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Rao, R.

Publications and source records attributed to Rao, R..

43 records · Page 3Linked to original sources

Evaluating Protein Transfer Learning with TAPE

Protein modeling is an increasingly popular area of machine learning research. Semi-supervised learning has emerged as an important paradigm in protein modeling due to the high cost of acquiring supervised protein labels, but the current literature is fragmented when it comes to datasets and standardized evaluation techniques. To facilitate progress in this field, we introduce the Tasks Assessing Protein Embeddings (TAPE), a set of five biologically relevant semi-supervised learning tasks spread across different domains of protein biology. We curate tasks into specific training, validation, and test splits to ensure that each task tests biologically relevant generalization that transfers to real-life scenarios. We bench-mark a range of approaches to semi-supervised protein representation learning, which span recent work as well as canonical sequence learning techniques. We find that self-supervised pretraining is helpful for almost all models on all tasks, more than doubling performance in some cases. Despite this increase, in several cases features learned by self-supervised pretraining still lag behind features extracted by state-of-the-art non-neural techniques. This gap in performance suggests a huge opportunity for innovative architecture design and improved modeling paradigms that better capture the signal in biological sequences. TAPE will help the machine learning community focus effort on scientifically relevant problems. Toward this end, all data and code used to run these experiments are available at https://github.com/songlab-cal/tape.

synthetic biology↗

Delays, behaviour and transmission: modelling the impact of effective private provider engagement on tuberculosis control in urban India

In India, the country with the worlds largest burden of tuberculosis (TB), most patients first seek care in the private healthcare sector, which is fragmented and unregulated. Ongoing initiatives are demonstrating effective approaches for engaging with this sector, and form a central part of Indias recent National Strategic Plan: here we aimed to address their potential impact on TB transmission in urban settings, when taken to scale. We developed a mathematical model of TB transmission dynamics, calibrated to urban populations in Mumbai and Patna, two major cities in India where pilot interventions are currently ongoing.\n\nWe found that, when taken to sufficient scale to capture 75% of patient-provider interactions, the intervention could reduce incidence by upto 21.3% (95% Bayesian credible interval (CrI) 13.0 - 32.5%) and 15.8% (95% CrI 7.8 - 28.2%) in Mumbai and Patna respectively, between 2018 and 2025. There is a stronger impact on TB mortality, with a reduction of up to 38.1% (95% CrI 20.0 - 55.1%) in the example of Mumbai. The incidence impact of this intervention alone may be limited by the amount of transmission that has already occurred by the time a patient first presents for care: model estimates suggest an initial patient delay of 4-5 months before first seeking care, followed by a diagnostic delay of 1-2 months before ultimately initiating TB treatment. Our results suggest that the transmission impact of such interventions could be maximised by additional measures to encourage early uptake of TB services.

systems biology↗

A Moonlighting Role for SPCA2 in E-cadherin Biogenesis and Suppression of Epithelial-Mesenchymal Transition

Progression of benign tumors to invasive, metastatic cancer requires loss of the cell-adhesion protein E-cadherin. Although intensive efforts have focused on gene repression and silencing mutations, much less is known about posttranslational control of E-cadherin expression in cancer. SPCA2 is a secretory pathway Ca2+-ATPase that is down-regulated in metastatic breast cancer. We show that SPCA2 is tightly co-expressed with epithelial signature genes and required for E-cadherin biogenesis and cell surface expression. Unexpectedly, this function is uncoupled from Ca2+ pumping and mediated by binding to E-cadherin. Loss of SPCA2 is sufficient to disrupt cell-cell adhesion in tumorspheres and elicit mesenchymal gene expression through Hippo-YAP signaling. These findings point to a causal link between low SPCA2 levels and the epithelial-mesenchymal transition required for breast cancer metastasis.\n\nHighlightsO_LISPCA2 is an epithelial marker transcriptionally linked to E-cadherin expression\nC_LIO_LILoss of SPCA2 impairs E-cadherin biogenesis independent of Ca2+ pump activity\nC_LIO_LISPCA2 is required for tumorsphere formation and Hippo-YAP signaling to antagonize epithelial-mesenchymal transition\nC_LIO_LIDown-regulation of SPCA2 in metastatic cancers may contribute to malignancy\nC_LI\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=168 SRC=\"FIGDIR/small/379586_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (28K):\norg.highwire.dtl.DTLVardef@6b1e14org.highwire.dtl.DTLVardef@83edbborg.highwire.dtl.DTLVardef@16cbc5corg.highwire.dtl.DTLVardef@1c2752a_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

Noninvasive Vagus Nerve Stimulation Alters Neural Response and Physiological Autonomic Tone to Noxious Thermal Challenge

The mechanisms by which noninvasive vagal nerve stimulation (nVNS) affect central and peripheral neural circuits that subserve pain and autonomic physiology are not clear, and thus remain an area of intense investigation. Effects of nVNS vs sham stimulation on subject responses to five noxious thermal stimuli (applied to left lower extremity), were measured in 30 healthy subjects (n=15 sham and n=15 nVNS), with fMRI and physiological galvanic skin response (GSR). With repeated noxious thermal stimuli a group x time analysis showed a significantly (p < .001) decreased response with nVNS in bilateral primary and secondary somatosensory cortices (SI and SII), left dorsoposterior insular cortex, bilateral paracentral lobule, bilateral medial dorsal thalamus, right anterior cingulate cortex, and right orbitofrontal cortex. A group x time x GSR analysis showed a significantly decreased response in nVNS group (p < .0005) in bilaterally in SI, lower and mid medullary brainstem, and inferior occipital cortex. Finally, nVNS treatment showed decreased activity in pronociceptive brainstem nuclei (e.g. the reticular nucleus and rostral ventromedial medulla) and key autonomic integration nuclei (e.g. the rostroventrolateral medulla, nucleus ambiguous, and dorsal motor nucleus of the vagus nerve). In aggregate, noninvasive vagal nerve stimulation reduced the physiological response to noxious thermal stimuli and impacted neural circuits important for pain processing and autonomic output.

neuroscience↗

NHA2 promotes cyst development in an in vitro model of polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1 and PKD2 encoding polycystin-1 (PC1) and polycystin-2 (PC2), respectively. The molecular pathways linking polycystins to cyst development in ADPKD are still unclear. Intracystic fluid secretion via ion transporters and channels plays a crucial role in cyst expansion in ADPKD. Unexpectedly, we observed significant and selective up-regulation of NHA2, a member of the SLC9B family of Na+/H+ exchangers that correlated with cyst size and disease severity in ADPKD patients. Using three-dimensional cultures of MDCK cells to model cystogenesis in vitro, we show that ectopic expression of NHA2 is causal to increased cyst size. Induction of PC1 in MDCK cells inhibited NHA2 expression with concordant inhibition of Ca2+ influx through store-dependent and independent pathways, whereas reciprocal activation of Ca2+ influx by a dominant negative, membrane-anchored C-terminal tail fragment of PC1 elevated NHA2. We show that NHA2 is a target of Ca2+/NFAT signaling and is transcriptionally induced by methylxanthine drugs such as caffeine and theophylline, which are contraindicated in ADPKD patients. Finally, we observe robust induction of NHA2 by vasopressin, which is physiologically consistent with increased levels of circulating vasopressin and up-regulation of vasopressin V2 receptors in ADPKD. Our findings have mechanistic implications on the emerging use of vasopressin V2 receptor antagonists such as tolvaptan as safe and effective therapy for PKD and reveal a potential new regulator of transepithelial salt and water transport in the kidney.

physiology↗

A conserved mechanism for regulation of endo-lysosomal pH by histone deacetylases

The pH of the endo-lysosomal system is tightly regulated by a balance of proton pump and leak mechanisms that are critical for storage, recycling, turnover and signaling functions in the cell. Dysregulation of endo-lysosomal pH has been linked to aging, amyloidogenesis, synaptic dysfunction, and various neurodegenerative disorders including Alzheimers disease. Therefore, understanding mechanisms that regulate luminal pH may be key to identifying new targets for treatment of these disorders. Meta-analysis of yeast microarray databases revealed that nutrient limiting conditions upregulated transcription of the endosomal Na+/H+ exchanger Nhx1 by inhibition of the histone deacetylase (HDAC) Rpd3, resulting in vacuolar alkalinization. Consistent with these findings, Rpd3 inhibition by the HDAC inhibitor and antifungal drug trichostatin A induced Nhx1 expression and vacuolar alkalinization. Bioinformatics analysis of Drosophila and mouse databases revealed that caloric control of Nhx1 orthologs DmNHE3 and NHE6 respectively, was also mediated by histone deacetylases. We show that NHE6 is a target of cAMP-response element-binding (CREB) protein, providing a molecular mechanism for nutrient and HDAC dependent regulation of endosomal pH. Control of NHE6 expression by pharmacological targeting of the CREB pathway can be used to regulate endosomal pH and restore defective amyloid A{beta} clearance in an ApoE4 astrocyte model of Alzheimers disease. These observations from yeast, fly, mouse and cell culture models reveal an evolutionarily conserved mechanism for regulation of endosomal NHE expression by histone deacetylases and offer new therapeutic strategies for modulation of endo-lysosomal pH in fungal infection and human disease.

molecular biology↗

The Amyloid Clearance Defect in ApoE4 Astrocytes is Corrected by Epigenetic Restoration of NHE6

The accumulation of amyloid protein A{beta} in senile plaques is a key driver and hallmark of Alzheimer disease (AD), a major cause of death and dementia in the elderly. The strongest genetic risk factor in sporadic AD is the {varepsilon}4 allele of Apolipoprotein E (ApoE4), which potentiates pre-symptomatic endosomal dysfunction and defective clearance of A{beta}, although how these two pathways are linked has been unclear. Here, we show that aberrant accumulation of endosomal protons in ApoE4 astrocytes traps the LRP1 receptor in non-productive intracellular compartments, leading to loss of surface expression and A{beta} clearance. Hyperacidification of endosomal pH is caused by selective down regulation of the Na+/H+ exchanger NHE6, which functions as a critical proton leak pathway, in ApoE4 brain and astrocytes. In vivo, the NHE6KO mouse model shows elevated A{beta} in the brain. Epigenetic restoration of NHE6 expression with histone deacetylase inhibitors normalized ApoE4-specific defects in endosomal pH, LRP1 trafficking and amyloid clearance. Thus, NHE6 is a prominent effector of ApoE4 and emerges as a promising therapeutic target in Alzheimer disease.

neuroscience↗