Miracle-dz/UniFAR-FTUs huggingface dataset:
Incorporating knowledge of plates in batch normalization improves generalization of deep learning for microscopy images

Data collected by high-throughput microscopy experiments are affected by batch effects, stemming from slight technical differences between experimental batches. Batch effects significantly impede machine learning efforts, as models learn spurious technical variation that do not generalize. We introduce batch effects normalization (BEN), a simple method for correcting batch effects that can be applied to any neural network with batch normalization (BN) layers. BEN aligns the concept of a “batch” in biological experiments with that of a “batch” in deep learning. During each training step, data points forming the deep learning batch are always sampled from the same experimental batch. This small tweak turns the batch normalization layers into an estimate of the shared batch effects between images, allowing for these technical effects to be standardized out during training and inference. We demonstrate that BEN results in dramatic performance boosts in both supervised and unsupervised learning, leading to state-of-the-art performance on the RxRx1-Wilds benchmark.1
Canonical and Non-Canonical Psychedelic Drugs Induce Common Network Changes in Human Cortex

The neurobiology of the psychedelic experience is not fully elucidated. Identifying common brain network changes induced by both canonical (i.e., acting at the 5-HT2 receptor) and non-canonical psychedelics would provide mechanistic insight into state-specific characteristics. We analyzed whole-brain functional connectivity based on resting-state fMRI data in humans, acquired before and during the administration of nitrous oxide, ketamine, and lysergic acid diethylamide. We report that, despite distinct molecular mechanisms and modes of delivery, all three psychedelics reduced within-network functional connectivity and enhanced between-network functional connectivity. More specifically, all drugs tested increased connectivity between right temporoparietal junction and bilateral intraparietal sulcus as well as between precuneus and left intraparietal sulcus. These regions fall within the posterior cortical “hot zone,” posited to mediate the content of consciousness. Thus, both canonical and non-canonical psychedelics modulate networks within an area of known relevance for conscious experience, identifying a biologically plausible candidate for their subjective effects.
Inferring transmission routes for foot-and-mouth disease virus within a cattle herd using approximate Bayesian computation

To control an outbreak of an infectious disease it is essential to understand the different routes of transmission and how they contribute to the overall spread of the pathogen. With this information, policy makers can choose the most efficient methods of detection and control during an outbreak. Here we demonstrate a method for assessing the contribution of different routes of transmission using approximate Bayesian computation with sequential Monte Carlo sampling (ABC-SMC). We apply this to infer parameters of an individual based model of within-herd transmission of foot-and-mouth disease virus (FMDV), incorporating transmission through direct contact and via environmental contamination. Additionally, we use ABC-SMC for model selection to assess the plausibility of either transmission route alone being responsible for all infections. We show that direct transmission likely contributes the majority of infections during an outbreak of FMD but there is an accumulation of environmental contamination that can cause infections within a farm and also have the potential to spread between farms via fomites.
Opto-RhoGEFs, an optimized optogenetic toolbox to reversibly control Rho GTPase activity on a global to subcellular scale, enabling precise control over vascular endothelial barrier strength

The inner layer of blood vessels consists of endothelial cells, which form the physical barrier between blood and tissue. This vascular barrier is tightly regulated to allow the passage of essential molecules like oxygen, carbon-dioxide, water, ions, and nutrients. The vascular endothelial barrier is defined by cell-cell contacts through adherens and tight junctions. To further investigate the signaling in the endothelium that regulates vascular barrier strength, we focused on Rho GTPases, regulators of the actin cytoskeleton and known to control junction integrity. Rho GTPase signaling is confined in space and time. To manipulate the signaling in a temporal and spatial manner we applied optogenetics. Guanine exchange factor (GEF) domains from ITSN1, TIAM1 and p63RhoGEF, activating Cdc42, Rac and Rho respectively, were integrated into the optogenetic recruitment tool iLID. This tool allows for activation at the subcellular level in a reversible and non-invasive manner and thereby to recruit a GEF to local areas at the plasma membrane, enabling the local activation of specific Rho GTPases. The membrane tag of iLID was optimized and a HaloTag was applied to gain more flexibility for multiplex imaging. The resulting Opto-RhoGEFs were tested in an endothelial cell monolayer and demonstrated precise temporal control of vascular barrier strength by a cell-cell overlap-dependent, VE-cadherin-independent, mechanism. Furthermore, Opto-RhoGEFs enabled precise optogenetic control in endothelial cells over morphological features such as cell-size, -roundness, local extension, and cell contraction. In conclusion, we have optimized and applied the optogenetic iLID GEF recruitment tool i.e. Opto-RhoGEFs, to study the role of Rho GTPases in the vascular barrier of the endothelium and found that membrane protrusions at the junction region can rapidly increase barrier integrity independent of VE-cadherin.
Divorce rate in birds increases with male promiscuity and migration distance

Socially monogamous animals may break up their partnership after one breeding season by a so-called ‘divorce’ behaviour. Divorce rate immensely varies across avian taxa that have a predominantly monogamous social mating system. Although a range of factors associated with divorce have been tested, there is not a consensus regarding the large-scale variation and relationships among associated factors. Moreover, the impact of sexual roles in divorce still needs further investigation. Here, we applied phylogenetic comparative methods to analyze one of the largest datasets ever compiled that included divorce rates from published case studies of 232 avian species from 25 orders and 61 families. We tested correlations between divorce rate and a group of factors that are closely related to pair bond strength: promiscuity of both sexes, migration distance, and adult mortality. Our results showed that only male promiscuity, but not female promiscuity, had a critical relationship with divorce rate. Furthermore, migration distance was positively correlated with divorce rate and indirectly affected divorce rate via male promiscuity. These findings indicated that divorce might not be simply explained as an adaptive strategy or neutral occurrence, but could be a mixed response to sexual conflict and stress from the ambient environment.
A novel brain penetrant PDGFRα inhibitor HY-008 is effective against glioblastoma

Background Glioblastoma multiforme (GBM) is the most common primary intracranial malignant tumor in adults, with poor prognosis and high recurrence. Routine treatments of GBM show unsatisfactory efficiency in improving patients’ survival because of limited area of surgical resection and drug resistance. New therapeutic agents are needed to improve GBM treatment efficiency, but the blood-brain barrier (BBB) permeability is a major hurdle. Here, we report HY-008 as a promising therapeutic drug targeting PDGFRα signaling with high BBB permeability and efficient inhibiting effects both in vitro and in vivo. Methods Through structural modification and medicinal chemistry efforts, HY-007 and HY-008 were developed. The brain and plasma pharmacokinetic profiles of these two compounds were assessed. The inhibitory efficiency of HY-007 and HY-008 on GBM cell survival and PDGFRα signaling were evaluated. The efficacy of HY-007 and HY-008 as a single agent or HY-008 in combination with temozolomide (TMZ) was investigated using transformed mouse astrocyte and glioma stem-like cell (GSC) orthotopic xenograft models. Results HY-007 and HY-008 both had good brain permeability and desirable PK profiles with mild hERG inhibition, while HY-008 is more brain permeable than HY-007. In vitro, HY-007 and HY-008 both significantly inhibited viability of the established GBM cells with PDGF-A overexpression and transformed mouse astrocytes with PDGF-A/PDGFRα overexpression by targeting the PDGFRα signaling activated Erk1/2 and Akt. In vivo, HY-007 and HY-008 both effectively inhibited orthotopic GBM tumor xenograft growth and prolonged the survival of mice, and HY-008 showed less toxicity and better therapeutic effect. In addition, HY-008 increased sensitivity of TMZ, exhibited treatment efficiency both as a single agent and in combination with TMZ, providing significant survival benefits for GBM tumor xenograft-bearing mice. Conclusions Our data demonstrate that HY-008 is a promising therapeutic agent in GBM treatment and a combination HY-008 with TMZ could serves as a potential efficient therapeutic option for improving GBM clinical treatment.
Identifying cell culturing parameters that improve endocytic uptake of the HIV-TAT cell penetrating peptide

Delivery tools, including cell-penetrating peptides (CPPs) are often inefficient due to a combination of poor endocytosis and endosomal escape. Herein, the impact of cell culturing techniques on the endocytic uptake of a typical CPP, the TAT peptide (derived from HIV1-TAT), was quantified. Parameters previously found to generally modulate endocytosis such as cell density, washing steps, and cell aging did not affect TAT endocytosis. In contrast, cell dissociation methods, media, temperature, serum starvation, and media composition all contributed to changes in uptake. The combination of these parameters in worst versus best-uptake protocols, led to changes in uptake of more than 13-fold and indicated that small variations in cell culturing techniques have a cumulative effect on CPP uptake. More specifically, modulating cell culture protocols does not result in an increased amount of peptide inside endosomes, rather the number of TMR-TAT containing endosomes increases. Taken together this study highlights how technical aspects of cell culture protocols can be used to improve experimental reproducibility, as well as parameters that can be potentially exploited to improve CPP accumulation in endosomes, and hence increase the possibility of endosomal escape and cytosolic access.
Efficient simulation of neural development using shared memory parallelization

The Neural Development Simulator, NeuroDevSim, is a Python module that simulates the most important aspects of development: growth, migration and pruning. It uses an agent-based modeling approach inherited from the NeuroMaC software. Each cycle, agents called fronts execute code. In the case of a growing dendritic or axonal front this will be a choice between extension, branching or growth termination. Somatic fronts can migrate to new positions and any front can be retracted to prune parts of neurons. NeuroDevSim is a multi-core program that uses an innovative shared memory approach to achieve parallel processing without messaging. We demonstrate close to linear strong scaling for medium size models for up to 32 cores and have run large models successfully on 128 cores. Most of the shared memory parallelism is achieved without memory locking. Instead cores have write privileges to private sections of arrays only, while being able to read the entire shared array. Memory conflicts are avoided by a coding rule that allows only active fronts to use methods that need writing access. The exception is collision detection, which is needed to avoid growth of physically overlapping structures. Here a locking mechanism was necessary to control access to grid points that register the location of nearby fronts. A custom approach using a serialized lock broker was able to manage both read and write locking. NeuroDevSim allows easy modeling of neural development for models ranging from a few complex to thousands of simple neurons or a mixture of both.
Variability of visual field maps in human early extrastriate cortex challenges the canonical model of organization of V2 and V3

Visual field maps in human early extrastriate areas (V2 and V3) are traditionally thought to form mirror-image representations which surround the primary visual cortex (V1). According to this scheme, V2 and V3 form nearly symmetrical halves with respect to the calcarine sulcus, with the dorsal halves representing lower contralateral quadrants, and the ventral halves representing upper contralateral quadrants. This arrangement is considered to be consistent across individuals, and thus predictable with reasonable accuracy using templates. However, data that deviate from this expected pattern have been observed, but mainly treated as artifactual. Here we systematically investigate individual variability in the visual field maps of human early visual cortex using the 7T Human Connectome Project (HCP) retinotopy dataset. Our results demonstrate substantial and principled inter-individual variability. Visual field representation in the dorsal portions of V2 and V3 was more variable than in their ventral counterparts, including substantial departures from the expected mirror-symmetrical patterns. In addition, left hemisphere retinotopic maps were more variable than those in the right hemisphere. Surprisingly, only one-third of individuals had maps that conformed to the expected pattern in the left hemisphere. Visual field sign analysis further revealed that in many individuals the area conventionally identified as dorsal V3 shows a discontinuity in the mirror-image representation of the retina, associated with a Y-shaped lower vertical representation. Our findings challenge the current view that inter-individual variability in early extrastriate cortex is negligible, and that the dorsal portions of V2 and V3 are roughly mirror images of their ventral counterparts.
Presymptomatic neuroanatomical and cognitive biomarkers of alpha-synuclein propagation in a mouse model of synucleinopathy

There is significant evidence suggesting aggregated misfolded alpha-synuclein, a major component of Lewy bodies, propagates in a prion-like manner contributing to disease progression in Parkinson’s disease (PD) and other synucleinopathies. Animal models are essential for understanding and developing treatments for these diseases. However, despite modelling human pathology, most endpoints studied in mice do not translate to humans. Furthermore, the progression by which alpha-synuclein misfolding affects human-relevant measures such as brain volume and underlying subtle, high-level cognitive deficits is poorly understood. Here we used a mouse model of synucleinopathy; hemizygous M83 human A53T alpha-synuclein transgenic mice inoculated with recombinant human alpha-synuclein preformed fibrils (PFF) injected in the right striatum to initiate alpha-synuclein misfolding and aggregation. We examined alpha-synuclein-induced atrophy at 90 days post-injection using ex vivo magnetic resonance imaging as well as high-level cognition and motor function, as biomarkers of alpha-synuclein toxicity. We observed widespread atrophy in bilateral regions that project to or receive input from the injection site, highlighting a network of regions that are consistent with structural changes observed in humans with PD. Moreover, we detected early deficits in reversal learning with touchscreen testing in PFF-injected mice prior to motor dysfunction, consistent with the pathology observed in cortical-striatal and thalamic loops. We show, using translational approaches in mice, that progression of prion-like spreading of alpha-synuclein causes selective atrophy via connected brain regions leading to high-level cognitive deficits. We propose that precise imaging and cognitive biomarkers can provide a more direct and human-relevant measurement of alpha-synuclein-induced toxicity in pre-clinical testing. Significance Statement The work described in this manuscript showcases the utility of state-of-the-art methodologies (magnetic resonance imaging and touchscreen behavioural tasks) to examine endophenotypes, both in terms of symptomatology and neuroanatomy, of alpha-synuclein propagation in a mouse model of synucleinopathy. Our work further validates the M83-Hu-PFF mouse model of synucleinopathy-associated pathogenesis of neurodegenerative diseases while highlighting precise imaging and cognitive biomarkers of protein misfolding toxicity. Specifically, we identified rapid and translational biomarkers that can serve as a proxy for the direct examination of cellular levels for pathology. We anticipate that these biomarkers can measure progression of toxicity, specifically in the early phases, and may be more reliable than end stage pathology and more useful as endpoints in the examination of novel therapeutics.
The Impact of Protein Dynamics on Residue-Residue Coevolution and Contact Prediction

The need to maintain protein structure constrains evolution at the sequence level, and patterns of coevolution in homologous protein sequences can be used to predict their 3D structures with high accuracy. Our understanding of the relationship between protein structure and evolution has traditionally been benchmarked by computational models’ ability to predict contacts from a single representative, experimentally determined structure per protein family. However, proteins in vivo are highly dynamic and can adopt multiple functionally relevant conformations. Here we demonstrate that interactions that stabilize alternate conformations, as well those that mediate conformational changes, impose an underappreciated but significant set of evolutionary constraints. We analyze the extent of these constraints over 56 paralogous G protein coupled receptors (GPCRs), β-arrestin and the human SARS-CoV2 receptor ACE2. Specifically, we observe that contacts uniquely found in molecular dynamics (MD) simulation data and alternate-conformation crystal structures are successfully predicted by unsupervised language models. In GPCRs, adding these contacts as positives increases the percentage of top contacts classified as true positives, as predicted by a state-of-the-art language model, from 69% to 87%. Our results show that protein dynamics impose constraints on molecular evolution and demonstrate the ability of unsupervised language models to measure these constraints.
The Golgi complex is a regulatory hub for homologous recombination-mediated DNA repair

The Golgi complex has long been recognised as an important homeostasis hub, where a multitude of signalling pathways and essential cellular processes intersect. Yet its communication with the cell nucleus remains largely unexplored. To this end, we have analysed genome-scale localisation data of the Human Protein Atlas which revealed an unexpected high number of Golgi and nuclear dual-localisation proteins and several pathways including surprising DNA repair. Amongst these proteins we found RAD51C, a regulatory Homologous Recombination (HR) repair protein, that localises to the Golgi and in response to double-strand DNA breaks, the Golgi protein population of RAD51C redistributes to form DNA repair foci. Depletion of the Golgin Giantin induces the redistribution of the RAD51C Golgi pool to form nuclear foci, independent of DNA damage induction. Concurrent with a significant increase in genomic instability and inhibition of HR signalling regulators. Altogether, we present evidence for a novel pathway where the Golgi is a central regulatory hub for HR-mediated DNA repair and potentially other repair pathways.
A metabolomic view on local climate adaptation: Latitudinal divergence of heat and drought responses in a coastal plant

Studying natural variation in multi-stress resistance is central for predicting and managing the population dynamics of wild plant species under rapid global change. Yet, it remains a challenging goal in this field to integrate knowledge on the complex biochemical underpinnings for the targeted ‘non-model’ species. Here, we studied latitudinal divergence in combined drought and heat stress resistance in European populations of the dune plant Cakile maritima, by combining comprehensive plant phenotyping with metabolic profiling via FT-ICR-MS and UPLC-TQ-MS/MS. We observed pronounced constitutive divergence in growth phenology, leaf functional traits and defence chemistry (glucosinolates, alkaloids) among population origins. Most importantly, the magnitude of growth reduction under stress was partly weaker in southern plants and associated with divergence in plastic growth responses (root expansion, leaf abscission) and the stress-induced modulation of primary and specialized metabolites with known central functions not only in plant abiotic but also biotic stress resistance. Our study supports that divergent selection has shaped the constitutive and stress-induced expression of numerous morphological and biochemical functional traits to mediate higher abiotic stress resistance in southern Cakile populations, and highlights that metabolomics is a powerful tool to explore the mechanistic underpinnings of local stress adaptation in ‘non-model’ species. Highlight Plant defence chemistry and its modulation by abiotic stress exhibits latitudinal clines across natural populations of a coastal plant.
Capital structure phenomenon in Indonesia

This study aims to provide empirical evidence regarding the capital structure phenomenon in non-financial sector companies in Indonesia. The study population was all non-financial companies listed on the Indonesia Stock Exchange for the 2014-2018 period. The research sample of 1,770 companies obtained through the purposive sampling method. This research uses descriptive study method. The result of this study show that the basic industry and chemical sectors have the highest average use of debt than other non-financial sectors in the 2014-2018 period. Meanwhile, the consumer goods industry is the non-financial sector, with the lowest average debt utilization level in the 2014-2018 period. This study sees that, in general, the company's capital structure changes with changes in macroeconomic conditions.
Integrated Perception, Planning and Feedback Control for Generalizable Robotic Manipulation

Humans can easily adapt their manipulation skills to unseen objects, new environment and different tasks. However, existing robot manipulators are typically limited to known object instance and skill transferring is challenging. In this thesis, we take a step further by formulating a manipulation framework that can achieve precise, reliable and dexterous manipulation while being generalizable to potentially unknown object instances. To achieve it, we propose keypoint affordances, an object representation consists of 3D semantic keypoints. This object representation captures task-related geometric information while ignoring irrelevant details, which enables our method to handle unknown objects with potentially large shape variations. We implement perception, planning and feedback control modules on top of keypoint affordances and integrate them into a fully functionally perception-toaction manipulation pipeline. Extensive experiments demonstrate our method can reliably accomplish a variety of challenging tasks with never-before seen objects. Thesis Supervisor: Russ Tedrake Title: Professor of Electrical Engineering and Computer Science