exhibited decreased histamine-evoked VWF release, similar to Rab27A-depleted cells. In conclusion, MADD acts as a master regulator of VWF secretion by coordinating the activation and membrane targeting of secretory Rabs to WPBs