Biology subjects

Mohan, H.

Publications and source records attributed to Mohan, H..

8 recordsLinked to original sources

bioRxiv2025

Cation-exchange synthesized Zn-doped Ag2S Nanostructures for Photothermal and Photodynamic Therapies across Breast Cancer Subtypes

Photothermal therapy (PTT) and photodynamic therapy (PDT) require nanostructures capable of efficiently converting red-light energy into both heat and reactive oxygen species (ROS). However, simultaneously achieving high photothermal conversion efficiency and strong ROS generation remains challenging. Here, we report zinc-doped Ag2S (ZSS) nanostructures, synthesized via controlled cation exchange, in which Zn incorporation modulates the electronic structure of Ag2S and improves charge separation, thereby enhancing red-light-activated PTT/PDT performance while preserving intrinsic biocompatibility. Among the series, ZSS(0.15) demonstrated optimized charge-carrier dynamics, a high photothermal conversion efficiency of 67.26%, and approximately four-fold higher singlet oxygen (1O2) generation relative to methylene blue under 660 nm irradiation. These physicochemical enhancements translated into potent therapeutic outcomes: in-vitro, ZSS(0.15) achieved an IC50 of 15 {micro}g/mL under irradiation, corresponding to approximately a 1.5-fold enhancement in cytotoxic potency compared to pristine Ag2S, and induced apoptosis via activation of the p53/Bax/Caspase pathway. In-vivo, ZSS(0.15) with laser irradiation achieved [~]97% tumor volume suppression without systemic toxicity. Extending evaluation across multiple breast cancer cell lines representing distinct molecular subtypes further confirmed broad-spectrum in-vitro efficacy. Altogether, these findings demonstrate that controlled Zn incorporation into Ag2S effectively enhances red-light-driven photothermal conversion and 1O2 generation, establishing a rational materials strategy for improving synergistic PTT/PDT performance. GRAPHICAL ABSTRACTA Zn-doped Ag2S nanoplatform (ZSS(0.15)) enables synergistic photothermal and photodynamic therapy under 660-nm laser irradiation, triggering p53-mediated mitochondrial apoptosis via ROS generation and caspase-3 activation, achieving [~]97% tumor regression in-vivo without detectable systemic toxicity. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=136 SRC="FIGDIR/small/684667v2_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@1d93519org.highwire.dtl.DTLVardef@12d18f4org.highwire.dtl.DTLVardef@1c14608org.highwire.dtl.DTLVardef@1dcd9f8_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

Distinct neurogenic pathways shape the diversification and mosaic organization of cortical output channels

The cerebral cortex broadcasts its output to subcortical regions through the projections of diverse extratelencephalic neurons (ETs) derived from either direct (dNG-ETd) or indirect (iNG-ETi) neurogenesis, but the differential contributions of these neurogenic pathways to cortical output organization remain unknown. Establishing a lineage-based viral targeting strategy in mice, we uncover that ETi massively amplifies and diversifies ETd projections across the cortex. Whereas ETd primarily targets the forebrain and midbrain, ETi dominates the hindbrain (e.g., brainstem/spinal action centers, lemniscal sensory stations), hypothalamic, and neuromodulatory regions with cortical area-specific projections. Numerous corticofugal subpopulations derive solely from iNG-ETi. Area-specific spinal projections of ETi but not ETd emerge from the postnatal pruning of an initial cortex-wide population. In the motor cortex, ETd or ETi activation induced distinct movements: either head-trunk, or additionally, coordinated orofacial-forelimb movements, respectively. Thus, two foundational neurogenic pathways with distinct evolutionary history differentially shape the area-specific diversification of cortical output channels.

neuroscience↗

bioRxiv2023

Cortical network and projection neuron types that articulate serial order in a skilled motor behavior

The coordination of forelimb and orofacial movements to compose an ethological reach-to-consume behavior likely involves neural communication across brain regions. Leveraging wide-field imaging and photo-inhibition to survey across the cortex, we identified a cortical network and a high-order motor area (MOs-c), which coordinate action progression in a mouse reach-and-withdraw-to-drink (RWD) behavior. Electrophysiology and photo-inhibition across multiple projection neuron types within the MOs-c revealed differential contributions of pyramidal tract and corticothalamic (CTMOs) output channels to action progression and hand-mouth coordination. Notably, CTMOs display sustained firing throughout RWD sequence and selectively enhance RWD-relevant activity in postsynaptic thalamus neurons, which also contribute to action coordination. CTMOs receive converging monosynaptic inputs from forelimb and orofacial sensorimotor areas and are reciprocally connected to thalamic neurons, which project back to the cortical network. Therefore, motor cortex corticothalamic channel may selectively amplify the thalamic integration of cortical and subcortical sensorimotor streams to coordinate a skilled motor sequence.

neuroscience↗

bioRxiv2022

A cortical circuit for orchestrating oromanual food manipulation

The seamless coordination of hands and mouth--whether in humans eating corn on the cob or mice extracting sunflower seeds--represents one of evolutions most sophisticated motor achievements. Whereas spinal and brainstem circuits implement basic forelimb and orofacial actions, whether there is a specialized cortical circuit that assembles these actions to enable skilled oromanual manipulation remains unclear. Here, we discover a cortical area and its cell-type-specific circuitry that govern oromanual food manipulation in mice. An optogenetic screen of cortical areas and projection neuron types identified a rostral forelimb-orofacial area (RFO), wherein activation of pyramidal tract (PTFezf2) and intratelencephalic (ITPlxnD1) neurons induced concerted posture, forelimb and orofacial movements resembling eating. In a freely moving pasta-eating behavior, pharmacological RFO inactivation impaired the sitting posture, hand recruitment, and oromanual coordination in pasta eating. RFO PTFezf2 and ITPlxnD1 activity was closely correlated with oromanual pasta manipulation and hand-assisted biting. Optogenetic inhibition revealed that PTsFezf2 regulate dexterous hand and mouth movements while ITsPlxnD1 play a more prominent role in oromanual coordination. RFO forms the hub of an extensive network, with reciprocal connections to cortical forelimb and orofacial sensorimotor areas, as well as insular and visceral areas. Within this cortical network, RFO PTsFezf2 project unilaterally to multiple subcortical, brainstem and spinal areas associated with forelimb and orofacial control, while ITsPlxnD1 project bilaterally to the entire network and the ventrolateral striatum, and can mediate concurrent forelimb and mouth movement in part through their striatal projection. Together, these findings uncover the cell-type-specific implementation of a cortical circuit that orchestrates oromanual manipulation, essential for skilled feeding.

neuroscience↗

bioRxiv2022

CRISPR correction of GBA mutation in hiPSCs restores normal function to Gaucher macrophages and increases their susceptibility to Mycobacterium tuberculosis

Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by mutations in the {beta}-glucocerebrosidase (GCase) GBA gene, which result in macrophage dysfunction. To investigate whether correction of GBA mutations restores normal function to Gaucher macrophages, we performed CRISPR editing of homozygous L444P (1448T[->]C) GBA mutation in Type 2 GD (GBA-/-) hiPSCs, which yielded both heterozygous (GBA+/-) and homozygous (GBA+/+) isogenic lines. Macrophages derived from GBA-/-, GBA+/- and GBA+/+ hiPSCs, were compared for GCase enzymatic activity, motility, and phagocytosis, all of which showed that GBA mutation correction restores normal macrophage functions. Furthermore, we investigated whether lysosomal disorders drive susceptibility to Mycobacterium tuberculosis, by infecting GBA-/-, GBA+/- and GBA+/+ macrophages with the virulent H37Rv lab strain. The results showed that impaired mobility and phagocytic activity of Gaucher macrophages, correlated with reduced levels of TB engulfment and TB multiplication, supporting the hypothesis that GD may be protective against tuberculosis.

genomics↗

bioRxiv2021

Cortical glutamatergic projection neuron types contribute to distinct functional subnetworks

The cellular basis of cerebral cortex functional architecture remains not well understood. A major challenge is to monitor and decipher neural network dynamics across broad cortical areas yet with projection neuron (PN)-type resolution in real time during behavior. Combining genetic targeting and wide-field imaging, we monitored activity dynamics of subcortical-projecting (PTFezf2) and intratelencephalic-projecting (ITPlxnD1) types across dorsal cortex of mice during different brain states and behaviors. ITPlxnD1 and PTFezf2 neurons showed distinct activation patterns during wakeful resting, spontaneous movements, and upon sensory stimulation. Distinct ITPlxnD1 and PTFezf2 subnetworks were dynamically tuned to different sensorimotor components of a naturalistic feeding behavior, and optogenetic inhibition of ITsPlxnD1 and PTsFezf2 in subnetwork nodes disrupted distinct components of this behavior. Lastly, ITPlxnD1 and PTFezf2 projection patterns are consistent with their subnetwork activation patterns. Our results show that, in addition to the concept of columnar organization, dynamic areal and PN type-specific subnetworks are a key feature of cortical functional architecture linking microcircuit components with global brain networks.

neuroscience↗

bioRxiv2021

Pyramidal cell types drive functionally distinct cortical activity patterns during decision-making

Understanding how cortical circuits generate complex behavior requires investigating the cell types that comprise them. Functional differences across pyramidal neuron (PyN) types have been observed within cortical areas, but it is not known whether these local differences extend throughout the cortex, nor whether additional differences emerge when larger-scale dynamics are considered. We used genetic and retrograde labeling to target pyramidal tract (PT), intratelencephalic (IT) and corticostriatal projection neurons and measured their cortex-wide activity. Each PyN type drove unique neural dynamics, both at the local and cortex-wide scale. Cortical activity and optogenetic inactivation during an auditory decision task also revealed distinct functional roles: all PyNs in parietal cortex were recruited during perception of the auditory stimulus, but, surprisingly, PT neurons had the largest causal role. In frontal cortex, all PyNs were required for accurate choices but showed distinct choice-tuning. Our results reveal that rich, cell-type-specific cortical dynamics shape perceptual decisions.

neuroscience↗

bioRxiv2020

Nicotinamide promotes differentiation of pancreatic endocrine progenitors from human pluripotent stem cells through poly (ADP-ribose) polymerase inhibition

The generation of pancreatic endocrine progenitor cells is an important step in the differentiation of beta cells from human pluripotent stem cells (hPSC). This stage is marked by the expression of Nkx6.1, a transcription factor with well understood downstream targets but with unclear upstream regulators. In hPSC differentiation, Nkx6.1 is strongly induced by nicotinamide, a derivative of vitamin B3, which has three known functions within a cell. Nicotinamide inhibits two classes of enzymes known as poly-ADP-ribose polymerases (PARPs) and sirtuins. It also contributes to the cellular pool of nicotinamide adenosine deoxynucleotide (NAD+) after conversion in the nicotinamide salvage pathway. Induction of Nkx6.1 expression in pancreatic endocrine progenitors by nicotinamide was mimicked by 3 PARP inhibitors (PJ34, olaparib, NU1025). Small molecule inhibition of the nicotinamide salvage pathway reduced Nkx6.1 expression but not Pdx1 expression and caused alteration in NAD+/NADH ratio. Nkx6.1 expression was not affected by sirtuin inhibition. Metabolic profiling of differentiating pancreatic and endocrine progenitors showed that oxygen consumption increases as differentiation progresses, and that nicotinamide reduces oxygen consumption rate. Expression of Nkx6.1 and other beta cell related genes, including Ins2 and Pdx1 increased in mouse islets after exposure to nicotinamide. In summary, nicotinamide induced Nkx6.1 expression in differentiating human pancreatic endocrine progenitors through inhibition of the PARP family of enzymes. Nicotinamide administration was also associated with increased NAD+/NADH ratio, without affecting Nkx6.1 expression. Similarly, the association between nicotinamide and Nkx6.1 expression was also seen in isolated mouse islets. These observations show a link between the regulation of beta cell identity and the effectors of NAD+ metabolism, suggesting possible therapeutic targets in the field of diabetes.

developmental biology↗