Biology Department Theses and Dissertations

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Low Intensity UVB as an Immunostimulant in the Yellow Mealworm Tenebrio molitor (Coleoptera: Tenebrionidae)
(2025-03) Smith, Michael Bartlett; Picard, Christine J.; Barrett, Meghan R.; Tomberlin, Jeffery K.
As the demand for sustainable proteins grows, insect farming has emerged as a promising solution. The yellow mealworm (Tenebrio molitor), among other commercially farmed species, presents a variety of environmental and nutritional advantages over conventional livestock. However, mealworm colonies are vulnerable to pathogens, necessitating novel strategies for enhancing their immune resilience. Here, we employed a transcriptomic approach to investigate the immunostimulatory effects of low-intensity ultraviolet B (UVB) irradiation on mealworm larvae. Approximately 3-week-old mealworms were exposed to UVB light for 14 days, followed by fungal challenge (Beauveria bassiana). UVB irradiation did not confer significant differences in survival at 14 days post-challenge and had a negative effect on larval weight. Genome-wide differential gene expression analysis revealed significant dysregulation of Toll pathway transcripts, including those encoding three antimicrobial peptides (AMPs), immediately after UVB exposure. Targeted gene expression analysis validated the upregulation of tenecin 4 via a response in the fat body at one and 14 days after the initiation of UVB irradiation. This study indicates that while UVB irradiation positively modulates AMP production in mealworms, its impact on enhancing resistance to pathogens remains uncertain. These observations lay the groundwork for additional studies exploring the effects of UVB irradiation on insect immune systems and its potential implications for insect farming.
Behavioral and Molecular Analysis of a Dyrk1a Functional Reduction in the Ts65Dn Mouse Model of Down Syndrome
(2025-05) Duerst, Alyssa Nicole; Roper, Randall; Marrs, Kathleen; Perrin, Benjamin
Children with Down syndrome (DS) experience learning, physical, and motor delays early in life. Overexpression of Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), a gene located on human chromosome 21 (Hsa 21), is in triplicate in DS and is thought to be a contributing cause of some neurodevelopmental delays seen in DS. The Ts65Dn mouse model of DS similarly contains triplication of Dyrk1a, along with 90 other orthologous Hsa 21 genes. Ts65Dn pups have shown to have significant DYRK1A protein overexpression on postnatal day 6 (P6) in the hippocampus, cerebral cortex, and cerebellum. We hypothesize that reduction of DYRK1A prior to this timepoint of overexpression will improve neurodevelopmental phenotypes in these pups. Dyrk1a was reduced from three to two copies in Ts65Dn pups at P0 to correspond with a second trimester DYRK1A reduction in developing fetuses with DS. Physical and behavioral assessments were performed on these pups from P3-P21. Ts65Dn pups showed physical, motor, and behavioral deficits as compared to euploid pups. However, Dyrk1a reduction in Ts65Dn pups did not result in vast behavioral improvements. This may be correlated with the failure of Dyrk1a functional reduction to normalize DYRK1A protein and mRNA levels seen in the P21 hippocampus, cerebral cortex, and cerebellum of these animals. Although no overall behavioral improvements were seen in the neonatal period analyzed, improvements in phenotypes may emerge later in life, as Dyrk1a functional reduction did improve Ts65Dn male pups’ emergence of running. A combination of different overexpressed protein targets in DS or an earlier Dyrk1a reduction may be ways to better explore DYRK1A reduction effects in early life.
Covariate and Co-Structural Influences on Human Facial Morphology: Decoding the Structural Blueprint Behind Facial Shape
(2025-05) Wilke, Franziska; Walsh, Susan; Roper, Randall; Balakrishnan, Lata; Wilson, Jeremy; Wetherill, Leah; Lapish, Christopher
The human face is one of the most intricate yet informative structures, serving as a key identifier in forensic investigations, an indicator of medical conditions, and a crucial factor in surgical planning. Over the past few decades, significant effort has been dedicated to understanding the genetic architecture underlying facial morphology. However, this focus often overlooks the substantial influence of covariates, such as biogeographic ancestry, and structural components like the skull. While these factors are acknowledged, their anthropological is frequently reduced to statistical models that bypass anatomical considerations. Furthermore, many of the complex models developed to reconstruct facial shape are not yet practically applicable. This dissertation addresses these gaps by investigating how regional, rather than just global, biogeographic ancestry influences facial morphology and whether genetic models of biogeographic ancestry align with phenotypic expression. Our findings indicate that broad categorizations such as “European” do not fully capture ancestral variation, yet incorporating too many genetic principal components risks overcorrection. To address this, we introduce a novel standardized, phenotype-based approach using consensus faces. Additionally, we present a validated, standardized method for efficiently masking and analyzing the human skull using over 6,000 quasi-landmarks. This methodology is further expanded to include a facial mask, where both the skull and face are intrinsically linked through anatomically corresponding quasi-landmarks. This innovation enables the simultaneous study of facial soft tissue thickness (FSTT), cranial shape, and facial morphology in a computationally efficient manner that has not been previously achieved. The use of correspondence masks permits modeling of the relationship between the skull and face, facilitating craniofacial reconstruction and laying the foundation for an open-source FSTT and facial measurement database. Ultimately, this dissertation explores standardization, global applicability, with the aim of facilitating real-world applications of a scientifically transparent computational approach to facial image projection from skeletal remains. By integrating genetic, anthropological, and statistical approaches, it describes a streamlined methodology that can harness structural knowledge of facial variation to develop practical tools useful in forensic and medical applications. Moreover, it highlights the need for global large-scale collaborative research to further advance this field on both fundamental science and applied levels.
Understanding The Role Of Transforming Growth Factor-β Activated Kinase-1 During Inflammation in Diabetic Retinopathy
(2024-12) Poudel, Umanga; Belecky-Adams, Teri; Slayback-Barry, Denise; Dai, Guoli
The role of microglial TAK1 in inflammation during diabetic retinopathy is not well understood but is known to affect the health of neurovascular units through the activation of inflammatory factors and cytokines. Loss in barrier activity in the neurovascular unit leads to leukocyte infiltration leading to the activation of microglia. The role of TAK1 was investigated in murine retinal microglial cultures in vitro by looking into the activation of TAK1 and downstream MAP kinase p38 activated by the treatment of pro-inflammatory factors; LPS and TNF-α, through western blotting. Treatment with LPS showed negative regulation of p38 by TAK1 in vitro in cells treated in non-diabetic conditions. Under conditions that mimicked hyperglycemia, TAK1 activation was not seen in murine retinal microglia treated with pro-inflammatory factor; LPS 20ng/ml or TNF-α 50pg/ml for 1hr. Moreover, there were no significant changes in murine retinal microglia treated with TAK1i subsequently after LPS 20ng/ml treatment for 1hr. On the contrary, the downstream MAPK p38 activation was not seen in murine retinal microglia treated in conditions that mimicked hyperglycemia while it showed significant response to changes in osmolarity. The in vivo study in retinal flat mounts showed TMEM119 as a potential candidate that could drive the td-Tomato expression in murine retinal microglia as 95% of the cells were colabelled with murine retinal microglia td-Tomato driven by TMEM119 and IBA1 which was further supported by the conditional TAK1 knockout experiment which showed 95% of the cells had TAK1 knocked out from the murine retinal microglia, confirming TMEM119 as excellent candidate for protein expression in murine retinal microglia.
Utility and Efficacy of Human Tissue Xenograft in Bone Healing
(2024-12) Ganguly, Upasana; Kacena , Melissa A.; Li, Jiliang; Roper, Randall J.
Connective Tissue Matrix (CTM) allografts are structural implants intended to supplement or replace damaged or inadequate tissues. Generated from human amnion, chorion, and umbilical elements, these allografts contain structural proteins as well as tissue-specific and –agnostic growth factors. In these studies, we examined the efficacy of CTM allografts to improve bone healing and whether CTM alters injury-associated pain behaviors in a pre-clinical animal model. The study involved two surgery models: a surgically induced femoral fracture model and a segmental bone defect (SBD) model. In the femoral fracture model, 12-week-old male C57BL/6J mice were divided into four groups: Saline Control, CTM Membrane, CTM Paste, and CTM Membrane + Paste. For the SBD model, the same age strain of male mice was divided into five groups: Saline Control, BMP-2, CTM Paste, CTM Membrane, and CTM Membrane + Paste. Complete blood count analysis demonstrated no significant alterations in blood cell numbers due to CTM treatments in the femoral fracture model. Despite the presence of various pro-inflammatory cytokines and growth factors in CTM, treated mice showed no significant increase in pain-associated behaviors post-fracture. Bioluminescence imaging demonstrated a significant reduction in inflammation for the CTM Membrane + Paste group on day 14 post-surgery. µCT analysis indicated significant improvement in the mineralized callus area for the CTM Membrane + Paste group when compared to all the other groups in the surgically induced femoral fracture model. Histomorphometric analysis further supported these findings, revealing an increased bone percentage in the callus area for CTM Membrane + Paste group compared to Saline controls in the surgical fracture model. However, biomechanical testing indicated no significant differences between Saline Control and the CTM treated groups. Interestingly, an increasing trend was observed in stiffness and toughness for the CTM Membrane group. Surgical fracture, being a simpler model of fracture, and heal without intervention with time. Hence, that led us to test our hypothesis that CTM products can promote bone healing in a more difficult model, of SBD mice. Long-term evaluations at 13 weeks for the SBD model showed that the BMP-2 group significantly increased the callus area compared to saline controls, with increasing trends observed in CTM-treated groups. Biomechanical testing demonstrated an increasing trend in the ultimate torque in all the groups when compared to Saline Control. Overall, the CTM Membrane + Paste group demonstrated promising potential in enhancing bone healing and reducing inflammation in the surgical fracture model, without triggering additional pain behaviors. The findings from the SBD model revealed that CTM Membrane + Paste has similar impact on bone healing, as observed in the surgical fracture model. Specifically, having a larger callus area as compared to Saline Control group and a significantly higher bone volume / tissue volume (BV/TV) percentage compared to all the other groups. These preclinical findings suggest that CTM allografts may promote fracture repair, providing rationale for further investigations, including a randomized controlled trial for human fractures in weightbearing bones.
Deciphering the Role of Eukaryotic Initiation Factor 5A in Pancreatic Organogenesis
(2024-08) Rutan, Caleb D.; Mastracci, Teresa L.; Berbari, Nicolas F.; Balakrishnan, Lata N.; Roh, Hyun Cheol
The pancreas is composed of a variety of cell types such as acinar, endocrine, and ductal cells, as well as endothelial cells and adipocytes. Whereas we understand the distinct functions of each, there remains an incomplete understanding of the molecular pathways and communications that exist between these cells that may influence development, growth, and function. Given that diabetes is characterized by the destruction or dysfunction of the insulin-producing pancreatic beta cell, a better understanding of the mechanisms that influence cell growth and maintenance in the pancreas is of therapeutic interest. Genome-wide association studies identified eukaryotic initiation factor 5A (eIF5A) to be within a type 1 diabetes susceptibility locus, which also suggests this translation factor may play a role in maintaining beta cell health. EIF5A is active once post-translationally modified by the rate-limiting enzyme deoxyhypusine synthase (DHPS) in a process known as hypusination, producing hypusinated eIF5A (eIF5AHYP). The functional loss of eIF5AHYP via pancreas-specific genetic deletion of Dhps or Eif5a within multipotent pancreatic progenitor cells (MPPCs) results in an mRNA translation defect detectable at E14.5 causing the decreased expression of many proteins required for exocrine growth and function. Moreover, DHPSΔPANC mice die by 6 weeks-of-age; however, eIF5AΔPANC mice survive up to 2 years-of-age. The postnatal phenotype of the eIF5AΔPANC model was investigated in this thesis.
The Role of β4 Subunit in Epilepsy Susceptibility
(2024-08) Fahim, Ahmed; Cummins, Theodore; Berbari, Nicolas F.; Mastracci, Teresa
Seizure involves a sudden, uncontrolled electrical disturbance of the brain due to many different causes apart from epilepsy, for example, high fever, low level of blood sugar, alcohol withdrawal, and many more, including the infections in the brain. In fact, epilepsy is a group of chronic neurological disorders characterized by recurrent unprovoked sudden-onset seizures. It stands as one of the prevalent brain disorders globally, impacting over 70 million individuals. The origins of epilepsy are multifaceted, coming from a mix of genetic and environmental factors including genetic predispositions, brain-related conditions (like tumors or strokes), infectious diseases, and traumatic brain injuries. Seizures can be partly referred to the dysregulation of ion channels, including voltage-gated sodium channels which will impact the action potential (electrical impulses that are responsible for the communication that takes place between neurons in the brain). These voltage-gated sodium channels mediate the depolarization responsible for the generation and conduction of action potentials. They are crucial in the generation and continuous electrical signals of the tissues that respond rapidly, like the neurons, and thus forming part of their function. In epilepsy, therefore, it is relevant to that domain in which abnormal functions of these sodium channels come up. Any change or dysfunction of these channels affect the excitability of the neurons themselves, with the consequence that an increased probability occurs in which abnormal electrical activity can be generated, hence the convulsions. Voltage-gated sodium channels are made up of large transmembrane proteins, having a single alpha subunit and related beta subunits. The beta subunit is an auxiliary protein that modulates channel gating, kinetics, surface expression, and the unique resurgent current, thereby influencing neuronal excitability and signaling. Resurgent currents represent a kind of current that can develop during action potential repolarization. They are characterized by a resurgent sodium current, the current which follows the initial sodium inflow in depolarization. Resurgent sodium currents are characterized by a rebound increase in sodium current during the repolarization phase of the action potential. Unlike the classic transient sodium current that inactivates rapidly upon membrane depolarization, the resurgent current is facilitated by the partial block and unblock of the sodium channel pore by the β subunit or other intracellular molecules during the repolarization phase. This allows sodium ions to flow into the cell when this blockage removed before it goes to closed state. It is believed widely to be of keen importance in neuronal excitability. The role of resurgent currents in epilepsy is likely genetically influenced with some environmental influence. Genetic mutations and dysregulation of the gene code for voltage-gated sodium channels, especially those related to beta subunits, can be linked to some atypical resurgent current. This increases the chance of having a seizure, which could develop into epilepsy. Four beta subunits have been identified up to now. As such, my investigation will focus on the beta 4 subunit and its possible involvement in increased susceptibility to seizures. My study will involve a genetically modified mouse β4 knockout (K.O) of the voltage-gated sodium channel, which will be compared with a wild type (WT) mouse model. To facilitate this comparison, I will prepare cortical brain slices from both the genetically modified and WT mice using a (Leica VT1200s vibratome). These slices will then be analyzed with multi-electrode arrays to detect electrical activity and measure the neurons' electrical responses. Additionally, I use 4-Aminopyridine, a potassium channel blocker, to stimulate electrical activity in the neurons and brain slices. Using the methodology outlined above, I aimed to investigate the ability to induce and measure neuronal activity in the β4 K.O mouse model. This involved comparing the neuronal activity between the β4 K.O and WT mice in terms of frequency and amplitude. The analysis of the recorded data was performed using Spike2 software, in conjunction with the multi-electrode array recordings. Furthermore, I explored whether variations in temperature (body temp vs 40℃) affect neuronal activity differently in β4 K.O compared to WT mice. In conclusion, my observations revealed that neuronal activity could indeed be induced in the β4 K.O mice, with a noted decrease in the frequency of this activity compared to WT mice, but an increase in amplitude. These outcomes were consistent at both normal body temperature and at an elevated temperature of 40°C, as analyzed using Spike2 software. However, when conducting a statistical analysis using a two-way ANOVA to compare between the β4 K.O and WT mice, and between body temperature and 40°C conditions, no significant differences were observed. Despite this, it is a general observation and conclusion that β4 K.O mice exhibit altered neuronal activity compared to WT mice. To gain a deeper understanding of the role of the β4 subunit on the alpha subunit of the voltage-gated sodium channel, adopting alternative methods such as patch clamp techniques or in vivo studies with intracranial electrodes may be beneficial. This suggestion comes considering various challenges and limitations encountered during my study, such as maintaining the viability of the slices for extended periods and minimizing noise in multi-electrode array (MEA) recordings. Mutations of β-subunit-encoding genes have been associated with such a wide array of debilitating diseases that include epilepsy, cancer, neuropathic pain, and febrile seizures, to some of the most prevalent conditions in neurodegeneration. Further study will be needed to better understand the biology of these important proteins and their potential for use as new targets for several disease states. Even so, the role of β4 remains somewhat controversial.
Role of Stenotrophomonas Maltophilia Pili Iin Biofilm And Virulence
(2024-08) Bhaumik, Radhika; Marrs, Kathleen; Anderson, Gregory; Berbari, Nicolas; Marrs, James A.; Gregory, Richard L.
Stenotrophomonas maltophilia is an emerging multidrug-resistant, Gram-negative opportunistic pathogen. It causes many hospital-acquired infections such as sepsis, endocarditis, meningitis, and catheter-related urinary tract infections. It also affects individuals with cystic fibrosis, exacerbating their lung condition. S. maltophilia often causes pathogenesis through the formation of biofilms. However, the molecular mechanisms S. maltophilia uses to carry out these pathogenic steps are unclear. The SMF-1 chaperone/usher pilus has been thought to mediate S. maltophilia attachment. To confirm this role, we created an isogenic deletion of the smf-1 pilin gene and observed a defect in biofilm compared to wild type. We also discovered 2 additional chaperone/usher pilus operons, mutation of which also caused attenuation in biofilm levels. Analysis of S. maltophilia clinical strains and S. maltophilia complete genomes listed in NCBI showed that these three pili are prevalent and highly conserved, suggesting a vital role in infection. Intriguingly, through TEM studies, we found that the mutation of one pilus is not phenotypically compensated by another. Infection of Galleria mellonella larvae revealed increased virulence of the pilus mutants. Additionally, we also demonstrated a relationship between pilus and flagella contributing to the overall biofilm development of S. maltophilia. Understanding their activity may help identify therapeutic targets for this pathogen.
Characterizing Changes in the Brain During Hydrocephalic Development and Exploring Potential Treatment Strategies
(2024-05) Reed, Makenna M.; Blazer-Yost, Bonnie; Belecky-Adams, Teri; Cummins, Theodore; Baucum, A. J.; Jantzie, Lauren
A neurological disorder, hydrocephalus, has an estimated global pediatric prevalence of 380,000 new cases each year [1]. It is a family of diseases that can occur at any age when cerebrospinal fluid builds up within the ventricles of the brain. Thus, the only available treatments are surgical, invasive, and prone to complications. There is a global need for successful treatment strategies without brain surgery. Choroid plexus epithelial cells (CPEC) are responsible for production of cerebrospinal fluid (CSF). Ependymal cells line the ventricles and play roles in CSF maintenance and waste clearance. Astrocytes perform various functions, one being blood-brain barrier (BBB) maintenance. Collectively these cells contribute to brain fluid/electrolyte regulation and barrier integrity. Increased glial fibrillary acidic protein (GFAP) fluorescence, a marker of activated astrocytes, appeared in hydrocephalic (Tmem67-/-) animals by immunohistochemistry as early as postnatal day (P)10. The tight junction proteins expressed in choroid plexus (CP); claudin-1 (Cl-1) and zona occludin 1 (ZO-1) fluorescent intensity increased in P15 hydrocephalic animals compared to wildtype (Tmem67+/+). These cells also contain aquaporins (AQP), aquaporin-1 (AQP1) and aquaporin-4 (AQP4), important in regulating CSF and interstitial fluid (ISF). Increased fluorescent intensity of AQP4 in the subventricular zone and increased AQP1 apical localization and protein amount in the CP was observed in hydrocephalic animals at postnatal day (P)15. Many of these may be targeted for the treatment of hydrocephalus. However, there is no consensus in pathological findings between models of hydrocephalus and these finding may not translate to common pharmacological targets. A transient receptor potential cation channel, subfamily vanilloid, member 4 (TRPV4) antagonist (RN1734) ameliorates hydrocephalus in a rat model of congenital hydrocephalus (Tmem67 model). It was hypothesized that targeting this mechanosensitive ion channel may slow production of CSF by targeting the CP. However, hydrocephalus pathology can have various effects on the brain. Astrocytes were visualized using fluorescent immunohistochemistry of glial fibrillary acidic protein (GFAP) and RN1734 did not seem to change immunoreactivity to wildtype untreated levels. Increased immunoreactivity of TRPV4 and AQP1 was observed in CP of untreated and RN1734 treated Tmem67-/- rats. AQP4 and TRPV4 immunoreactivity increased in the subventricular zone and periventricular white matter (WM) of hydrocephalic rats. With RN1734, TRPV4 immunoreactivity, but not AQP4, had similar immunoreactivity to wildtype untreated. Increased GFAP and AQP immunoreactivity may indicate residual inflammation in the Tmem67-/- rats. More experiments must be done to further elucidate TRPV4’s role in hydrocephalus pathology. Serum and glucocorticoid-regulated kinase 1 (SGK1) is a kinase implicated in cell volume regulation and CSF production. SI113, an SGK1 inhibitor, ameliorates hydrocephalus in the Tmem67 rodent model. The goal of this study was to determine if SI113 could be used with a new solvent other than dimethyl sulfoxide (DMSO), which can have possible toxic effects. 1-methyl-2-pyrrolidinone (NMP) has high solubility and ability to cross the BBB. These studies showed that NMP as a solvent did not have adverse effects on body weight, however thus far, it has not ameliorated hydrocephalus significantly at the concentration used in this study. There is a possibility that the concentration in NMP that we used was not efficacious enough. CSF and blood plasma samples from animals treated with SI113 24 hours and 30 minutes before euthanasia will be used to investigate the concentration of SI113 that remains in the circulation and the amount that crosses the BBB and blood-cerebrospinal fluid (BCSFB) barriers. We hope that the results will inform dosage for our future studies. Future studies may also examine SI113 mechanism of action in hydrocephalus. This thesis addresses hydrocephalus cell and molecular pathology in the Tmem67 model and examines potential treatment strategies. Future directions include comparing models of hydrocephalus to find common treatment strategies in the hope to find pharmaceutical strategies to better manage human hydrocephalus.
Dyrk1a Dynamics: The Influence of Gene Copy Number on Neurodevelopment in the Ts65dn Mouse Model of Down Syndrome
(2024-05) Hawley, Laura E.; Roper, Randall; Belecky-Adams, Teri; Cummins, Theodore; Goodlett, Charles; Hardy, Tabitha; Marrs, Kathleen
Down syndrome (DS) arises from the triplication of human chromosome 21 (Hsa21), leading to a spectrum of phenotypes characterized by neurodevelopmental and cognitive abnormalities. The Ts65Dn mouse model emulates DS by harboring three copies of genes found on Hsa21 resulting in trisomy 21 (Ts21)- like traits, including disruptions in neuronal pathways, delays in sensorimotor and behavior milestones, and deficits in learning and memory tasks. There is no cure for DS and available therapies primarily address symptoms stemming from Ts21-associated phenotypes. DYRK1A, a gene triplicated in Ts21, has a pivotal role in pathways of neurodevelopment and has been a focus of inhibition treatment research aimed at preempting abnormal brain phenotypes. This study aimed to find a point of substantial Dyrk1a expression dysregulation during a period of critical neonatal neurodevelopment and employ targeted pharmacological and genetic knockdown methods to alleviate the presence or severity of characteristically abnormal brain and behavior phenotypes. The hypothesis of this study was that administering a targeted intervention prior to a point of known overexpression in trisomic pups would ameliorate molecular, sensorimotor, and neurobehavioral deficits, redirecting growth trajectories of Ts65Dn neonatal pups towards more neurotypical outcomes. To test this hypothesis, the spatiotemporal pattern of DYRK1A expression was quantified during the first three weeks of neonatal development across the hippocampus, cerebral cortex, and cerebellum of the Ts65Dn mouse model and found to fluctuate according to the genotype, age, sex, and brain region of the subject. Dyrk1a protein and mRNA expression levels were delineated in trisomic animals by age, exploring the correlation between expression and age, sex, genotype, and brain region. Next a constitutive Dyrk1a knockdown model was integrated with the Ts65Dn model to investigate the impact of gene copy number reduction on protein and mRNA expression levels during phases of known DYRK1A dysregulation. On postnatal day 6, protein expression was rescued in all three brain regions of male animals but was rescued only in the cerebellum of females. There were no significant differences in mRNA transcript levels in either sex at this age. Finally, genetic elements were introduced into the Ts65Dn model to facilitate a spatiotemporally controlled functional reduction of Dyrk1a and discern how the timing of gene copy number reduction affects molecular and neurobehavioral development in a trisomic system. Results from these studies suggest that only functionally reducing Dyrk1a gene copy number on the day of birth is not sufficient to rescue the majority of deficits and delays present in the Ts65Dn mouse model of DS. These findings significantly enhance the understanding of trisomic Dyrk1a expression dynamics during neonatal development and shed light on tailored therapeutic approaches to modulate intrinsic DS characteristics based on age, sex, and phenotypic considerations.

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