Biology subjects

Bose, R.

Publications and source records attributed to Bose, R..

15 recordsLinked to original sources

bioRxiv2026

The crossmodal congruency task as a measure of intuitiveness of sensory feedback in the lower limb

People with lower limb amputation lack somatosensory feedback from their prosthesis, and this loss contributes to functional deficits, including balance and gait impairments. Recent advances in neuroprostheses have demonstrated that electrical stimulation of sensory nerves in the residual limb and spinal cord can restore lost sensations in the lower limb. To maximize the efficacy of these somatosensory neuroprostheses, the restored sensations should be intuitive, seamlessly integrating into the sensorimotor network. However, it is challenging to quantify the intuitiveness of these evoked sensations. Recent studies have proposed using crossmodal congruency effect (CCE) tasks for this purpose in people with upper-limb amputation. The current study tests the feasibility of the CCE task for assessing the intuitiveness of sensory feedback in the lower limb. We hypothesized that CCE score would reliably differentiate between a more natural (pneumatic) sensation and a less natural (electric) sensation at two locations: the knee and the foot. Across fifteen able-bodied individuals, we observed that the CCE task differentiates sensory modalities at the knee, but not at the foot. Identification of external factors affecting the CCE is needed before it can be implemented to measure intuitiveness of sensory feedback in lower-limb amputees.

bioengineering↗

bioRxiv2026

Functional Somatotopy of Lumbar Dorsal Rootlets and its Role in Selective Recruitment via Lateral Spinal Cord Stimulation

ObjectiveLateral spinal cord stimulation (LSCS) is a promising approach for restoring somatosensory feedback in lower-limb amputees, but its spatial selectivity remains limited. Percepts often spread to unintended regions of the residual limb, and reducing electrode contact size may not improve focality. This study investigated whether the anatomical organization of lumbar dorsal rootlets (DR) imposes fundamental constraints on LSCS selectivity. ApproachAcute neurophysiology experiments were performed in six adult cats. Both LSCS and individual DR stimulation were conducted in the same animals. For DR stimulation, bipolar hook electrodes were used to stimulate individual DR, while antidromic compound action potentials (CAPs) were recorded from femoral and sciatic nerve branches instrumented with nerve cuffs. For LSCS, custom 32-contact epidural paddle electrodes were placed over the lateral surface of the spinal cord at corresponding vertebral levels. Recruitment thresholds, dynamic ranges, and response patterns were analyzed across spinal levels, and DR recruitment patterns were directly compared to those evoked by LSCS within the same animals. Main resultsA clear rostrocaudal organization was observed across spinal levels during stimulation of individual DR, with femoral branches predominantly recruited at L4-L5 and sciatic branches at L6-L7. However, no somatotopic organization was found across DR within each spinal level; individual DR frequently co-activated multiple branches within the same group, and selective recruitment could only be maintained over a narrow dynamic range (median [~]10 {micro}A). LSCS exhibited even a narrower dynamic range ([~]5 {micro}A) but closely mirrored DR recruitment patterns, indicating that LSCS activates sensory afferents in a manner determined by the organizational structure of the DR. SignificanceThese findings demonstrate that the limited spatial selectivity of LSCS can largely be attributed to the coarse organization of DR within each root level rather than due to limitations of epidural electrode design. Moving electrodes intradurally or reducing contact size further is unlikely to substantially improve focality. Instead, improving paddle stability to ensure consistent placement over the appropriate spinal levels may be a more effective strategy for enhancing percept localization.

neuroscience↗

bioRxiv2026

Mapping RNA structure assembly and remodeling in biomolecular condensates

Biomolecular condensates concentrate RNA and protein machinery that facilitate RNA processing, ribonucleoprotein assembly, and gene regulation. Some evidence supports that condensates can modulate RNA folding, but measuring RNA structure within native condensates remains an unsolved challenge. Here we introduce RAID-MaP, a strategy that combines APEX proximity labeling with dimethyl sulfate (DMS) chemical probing to measure RNA structure within defined subcellular compartments. We applied RAID-MaP to resolve late stages of ribosomal RNA (rRNA) folding within the granular component (GC) of the nucleolus, revealing that both the 18S and 28S rRNAs feature widespread differences in structure compared to assembled ribosomes consistent with ongoing folding of both secondary and tertiary structure. We further combined RAID-MaP with transcription inhibition to resolve kinetics of rRNA maturation. The maturation kinetics of both subunits progressed on comparable timescales but with characteristic domain-level ordering, with late GC-resident intermediates often becoming more protected than mature ribosomes suggestive of stabilization by nucleolar accessory factors. Perturbing this 28S assembly pathway using antisense oligonucleotides produces distinct nucleolar phenotypes depending on whether early versus late folding domains are disrupted, demonstrating a direct link between rRNA folding and phase separation. We additionally applied RAID-MaP to discover that the 7SK small nuclear RNA undergoes spatially regulated structural switching consistent with localized release of the transcription factor P-TEFb at sites of active transcription. Together, our results establish subcellular spatial control of RNA structure as a new dimension of RNA regulation.

biochemistry↗

bioRxiv2026

Ubiquitous low-energy RNA fluctuations and energetic coupling measured by chemical probing

RNA function is governed by RNA folding, but strategies for measuring RNA folding thermodynamics are limited, and fundamental questions such as the energy of base pair opening remain debated. Here we introduce Probing-Resolved Inference of Molecular Energetics (PRIME) to extract nucleotide-resolution RNA structural energetics from scalable chemical probing experiments. Applying PRIME to diverse RNAs, we find that RNA base pairs and tertiary interactions dynamically open with free energies of 0.5-3 kcal/mol, revealing that RNA nucleotides ubiquitously sample open conformations at biologically accessible energies. PRIME further resolves energetic coupling across RNAs, providing an energetic understanding of RNA structural dynamics and long-range coordination in RNA folding. PRIME represents a widely accessible strategy for interrogating RNA thermodynamics, enabling mechanistic understanding and engineering of RNA biology.

biophysics↗

bioRxiv2025

HER2; p53 Co-mutated Cancers Show Increased Histone Acetylation and are Sensitive to Neratinib plus Trastuzumab Deruxtecan.

In metastatic breast cancer, HER2-activating mutations often co-occur with TP53 mutations, a combination linked to poor response to neratinib and worse prognosis. To model this clinical challenge, we bred HER2 V777L transgenic mice with two TP53 mutant alleles: TP53 R172H (the murine homolog of human TP53 R175H) and TP53fl/fl, which mimics p53 truncations common in human tumors. TP53 mutations accelerated tumor development and reduced survival in HER2-mutant mice. These co-mutant tumors were resistant to neratinib but remained sensitive to exatecan, the topoisomerase I (TOP1) inhibitor payload in trastuzumab deruxtecan (T-DXd). Mechanistically, TP53 mutant tumors exhibited upregulation of histone acetylation, hypertranscription of DNA repair factors, increased chromatin accessibility, and rendered cells more susceptible to TOP1 inhibitors via G2/M arrest and apoptosis. This vulnerability is dependent on transcriptional activity of TP53 mutations, highlighting a novel strategy to treat HER2;TP53 co-mutant breast cancers using TOP1-targeted therapies. Statement of SignificanceTP53 mutations sensitize HER2-mutant cancers to TOP1 inhibitors via chromatin accessibility and hyper-transcription, supporting combination therapy with neratinib and T-DXd in TP53/HER2 co-mutant breast cancers.

cancer biology↗

bioRxiv2025

Cerebellum metastasis model of HER2-positive breast cancer unveils key role of IL34-induced Arg1+ macrophages.

Brain metastases occur in up to 40% of Stage IV breast cancer patients. The cerebellum is a frequent location for metastases in HER2-positive breast cancer patients, but the mechanisms for this are unknown. Here, we developed a syngeneic, immunocompetent mouse model for breast cancer brain metastases by stereotactically injecting mouse HER2-overexpressing breast cancer organoids into the cerebellum. Growth of these cerebellar metastases was monitored by MRI and trastuzumab optical imaging using a near-infrared fluorophore conjugated to trastuzumab. Spatial transcriptomics identified interleukin-34 production by breast cancer cells inducing ARG1+ macrophages at the invading edge of the metastasis. Treatment with a blocking antibody to interleukin-34s receptor, CSF1R, produced tumor shrinkage. These findings have immediate translation potential as a CSF1R-blocking antibody is FDA-approved. Further, it demonstrates that cancer-associated inflammation bordering the brain metastasis promotes metastatic growth and offers a molecularly targeted strategy to treat inflammation in brain metastasis. Graphical summary O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/660224v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@9f1a50org.highwire.dtl.DTLVardef@178acc5org.highwire.dtl.DTLVardef@196d803org.highwire.dtl.DTLVardef@3fe631_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

Stochastically Emergent Tumors offer in vivo whole genome interrogation of cancer evolution from non-malignant precursors

Interrogating the stochastic events underlying tumor evolution from non-malignant precursors is crucial for understanding therapy resistance. Current methods are complicated by chromosomal instability, obscuring driver identification and yielding non-representative genetics. Inspired by patient tumors that evolve without chromosomal instability, we developed Stochastically Emergent Tumors (SETs) by inducing mismatch repair deficiency in non-malignant precursors, then engrafting in mice. Barcoded SETs exhibited increased tumoral and drug target heterogeneity over current models. SETs delineated the stochastic contributions, mutational landscapes, and selective pressures distinguishing tumorigenesis from non-malignant precursor in vitro growth. SETs are an unlimited source for diverse Stochastically Emergent cell Lines (SELs), bolstering under-represented cancers. Since SETs composition dynamically reflects therapy exposure, they are a whole-genome platform for precision oncology. We identified three novel genetic drivers (ZFHX3, CIC, KMT2D) of differential prostate cancer therapy responses. These alterations are enriched in patients of African and Chinese ancestry and correlate with significant differences in survival.

cancer biology↗

bioRxiv2025

Protometabolically generated NADH mediates material properties of aqueous dispersions to coacervate microdroplets

Macromolecular assembly between biomolecules dictates the material state of aqueous dispersions like the cytoplasm. The formation of protein precipitates, fibres, or liquid droplets have been associated with the regulation of biochemical function and disease. However, the effect of small molecules and metabolites on tuning phase behaviour remains underexplored. Here we use the protometabolic reduction of NAD+ to NADH by pyruvate to study the effect of NADH production on the phase properties of polyarginine in bicarbonate buffer. Our results show that reduction of NAD+ in the presence of polyarginine can tune the material properties of the dispersion between precipitates, homogeneous solution and liquid droplets depending on the buffer concentration. In-situ droplet formation results in 2-3 times higher reaction rate and NADH yield, compared to homogeneous solution. Our results demonstrate how small molecules can significantly impact material properties in aqueous dispersions and the positive effect of heterogeneous dispersions on primitive metabolic reactions. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=104 SRC="FIGDIR/small/642830v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@19261c8org.highwire.dtl.DTLVardef@151aae5org.highwire.dtl.DTLVardef@aaa110org.highwire.dtl.DTLVardef@342e16_HPS_FORMAT_FIGEXP M_FIG C_FIG

synthetic biology↗

bioRxiv2024

Simultaneous mapping of RNA secondary, tertiary, and quaternary structure in living cells by multi-site DMS probing

Identifying tertiary structures and protein binding sites on RNA molecules remains a key challenge in RNA biology. We report a new chemical probing strategy termed multi-site DMS-MaP (msDMS-MaP) that exploits base tautomerization during mutational profiling reverse-transcription to measure typically invisible DMS-induced modifications at the N7 position of G. These N7-G modifications are now resolved concurrently with conventional N1 and N3 modifications with only minor modifications to established protocols, providing a multi-dimensional, single-molecule readout of RNA structure. We show that N7-G reactivity specifically reports on RNA tertiary and quaternary structure, enabling identification of diverse, functionally significant motifs such as cooperatively folding tertiary domains and protein binding sites in living cells. We apply msDMS-MaP to obtain a map of the quaternary structural ensemble of the 7SK non-coding snRNP, revealing unique protein binding sites across three 7SK structural isoforms. msDMS-MaP represents a broadly applicable strategy for enhanced RNA functional motif discovery and characterization.

biochemistry↗

bioRxiv2023

Neratinib Synergizes with Trastuzumab Antibody Drug Conjugate or with Vinorelbine to Treat HER2 Mutated Breast Cancer Patient Derived Xenografts and Organoids.

HER2 (ERBB2) is a major therapeutic drug target in breast cancer and The Cancer Genome Atlas (TCGA) Breast Cancer project and other studies have identified HER2 activating mutations in breast cancers without HER2 gene amplification. HER2 activating mutations occur in 2-5% of metastatic breast cancer patients (MBC), and clinical trials have shown that the irreversible pan-HER tyrosine kinase inhibitor, neratinib, produces a 31-40% clinical benefit rate for HER2 mutated MBC patients. We developed breast cancer patient-derived xenografts (PDX) from ER+, HER2 mutated MBC patients and used them to test neratinib-based drug combinations. Using organoid culture of these PDX breast cancer cells, we performed rapid, high-throughput ex vivo screening assays to test novel drug combinations. These organoid culture experiments identified drug synergy with the neratinib plus ado-trastuzumab emtansine (T-DM1) and neratinib plus vinorelbine combinations and we validated these results with in vivo PDX experiments. Statement of SignificancePDXs are a ready source of human cancer organoids, and with thousands of PDXs already available worldwide, PDX derived organoids (PDxOs) can dramatically accelerate cancer drug testing. This strategy of PDxO drug testing is particularly useful for rare cancer subtypes or mutations to identify the most promising treatment strategies for clinical trials testing.

cancer biology↗

bioRxiv2023

Differential chromatin accessibility and transcriptional dynamics define breast cancer subtypes and their lineages

Breast cancer is a heterogeneous disease, and treatment is guided by biomarker profiles representing distinct molecular subtypes. Breast cancer arises from the breast ductal epithelium, and experimental data suggests breast cancer subtypes have different cells of origin within that lineage. The precise cells of origin for each subtype and the transcriptional networks that characterize these tumor-normal lineages are not established. In this work, we applied bulk, single-cell (sc), and single-nucleus (sn) multi-omic techniques as well as spatial transcriptomics and multiplex imaging on 61 samples from 37 breast cancer patients to show characteristic links in gene expression and chromatin accessibility between breast cancer subtypes and their putative cells of origin. We applied the PAM50 subtyping algorithm in tandem with bulk RNA-seq and snRNA-seq to reliably subtype even low-purity tumor samples and confirm promoter accessibility using snATAC. Trajectory analysis of chromatin accessibility and differentially accessible motifs clearly connected progenitor populations with breast cancer subtypes supporting the cell of origin for basal-like and luminal A and B tumors. Regulatory network analysis of transcription factors underscored the importance of BHLHE40 in luminal breast cancer and luminal mature cells, and KLF5 in basal-like tumors and luminal progenitor cells. Furthermore, we identify key genes defining the basal-like (PRKCA, SOX6, RGS6, KCNQ3) and luminal A/B (FAM155A, LRP1B) lineages, with expression in both precursor and cancer cells and further upregulation in tumors. Exhausted CTLA4-expressing CD8+ T cells were enriched in basal-like breast cancer, suggesting altered means of immune dysfunction among breast cancer subtypes. We used spatial transcriptomics and multiplex imaging to provide spatial detail for key markers of benign and malignant cell types and immune cell colocation. These findings demonstrate analysis of paired transcription and chromatin accessibility at the single cell level is a powerful tool for investigating breast cancer lineage development and highlight transcriptional networks that define basal and luminal breast cancer lineages.

cancer biology↗

bioRxiv2023

Oligodendrocyte precursor cells engulf synapses in a model of the developing human forebrain

Recent work in animal models suggests the role of oligodendrocyte precursor cells (OPCs) is not limited to oligodendrogenesis. Here, we report that OPCs derived from human induced pluripotent stem cells are capable of engulfing synaptosomes. We then develop a novel multi-lineage forebrain organoid in which OPCs alongside microglia display a spontaneous internalization of synaptic material in their phagolysosomes. Collectively, these findings suggest that OPCs contribute to synapse elimination in the developing human forebrain and provide a versatile platform for evaluating the interplay between microglia and OPCs in remodeling neuronal circuits in health and disease.

neuroscience↗

bioRxiv2022

Breast cancer mutations HER2 V777L and PIK3CA H1047R activate the p21/CDK4/6/Cyclin D1 axis driving tumorigenesis and drug resistance.

In metastatic breast cancer, HER2 activating mutations frequently co-occur with mutations in the PIK3CA, TP53, or E-cadherin genes. Of these co-occurring mutations, HER2 and PIK3CA mutations are the most prevalent gene pair, with approximately 40% of HER2 mutated breast cancers also having activating mutations in PIK3CA. To study the effects of co-occurring HER2 and PIK3CA mutations, we bred genetically engineered mice with the HER2V777L; PIK3CAH1047Rtransgenes (HP mice) and studied the resulting breast cancers both in vivo as well as ex vivo using cancer organoids. HP breast cancers show accelerated tumor formation in vivo and increased invasion and migration in in vitro assays. HP breast cancers have resistance to the pan-HER tyrosine kinase inhibitor, neratinib, but are effectively treated by neratinib plus trastuzumab deruxtecan. Proteomic and RNA-Seq analysis of HP breast cancers showed increased gene expression of Cyclin D1 and p21WAF1/Cip1 and changes in cell cycle markers. Combining neratinib with CDK4/6 inhibitors was another effective strategy for HP breast cancers with neratinib plus palbociclib showing a statistically significant reduction in mouse HP tumors as compared to either drug alone. We validated both the neratinib plus trastuzumab deruxtecan and neratinib plus palbociclib combinations using a human breast cancer patient-derived xenograft that has very similar HER2 and PIK3CA mutations. Both of these drug combinations are being tested in phase 1 clinical trials and this study provides valuable preclinical evidence for them.

cancer biology↗

bioRxiv2021

Stimulation of the Dorsal Root Ganglion using an Injectrode

ObjectiveThe goal of this work was to compare afferent fiber recruitment by dorsal root ganglion (DRG) stimulation using an injectable polymer electrode (Injectrode(R)) and a more traditional cylindrical metal electrode. ApproachWe exposed the L6 and L7 DRG in four cats via a partial laminectomy or burr hole. We stimulated the DRG using an Injectrode or a stainless steel electrode using biphasic pulses at three different pulse widths (80, 150, 300 s) and pulse amplitudes spanning the range used for clinical DRG stimulation. We recorded antidromic evoked compound action potentials (ECAPs) in the sciatic, tibial, and common peroneal nerves using nerve cuffs. We calculated the conduction velocity of the ECAPs and determined the charge-thresholds and recruitment rates for ECAPs from A, A{beta}, and A{delta} fibers. We also performed electrochemical impedance spectroscopy measurements for both electrode types. Main ResultsThe ECAP thresholds for the Injectrode did not differ from the stainless steel electrode across all primary afferents (A, A{beta}, A{delta}) and pulse widths; charge-thresholds increased with wider pulse widths. Thresholds for generating ECAPs from A{beta} fibers were 100.0 {+/-} 32.3 nC using the stainless steel electrode, and 90.9 {+/-} 42.9 nC using the Injectrode. The ECAP thresholds from the Injectrode were consistent over several hours of stimulation. The rate of recruitment was similar between the Injectrodes and stainless steel electrode and decreased with wider pulse widths. SignificanceThe Injectrode can effectively excite primary afferents when used for DRG stimulation within the range of parameters used for clinical DRG stimulation. The Injectrode can be implanted through minimally invasive techniques while achieving similar neural activation to conventional electrodes, making it an excellent candidate for future DRG stimulation and neuroprosthetic applications.

bioengineering↗

bioRxiv2017

The prognostic effects of somatic mutations in ER-positive breast cancer

More than 50 genes are recurrently affected by somatic mutation in estrogen receptor positive (ER+) breast cancer but prognostic effects have not been definitively established. Primary tumor DNA was therefore subjected to targeted sequencing from 625 postmenopausal (UBC-TAM series) and 328 premenopausal (MA12 trial) hormone receptor-positive (HR+) patients. Independent validation of prognostic interactions was achieved using independent data from the METABRIC study. Associations between MAP3K1 and PIK3CA with luminal A status and TP53 mutations with Luminal B/non-luminal tumors were observed, validating the methodological approach. In UBC-TAM, NF1 frame-shift nonsense (FS/NS) mutation was validated as a poor outcome driver. For MA12, poor outcome associated with PIK3R1 mutation was similarly validated. DDR1 mutations were strongly associated with poor prognosis in UBC-TAM despite stringent false-discovery correction (q=0.0003). In conclusion, uncommon recurrent somatic mutations should be further explored to create a more complete explanation of the highly variable outcomes that typify ER+ breast cancer.

genomics↗