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

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

Combined Analysis of the Binary-Lens Caustic-Crossing Event MACHO 98-SMC-1

We fit the data for the binary-lens microlensing event MACHO 98-SMC-1 from 5 different microlensing collaborations and find two distinct solutions characterized by binary separation d and mass ratio q: (d,q)=(0.54,0.50) and (d,q)=(3.65,0.36), where d is in units of the Einstein radius. However, the relative proper motion of the lens is very similar in the two solutions, 1.30 km/s/kpc and 1.48 km/s/kpc, thus confirming that the lens is in the Small Magellanic Cloud. The close binary can be either rotating or approximately static but the wide binary must be rotating at close its maximum allowed rate to be consistent with all the data. We measure limb-darkening coefficients for five bands ranging from I to V. As expected, these progressively decrease with rising wavelength. This is the first measurement of limb darkening for a metal-poor A star.Comment: 29 pages + 9 figures + 2 tables, submitted to Ap

Molecular Assessment of Bacterial Vaginosis by Lactobacillus Abundance and Species Diversity

Background To date, women are most often diagnosed with bacterial vaginosis (BV) using microscopy based Nugent scoring or Amsel criteria. However, the accuracy is less than optimal. The aim of the present study was to confirm the identity of known BV-associated composition profiles and evaluate indicators for BV using three molecular methods. Methods Evaluation of indicators for BV was carried out by 16S rRNA amplicon sequencing of the V5-V7 region, a tailor-made 16S rRNA oligonucleotide-based microarray, and a PCR-based profiling technique termed IS-profiling, which is based on fragment variability of the 16S-23S rRNA intergenic spacer region. An inventory of vaginal bacterial species was obtained from 40 females attending a Dutch sexually transmitted infection outpatient clinic, of which 20 diagnosed with BV (Nugent score 7–10), and 20 BV negative (Nugent score 0–3). Results Analysis of the bacterial communities by 16S rRNA amplicon sequencing revealed two clusters in the BV negative women, dominated by either Lactobacillus iners or Lactobacillus crispatus and three distinct clusters in the BV positive women. In the former, there was a virtually complete, negative correlation between L. crispatus and L. iners. BV positive subjects showed cluster profiles that were relatively high in bacterial species diversity and dominated by anaerobic species, including Gardnerella vaginalis, and those belonging to the Families of Lachnospiraceae and Leptotrichiaceae. Accordingly, the Gini-Simpson index of species diversity, and the relative abundance Lactobacillus species appeared consistent indicators for BV. Under the conditions used, only the 16S rRNA amplicon sequencing method was suitable to assess species diversity, while all three molecular composition profiling methods were able to indicate Lactobacillus abundance in the vaginal microbiota. Conclusion An affordable and simple molecular test showing a depletion of the genus Lactobacillus in combination with an increased species diversity of vaginal microbiota could serve as an alternative and practical diagnostic method for the assessment of BV

Organotypic Brain Cultures for Metastasis Research

We thank members of Brain Metastasis Group for critical discussion. Research in the Brain Metastasis Group is supported by MINECO-Retos SAF2017-89643-R (M.V.), Cancer Research Institute CLIP Award 2018 (M.V.), AECC (GCTRA16015SEOA) (M.V.), Bristol-Myers Squibb Melanoma Research Alliance Young Investigator Award 2017 (M.V.), Beug Foundation’s Prize for Metastasis Research 2017 (M.V.), Worldwide Cancer Research (19-0177) (M.V.), H2020-FETOPEN (828972) (M.V.), Fundación Ramón Areces (CIVP19S8163), and La Caixa-Severo Ochoa International PhD Program Fellowship (L.Z.). M.V. is a Ramón y Cajal Investigator (RYC-2013-13365) and an EMBO YIP investigator.N