bioRxiv Science⌕ Search

Biology subjects

Farina, M.

Publications and source records attributed to Farina, M..

5 recordsLinked to original sources

Biologically grounded locality priors close the data gap for vision transformers in neural prediction

For datasets with thousands of neurons and images, vision transformers have proven successful at predicting neural responses to stimuli. However, they are expected to underperform in low-data regimes, where CNNs and Gaussian processes are considered more effective. We ask whether transformers can be made competitive for small-scale neural prediction, and show that underperformance in this regime can be overturned with the right inductive bias. We equip a vision transformer with a differentiable per-neuron circular crop in feature space. The crop is centered on each neuron's receptive field, with a radius selected per neuron, so the model only sees the small image region that drives that neuron instead of the whole image. This makes the cost of attention scale with the size of the receptive field rather than with the size of the image. A single transformer stack is shared across all neurons: each neuron's specificity resides in the crop, not in the architecture. We call this model circular receptive-field vision transformer (CiRF-ViT). We evaluate it on small multi-electrode-array recordings of mouse and salamander retinas: a mouse preparation of 41 ganglion cells and two salamander preparations totaling 49 ganglion cells, each with only a few thousand stimulus-response pairs, two orders of magnitude below the scale at which transformers are typically trained. Against CNN and Gaussian-process baselines, CiRF-ViT reaches the highest mean explained variance on both datasets (0.94 on mouse, 0.95 on salamander). Probed with the local spike-triggered average (LSTA), a zero-shot test of context-dependent, nonlinear stimulus sensitivity, CiRF-ViT reproduces the qualitative polarity inversion that a linear model cannot capture by construction. A biologically grounded, per-neuron locality prior is therefore enough to make transformers competitive for neural prediction well below their usual data scale, while matching the reference models on an established functional signature of the retina's nonlinear computation.

neuroscience↗

Jak2V617F Reversible Activation Shows an Essential Requirement for Jak2V617F in Myeloproliferative Neoplasms

Janus kinases (JAKs) mediate cytokine signaling, cell growth and hematopoietic differentiation.1 Gain-of-function mutations activating JAK2 signaling are seen in the majority of myeloproliferative neoplasm (MPN) patients, most commonly due to the JAK2V617F driver allele.2 While clinically-approved JAK inhibitors improve symptoms and outcomes in MPNs, remissions are rare, and mutant allele burden does not substantively change with chronic JAK inhibitor therapy in most patients.3, 4 This has been postulated to be due to incomplete dependence on constitutive JAK/STAT signaling, alternative signaling pathways, and/or the presence of cooperating disease alleles;5 however we hypothesize this is due to the inability of current JAK inhibitors to potently and specifically abrogate mutant JAK2 signaling. We therefore developed a conditionally inducible mouse model allowing for sequential activation, and then inactivation, of Jak2V617F from its endogenous locus using a Dre-rox/Cre-lox dual orthogonal recombinase system. Deletion of oncogenic Jak2V617Fabrogates the MPN disease phenotype, induces mutant-specific cell loss including in hematopoietic stem/progenitor cells, and extends overall survival to an extent not observed with pharmacologic JAK inhibition. Furthermore, reversal of Jak2V617F in MPN cells with antecedent loss of Tet26, 7 abrogates the MPN phenotype and inhibits mutant stem cell persistence suggesting cooperating epigenetic-modifying alleles do not alter dependence on mutant JAK/STAT signaling. Our results suggest that mutant-specific inhibition of JAK2V617F represents the best therapeutic approach for JAK2V617F-mutant MPN and demonstrate the therapeutic relevance of a dual-recombinase system to assess mutant-specific oncogenic dependencies in vivo.

cancer biology↗

CXCL8/CXCR2 signaling mediates bone marrow fibrosis and represents a therapeutic target in myelofibrosis

Pro-inflammatory signaling is a hallmark feature of human cancer, including in myeloproliferative neoplasms (MPNs), most notably myelofibrosis (MF). Dysregulated inflammatory signaling contributes to fibrotic progression in MF; however, the individual cytokine mediators elicited by malignant MPN cells to promote collagen-producing fibrosis and disease evolution remain yet to be fully elucidated. Previously we identified a critical role for combined constitutive JAK/STAT and aberrant NF-{kappa}B pro-inflammatory signaling in myelofibrosis development. Using single-cell transcriptional and cytokine-secretion studies of primary MF patient cells and two separate murine models of myelofibrosis, we extend this previous work and delineate the role of CXCL8/CXCR2 signaling in MF pathogenesis and bone marrow fibrosis progression. MF patient hematopoietic stem/progenitor cells are enriched in a CXCL8/CXCR2 gene signature and display dose-dependent proliferation and fitness in response to exogenous CXCL8 ligand in vitro. Genetic deletion of Cxcr2 in the hMPLW515L adoptive transfer model abrogates fibrosis and extends overall survival, and pharmacologic inhibition of the CXCR1/2 pathway improves hematologic parameters, attenuates bone marrow fibrosis, and synergizes with JAK inhibitor therapy. Our mechanistic insights provide a rationale for therapeutic targeting of the CXCL8/CXCR2 pathway in MF patients at risk for continued fibrotic progression.

cancer biology↗

Disruption of augmin-mediated microtubule nucleation in neural stem cells causes p53-dependent apoptosis and aborts brain development.

Microtubules that assemble the mitotic spindle are generated by three different mechanisms: centrosomal nucleation, chromatin-mediated nucleation, and nucleation from the surface of other microtubules mediated by the augmin complex. Impairment of centrosomal nucleation in apical progenitors of the developing mouse brain induces p53-dependent apoptosis and causes non-lethal microcephaly. Whether disruption of non-centrosomal nucleation has similar effects is unclear. Here we show, using mouse embryos, that conditional knockout of the augmin subunit Haus6 in apical progenitors led to spindle defects and mitotic delay. This triggered massive apoptosis and complete abortion of brain development. Co-deletion of p53 rescued cell death, but brain development was still aborted. This could be explained by exacerbated mitotic errors and resulting chromosomal defects including increased DNA damage. Surviving progenitors had lost apico-basal polarity and failed to organize a pseudostratified epithelium. Thus, in contrast to the centrosomal nucleation pathway, augmin is crucial for apical progenitor mitosis, and, even in the absence of p53, for progression of brain development.

cell biology↗

Membrane Elastic Properties During Neural Progenitor/Neural Stem Cell Differentiation

Neural stem cells differentiate into several cell types that display distinct functions. However, little is known about how cell surface mechanics vary during the differentiation process. Here, by precisely measuring membrane tension and bending modulus, we map their variations and correlate them with changes in cell morphology along differentiation into neurons, astrocytes and oligodendrocytes. Both neurons and undifferentiated cells reveal a decrease in membrane tension over the first hours of differentiation followed by stabilization, with no change in bending modulus. Astrocytes membrane tension initially decreases and then increases after 72h, accompanied by consolidation of GFAP expression and striking actin reorganization, while bending modulus increases following observed alterations. For oligodendrocytes, the changes in membrane tension are less abrupt over the first hours but their values subsequently decrease, correlating with a shift from O4 to MBP expressions and a remarkable actin reorganization, while bending modulus remains constant. Oligodendrocytes at later differentiation stages show membrane vesicles with similar membrane tension but higher bending modulus as compared to the cell surface. Altogether, our results display an entire spectrum of how membrane elastic properties are varying, contributing to a better understanding of neural stem cell differentiation from a mechanobiological perspective.

biophysics↗