Miracle-dz/UniFAR-FTUs huggingface dataset:
Feeling Right: Regulatory Fit Theory and Early-Stage Entrepreneurial Investment Decisions

Abstract Recent advances in entrepreneurial investment decisions research implied that early-stage investment decisions, given their extreme uncertainty and unpredictability, were results of investors’ intuition processes. In other words, investors manage the high risks of early-stage investment decisions by finding justifications of future value against risk in the invested entrepreneurial projects. Although some studies have discussed the decision-making process of mid- and late-stage venture capital, there is still a lack of discussion on the early-stage investment decision-making mechanism. In this paper, we draw on regulatory fit theory to theorize how the fit of regulatory focus between investor and entrepreneur could lead to the investor’s early-stage investment decisions in terms of investment amount and speed. Across three experimental studies, we found empirical support for our proposed model. Specifically, investors who have similar regulatory focus with the entrepreneurs are more likely to invest a larger amount of funds at a faster speed. We further found that investor’s sense of rightness mediates the relationship between regulatory fit and investment decision, and investor’s previous investment experience plays a moderating role.
Dynamic proteomic and phosphoproteomic atlas of corticostriatal axons in neurodevelopment

Mammalian axonal development begins in embryonic stages and continues postnatally. After birth, axonal proteomic landscape changes rapidly, coordinated by transcription, protein turnover, and post-translational modifications. Comprehensive profiling of axonal proteomes across neurodevelopment is limited, with most studies lacking cell-type and neural circuit specificity, resulting in substantial information loss. We create a Cre-dependent APEX2 reporter mouse line and map cell-type specific proteome of corticostriatal projections across postnatal development. We synthesize analysis frameworks to define temporal patterns of axonal proteome and phosphoproteome, identifying co-regulated proteins and phosphorylations associated with genetic risk for human brain disorders. We discover proline-directed kinases as major developmental regulators. APEX2 transgenic reporter proximity labeling offers flexible strategies for subcellular proteomics with cell type specificity in early neurodevelopment, a critical period for neuropsychiatric disease.
Lipolysis of bone marrow adipocytes is required to fuel bone and the marrow niche during energy deficits

To investigate roles for bone marrow adipocyte (BMAd) lipolysis in bone homeostasis, we created a BMAd-specific Cre mouse model in which we knocked out adipose triglyceride lipase (ATGL, Pnpla2). BMAd-Pnpla2-/- mice have impaired BMAd lipolysis, and increased size and number of BMAds at baseline. Although energy from BMAd lipid stores is largely dispensable when mice are fed ad libitum, BMAd lipolysis is necessary to maintain myelopoiesis and bone mass under caloric restriction. BMAd-specific Pnpla2 deficiency compounds the effects of caloric restriction on loss of trabecular bone, likely due to impaired osteoblast expression of collagen genes and reduced osteoid synthesis. RNA sequencing analysis of bone marrow adipose tissue reveals that caloric restriction induces dramatic elevations in extracellular matrix organization and skeletal development genes, and energy from BMAd is required for these adaptations. BMAd-derived energy supply is also required for bone regeneration upon injury, and maintenance of bone mass with cold exposure.
Estimating the time structure of descending activation that generates movements at different speeds

In targeted movements of the hand, descending activation patterns must not only generate muscle activation, but must also adjust spinal reflexes from stabilizing the initial to stabilizing the final postural state. We estimate descending activation patterns that change minimally while generating a targeted movement within a given movement time based on a model of the biomechanics, muscle dynamics, and the stretch reflex. The estimated descending activation patterns predict human movement trajectories quite well. Their temporal structure varies across workspace and with movement speed, from monotonic profiles for slow movements to non-monotonic profiles for fast movements. Descending activation patterns at different speeds thus do not result from a not mere rescaling of invariant templates, but reflect varying needs to compensate for interaction torques and muscle dynamics. The virtual attractor trajectories, on which active muscle torques are zero, lie within reachable workspace and are largely invariant movements when represented in end-effector coordinates. Their temporal structure along movement direction changes from linear ramps to “N-shaped” profiles with increasing movement speed. Author summary What descending patterns of activation drive targeted movements? Based on a model that includes biomechanics, muscles dynamics and the stretch reflex we estimate the descending activation patterns by minimizing their change using optimal control, given a movement target and movement time. The resulting activation patterns predict experimentally observed human movements reasonably well. The temporal structure of the estimated descending activation patterns depends on the speed of the movement, varying from monotonic for slow to non-monotonic for fast movements. This structure reflects the need to compensate for interaction torques and muscle properties. From the model we are able to estimate the virtual attractor trajectories on which all active muscle torques are zero. These lie within reachable workspace, and are relatively uniform across workspace. Their time structure varies from linear ramps for slow movements to N-shaped temporal profiles for fast movements.
Polypyrimidine Tract-Binding Protein 1 (PTBP1) regulates CD4 T cell Activation independent of its role in proliferation

Our previous work found that the RNA binding protein polypyrimidine tract-binding protein (PTBP1) is critical for regulating multiple events in T cell activation including changes in proliferation, and expression of activation markers and cytokines. These changes corresponded to the regulation of the ERK1/2 and NF-κB pathways as well as through changes in steady-state RNA levels. Because proliferation is critical for driving T cell activation, it was unclear whether PTBP1 was required for optimal activation per se or whether changes were secondary to a requirement for initiating/sustaining proliferation. To address this question, the human T cell lymphoma cell line, Jurkat, which recapitulates many of the molecular events of TCR-induced activation, was used to understand how PTBP1 impacts early events in T cell activation with ongoing proliferation. Using two phenotypically distinct Jurkat subclones (D1.1 and B2.7), we first profiled global RNA expression patterns using RNAseq analysis and found marked differences between the two cell lines with the D1.1 line giving a more antigen-experienced phenotype. Reducing PTBP1 by shPTB expression, to 60% WT levels resulted in no significant decrease in proliferation in the two subclones. However, we observed that PTBP1 was required for both optimal expression of activation markers, CD25, CD38, CD69, and CD40L, and signaling through the ERK1/2, P38 and AKT pathways. Importantly, limiting PTBP1 had different effects on the activation signals for each cell line suggesting that the differentiation state of the cell is a critical factor in understanding the role of PTBP1 in T cell activation. This was further reinforced by our finding that PTBP1 regulated distinct groups of genes specific for each line. Together, our findings suggest that PTBP1 regulates specific T cell activation responses independent of its role in proliferation and that the initial phenotype of the T cell plays an essential role in the dependency of the cell on PTBP1 for driving these changes.
A reinforcement learning algorithm shapes maternal care in mice

The neural substrates for processing classical rewards such as food or drugs of abuse are well-understood. In contrast, the mechanisms by which organisms perceive social contact as rewarding and subsequently modify their interactions are unclear. Here we tracked the gradual emergence of a repetitive and highly-stereotyped parental behavior and show that trial-by-trial performance correlates with the history of midbrain dopamine (DA) neuron activity. We used a novel behavior paradigm to manipulate the subject’s expectation of imminent pup contact and show that DA signals conform to reward prediction error, a fundamental component of reinforcement learning (RL). Finally, closed-loop optogenetic inactivation of DA neurons at the onset of pup contact dramatically slowed emergence of parental care. We conclude that this prosocial behavior is shaped by an RL mechanism in which social contact itself is the primary reward. One-Sentence Summary Maternal interactions with offspring are shaped by a dopaminergic reinforcement learning mechanism.
Implicit Versus Explicit Timing – Separate or Shared Mechanisms?

Time implicitly shapes cognition, but time is also explicitly represented, for instance in the form of durations. Parsimoniously, the brain could use the same mechanisms for implicit and explicit timing. Yet, the evidence has been equivocal, revealing both joint versus separate signatures of timing. Here, we directly compared implicit and explicit timing using magnetoencephalography, whose temporal resolution allows investigating the different stages of the timing processes. Implicit temporal predictability was induced in an auditory paradigm by a manipulation of the foreperiod. Participants received two consecutive task instructions: discriminate pitch (indirect measure of implicit timing) or duration (direct measure of explicit timing). The results show that the human brain efficiently extracts implicit temporal statistics of sensory environments, to enhance the behavioral and neural responses to auditory stimuli, but that those temporal predictions did not improve explicit timing. In both tasks, attentional orienting in time during predictive foreperiods was indexed by an increase in alpha power over visual and parietal areas. Furthermore, pre-target induced beta power in sensorimotor and parietal areas increased during implicit compared to explicit timing, in line with the suggested role for beta oscillations in temporal prediction. Interestingly, no distinct neural dynamics emerged when participants explicitly paid attention to time, compared to implicit timing. Our work thus indicates that implicit timing shapes the behavioral and sensory response in an automatic way, and is reflected in oscillatory neural dynamics, while the translation of implicit temporal statistics to explicit durations remains somewhat inconclusive, possibly due to the more abstract nature of this task.
Persistent acetylation of newly synthesized histones inhibits DNA replication origin activity

Histone acetylation is a known regulator of DNA replication dynamics. In the yeast Saccharomyces cerevisiae , newly synthesized histone H3 deposited behind DNA replication forks are acetylated on lysine 56 (H3 K56ac) by the Rtt109 histone acetyltransferase. Two enzymes of the sirtuin family of deacetylases, Hst3 and Hst4, act redundantly to deacetylate this residue throughout chromosomes following S phase. Cells lacking Hst3 and Hst4 present constitutively acetylated H3 K56, which causes sensitivity to replication-blocking genotoxins and slow growth via mechanisms that remain poorly understood. Here, we present the results of a genome-wide screen aimed at identifying haploinsufficient genes that promote cell fitness in response to inhibition of sirtuins by nicotinamide (NAM). We find that heterozygous deletion alleles of genes involved in the regulation of DNA replication origins sensitize cells to NAM. Consistently, haploid cells harboring the hypomorphic temperature sensitive allele cdc7-4 present striking NAM-induced S phase progression defects at their semi-permissive temperature. We further show i) that Rap1-interacting factor 1 (Rif1), an inhibitor of Cdc7-dependent activation of replication origins, causes DNA damage and replication defects in cells exposed to NAM and in hst3 ∆ hst4 ∆ mutants, and ii) that cdc7-4 hst3∆ hst4∆ triple mutant cells present strong synthetic temperature sensitivity associated with defective activation of replication origin and delayed S phase progression. Our data further demonstrate that such replication defects are not due to intra-S phase checkpoint activation leading to inhibition of origin activity. We finally show that Rtt109-dependent acetylation of histone H3 lysine 56 and its associated Rtt101-Mms1 ubiquitin ligase complex cause the DNA replication defects observed in cdc7-4 hst3∆ hst4∆ cells. Overall, these results argue that abnormal regulation of nascent chromatin structure negatively influences DNA replication initiation in cells presenting reduced Dbf4-dependent kinase activity including those experiencing replicative stress.
Deletion of CEP164 in mouse photoreceptors post-ciliogenesis interrupts ciliary intraflagellar transport (IFT)

Centrosomal protein 164 (CEP164) is located at the edge of distal appendages in primary cilia and is necessary for basal body (BB) docking to the apical membrane. To investigate the function of CEP164 before and after BB docking in photoreceptors, we deleted CEP164 during retina embryonic development (Six3Cre), in postnatal rod photoreceptors (iCre75) and in mature retina using tamoxifen induction. BBs dock to the cell cortex during postnatal day 6 (P6) and extend a connecting cilium (CC) and an axoneme. P6 retina-specific knockouts (retCep164-/-) are unable to dock BBs, thereby preventing formation of a CC or outer segments (OS). In rod-specific knockouts (rodCep164-/-), Cre expression starts after P9 and CC/OS form. P16 rodCep164-/- rods have nearly normal OS lengths, and maintain OS attachment through P21 despite loss of CEP164. Intraflagellar transport components (IFT88, IFT57 and IFT140) were reduced at P16 rodCep164-/- BBs and CC tips and nearly absent at P21, indicating impaired intraflagellar transport. Nascent OS discs, labeled with a fluorescent dye on P14 and P18 and harvested on P19, showed continued rodCep164-/- disc morphogenesis but absence of P14 discs mid-distally, indicating OS instability. Tamoxifen induction with PROM1ETCre;Cep164F/F (tamCep164-/-) adult mice affected maintenance of both rod and cone OS. The results suggest that CEP164 is key towards recruitment and stabilization of IFT-B particles at BB/CC. Impairment of IFT may be the main driver of ciliary malfunction observed with hypomorphic CEP164 mutations. Author summary Centrosomal protein of 164 kDa (CEP164) is indispensable for docking of basal bodies to apical membranes and formation of primary cilia. Homozygous truncations of CEP164 are associated with severe ciliopathy whereas missense mutations generate milder forms of NPHP. Recessive mutations of CEP164 are associated with nephronophthisis (NPHP), Meckel-Gruber (MKS) and Bardet-Biedl syndromes (BBS) in which primary cilia fail to form, or do not function correctly. We found that deletion of CEP164 in mouse photoreceptors before docking of the basal body (BB) to the apical inner segment membrane prevents elaboration of connecting cilia (CC, equivalent to transition zones) and outer segments (OSs, modified primary cilia). We also generated mouse models in which deletion of CEP164 occurs after OS are established and observed that the BB/CC and axoneme are initially stable in the absence of CEP164. Loss of CEP164, however, diminished recruitment of IFT-B proteins to the BB/CC affecting intraflagellar transport (IFT), which is required for maintenance of cilia and OSs. We propose that, in ciliopathies caused by missense mutations (e.g., X1460WextX57 associated with LCA) impairment of IFT provides a mechanism for ciliary dysfunction and disease.
Discovering dynamical models of human behavior

Response time (RT) data collected from cognitive tasks are a cornerstone of psychology and neuroscience research, yet existing models of these data either make strong assumptions about the data generating process or are limited to modeling single trials. We introduce task-DyVA, a deep learning framework in which expressive dynamical systems are trained to reproduce sequences of RTs observed in data from individual human subjects. Models fitted to a large task-switching dataset captured subject-specific behavioral differences with high temporal precision, including task-switching costs. Through perturbation experiments and analyses of the models’ latent dynamics, we find support for a rational account of switch costs in terms of a stability-flexibility tradeoff. Thus, our framework can be used to discover interpretable cognitive theories that explain how the brain dynamically gives rise to behavior.
The S. cerevisiae m6A-reader Pho92 impacts meiotic recombination by controlling key methylated transcripts

N6-methyladenosine (m6A), the most abundant internal modification of eukaryotic mRNAs, participates in the post-transcriptional control of gene expression. In Saccharomyces cerevisiae, m6A is only found during meiosis. Although the deletion of the m6A- methyltransferase Ime4 impairs this process, the molecular impact of m6A on gene expression remains ill defined. Here we investigated the function of the budding yeast m6A reader Pho92. We found that Pho92 is specifically expressed during meiosis and impacts meiotic progression. We used high-throughput RNA sequencing and mapping of Pho92-binding sites following UV-crosslinking to show that Pho92 is recruited to specific mRNAs in an m6A-dependent manner during the meiotic prophase, preceding their down-regulation. Strikingly, point mutations altering m6A sites in mRNAs targeted by Pho92 are sufficient to delay their down-regulation and, in one case, to impact meiotic progression. Altogether, our results indicate that Pho92 facilitate the meiotic progression by accelerating the down-regulation of timely-regulated mRNAs during meiotic recombination.
Acetaldehyde makes a distinct mutation signature in single-stranded DNA

Acetaldehyde (AA), a by-product of ethanol metabolism, is acutely toxic due to its ability to react with various biological molecules including DNA and proteins, which can greatly impede key processes such as replication and transcription and lead to DNA damage. As such AA is classified as a group 1 carcinogen by the International Agency for Research on Cancer (IARC). Previous in vitro studies have shown that AA generates bulky adducts on DNA, with signature guanine-centered (GG→TT) mutations. However, due to its weak mutagenicity, short chemical half-life, and the absence of powerful genetic assays, there is considerable variability in reporting the genotoxic effects of AA in vivo. Here, we used an established yeast genetic reporter system and demonstrate that AA is highly mutagenic and makes strand-biased mutations on guanines (G→T) at a high frequency on single stranded DNA (ssDNA). We further demonstrate that AA-derived mutations occur through lesion bypass on ssDNA by the translesion polymerase Polζ. Finally, we describe a unique mutation signature for AA, which we then identify in several whole-genome and -exome sequenced cancers, particularly those associated with alcohol consumption.
High Neutralizing Antibody Levels Against Severe Acute Respiratory Syndrome Coronavirus 2 Omicron BA.1 and BA.2 After UB-612 Vaccine Booster

The highly transmissible Omicron variant has caused high rates of breakthrough infections among vaccinated and convalescent individuals. Here, we demonstrate that a booster dose of UB-612 vaccine candidate delivered 7-9 months after primary vaccination increases neutralizing antibody levels by 131-, 61- and 49-fold against ancestral SARS-CoV-2, Omicron BA.1 and BA.2 variants, respectively. Based on the RBD protein binding antibody responses, we estimated a ∼95% efficacy against symptomatic COVID-19 caused by the ancestral strain after a UB-612 booster. Our results support UB-612 vaccine as a potent booster against current and emerging SARS-CoV-2 variants.
Multiple forward scattering reduces the measured scattering coefficient of blood in visible-light optical coherence tomography

Optical properties of blood encode oxygen-dependent information. Noninvasive optical detection of these properties is increasingly desirable to extract biomarkers for tissue health. Recently, visible-light optical coherence tomography (vis-OCT) demonstrated retinal oxygen saturation (sO2) measurements using the depth-resolved spectrum of blood. Such measurements rely on differences between the absorption and scattering coefficients of oxygenated and deoxygenated blood. However, there is still broad disagreement, both theoretically and experimentally, on how vis-OCT measures blood’s scattering coefficient. Incorrect assumptions of blood’s optical properties can add additional uncertainties or biases into vis-OCT’s sO2 model. Using Monte Carlo simulation of a retinal vessel, we determined that vis-OCT almost exclusively detects multiple-scattered photons in blood. Meanwhile, photons mostly forward scatter in blood within the visible spectral range, allowing photons to maintain ballistic paths and penetrate deeply, leading to a reduction in the measured scattering coefficient. We defined a scattering scaling factor (SSF) to account for such a reduction and found that SSF varied with measurement conditions, such as numerical aperture, depth resolution, and depth selection. We further experimentally validated SSF in ex vivo blood phantoms pre-set sO2 levels and in the human retina, both of which agreed well with our simulation.
Identification of BAHD acyltransferases associated with acylinositol biosynthesis in Solanum quitoense (naranjilla)

Plants make a variety of specialized metabolites that can mediate interactions with animals, microbes and competitor plants. Understanding how plants synthesize these compounds enables studies of their biological roles by manipulating their synthesis in vivo as well as producing them in vitro. Acylsugars are a group of protective metabolites that accumulate in the trichomes of many Solanaceae family plants. Acylinositol biosynthesis is of interest because it appears to be restricted to a subgroup of species within the Solanum genus. Previous work characterized a triacylinositol acetyltransferase involved in acylinositol biosynthesis in the Andean fruit plant Solanum quitoense (lulo or naranjillo). We characterized three additional S. quitoense trichome expressed enzymes, and found that virus induced gene silencing of each caused changes in acylinositol accumulation. Surprisingly, the in vitro triacylinositol products of these enzymes are distinct from those that accumulate in planta. These enzymes, nonetheless, provide an opportunities to test the biological impact and properties of these triacylinositols in vitro.