Role of urocanic acid as an endogenous photoprotectant and as a therapeutic target for treating UV-induced melanoma and non-melanoma malignancies

Overexposure to UV (ultraviolet) radiation has been linked to a number of deleterious effects on human health, particularly epidermal malignancies, which consist of both melanoma and non-melanoma skin cancers, basal cell carcinoma and squamous cell carcinoma. In the 1950’s, an epidermal compound known as Urocanic Acid (UCA) was discovered whose trans isoform was shown to display photoprotective effects against UV radiation. Not long after, the cis-UCA isomer was found to act as a mediator of immune suppression, causing UCA to be removed from all cosmetic products on the commercial market, most notably sunscreen. Numerous studies conducted after this finding further corroborated cis-UCA’s immunosuppressive properties, showing evidence for the ability of cis-UCA to inhibit contact hypersensitivity responses, delayed-type hypersensitivity responses, and allograft rejection. Early evidence for a mechanism of action behind cis-UCA’s immunosuppressive properties were widespread, including modulation of antigen-presenting cells, interaction with histamine receptors, and regulation of cytokine expression. The immunosuppressive nature of cis-UCA quickly became associated with an ability to facilitate cancerous progression, particularly regarding epidermal malignancies. Interesting theories were raised about the evolutionary basis for cis-UCA’s immunosuppressive nature, including speculation that cis-UCA was meant to induce immunosuppression following ultraviolet exposure in order to prevent autoimmune responses against sunburned epidermal cells. After the turn of the 20th century, new research continued to facilitate modern day understanding of the role of UCA. Evidence showed that UCA was ultimately derived from filaggrin within the stratum corneum, interacted with key immune effectors including T-lymphocytes and Langerhans cells, and potentially contributed to acidification of the stratum corneum. Despite the negative reputation cis-UCA has received in regards to facilitating skin cancer evasion of the immune system, research has shown that its immunosuppressive effects may allow it to serve as potent anti-inflammatory therapeutic. In regards to skin cancer, targeting of UCA as a therapeutic varies widely. Some have suggested using UCA as a measure of sunscreen efficacy, as an indirect target that when inhibited can reduce tumor growth, and as a biomarker for skin cancer risk. Others have begun developing UCA-based mimics that retain the benefits of UCA, while avoiding any deleterious effects. The role of UCA in non-melanoma and melanoma malignancies is not well understood, making targeting of UCA as a therapeutic challenging. The aim of this paper is to comprehensively review the scientific literature regarding the pre-21st century history of UCA, followed by an in-depth analysis of post-21st century research. The objective is to determine the overall potential of UCA to serve as a therapeutic target for UV-associated health conditions, most notably dermatologic malignancies

The windows for kinetically mixed Z'-mediated dark matter and the galactic center gamma ray excess

One of the simplest hidden sectors with signatures in the visible sector is fermionic dark matter $\chi$ coupled to a $Z'$ gauge boson that has purely kinetic mixing with the standard model hypercharge. We consider the combined constraints from relic density, direct detection and collider experiments on such models in which the dark matter is either a Dirac or a Majorana fermion. We point out sensitivity to details of the UV completion for the Majorana model. For kinetic mixing parameter $\epsilon \le 0.01$, only relic density and direct detection are relevant, while for larger $\epsilon$, electroweak precision, LHC dilepton, and missing energy constraints become important. We identify regions of the parameter space of $m_\chi$, $m_{Z'}$, dark gauge coupling and $\epsilon$ that are most promising for discovery through these experimental probes. We study the compatibility of the models with the galactic center gamma ray excess, finding agreement at the 2-3$\sigma$ level for the Dirac model.Comment: 13 pages, 10 figures; v.2 added reference; v.3 minor clarifications, published versio

Multimediator models for the galactic center gamma ray excess

Tentative evidence for excess GeV-scale gamma rays from the galactic center has been corroborated by several groups, including the Fermi collaboration, on whose data the observation is based. Dark matter annihilation into standard model particles has been shown to give a good fit to the signal for a variety of final state particles, but generic models are inconsistent with constraints from direct detection. Models where the dark matter annihilates to mediators that subsequently decay are less constrained. We perform global fits of such models to recent data, allowing branching fractions to all possible fermionic final states to vary. The best fit models, including constraints from the AMS-02 experiment (and also antiproton ratio), require branching primarily to muons, with a $\sim 10-20\%$ admixture of $b$ quarks, and no other species. This suggests models in which there are two scalar mediators that mix with the Higgs, and have masses consistent with such a decay pattern. The scalar that decays to $\mu^+\mu^-$ must therefore be lighter than $2m_\tau \cong 3.6$ GeV. Such a small mass can cause Sommerfeld enhancement, which is useful to explain why the best-fit annihilation cross section is larger than the value needed for a thermal relic density. For light mediator masses $\sim (0.2-2)$ GeV, it can also naturally lead to elastic DM self-interactions at the right level for addressing discrepancies in small structure formation as predicted by collisionless cold dark matter.Comment: 18 pages, 14 figures; v2: updated CMB constraint and added references; v3 corrected direct detection cross sectio

Robust Tests for Treatment Effects Based on Censored Recurrent Event Data Observed over Multiple Periods

We derive semiparametric methods for estimating and testing treatment effects when censored recurrent event data are available over multiple periods. These methods are based on estimating functions motivated by a working “mixed-Poisson” assumption under which conditioning can eliminate subject-specific random effects. Robust pseudoscore test statistics are obtained via “sandwich” variance estimation. The relative efficiency of conditional versus marginal analyses is assessed analytically under a mixed time-homogeneous Poisson model. The robustness and empirical power of the semiparametric approach are assessed through simulation. Adaptations to handle recurrent events arising in crossover trials are described and these methods are applied to data from a two-period crossover trial of patients with bronchial asthma.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65405/1/j.1541-0420.2005.00357.x.pd

Comparative genomics of Cochlodinium and other marine dinoflagellates as inferred from Genome sequence analysis

Cochlodinium polykrikoides is one of the causative agents for harmful algal blooms occurring in the west cost of Sabah, which result in massive economic damage to the aquaculture and mariculture industries. Currently, limited information is available on the genomics of C polykrikoides. The objectives of this study were to develop a protocol for the construction of an expressed sequence tag (EST) library for C polykrikoides cells cultured under normalized conditions, to design gene specific primers using sequence information of related dinoflagellates and to test the gene specific primers against the DNA and RNA of C po/ykrikoides. Cochlodinium polykrikoides stock cultures were obtained from the Unit for Harmful Algal Blooms Studies (UHABs) of the Borneo Marine Research Institute, Universiti Malaysia Sa bah and cultured in f /2 medium. Optimization of total RNA isolation from C polykrikoides was performed using five different methods. Among the five methods tried, the RNA isolation protocol using the TRizol reagent produced the best results. Synthesis of cDNA was performed on successfully isolated RNA samples followed by cloning and direct sequencing of the purified clones. In addition, fourteen gene specific primer pairs were designed and synthesized using sequence information from other harmful algae species. Genomic DNA samples isolated from C polykn1<oides cells were used as templates for the PCR amplification carried out using the synthesized gene specific primers. Amplification products from three gene specific primers, psaAl F/R, COX-1 F/R and ATPsynC F/R were purified and subsequently cloned and directly sequenced. Based on the sequencing results, the cloned products were found to produce identity matches to genes encoding products from similar and related protein families, such as the oxidoreductases and cytochrome oxidases

Social isolation and social functioning in dementia syndromes: Mechanisms and interventions

Social functioning encompasses an individual’s ability to engage in diverse social contexts, from intimate relationships to broader societal settings. Our understanding of the extent to which social functioning is affected across dementia syndromes is limited. Moreover, the social environment has been profoundly reshaped in the wake of the COVID-19 pandemic, including the ramifications of prolonged social isolation. This thesis aims to uncover the mechanisms underlying social functioning in dementia and develop effective interventions to mitigate social isolation. Pervasive impairments in social functioning across dementia syndromes were revealed, driven in part by apathy and emotion recognition impairment. These findings also demonstrated the adverse effects of social isolation due to pandemic-related restrictions, including worsened neuropsychiatric symptoms in dementia and carer mental health. In response to these challenges, a tailored carer intervention was developed to enhance carers’ capacity to support people with dementia during COVID-19 lockdowns. This led to improved carer self-efficacy, reduced loneliness and decreased distress related to neuropsychiatric symptoms. Moving beyond the pandemic, social functioning and post-diagnostic care were explored through qualitative methods to co-design a carer program in dementia. This approach revealed a wide spectrum of unmet needs, shedding light on the caregiving experience and the importance of developing person-centred support to address these needs. Taken together, these studies underscore the critical need for effective post-diagnostic support, both during the pandemic and beyond. These novel findings have important clinical implications for evaluating and managing social functioning impairments in dementia. Importantly, these investigations forge pathways for effective interventions and shape post-diagnostic care that holistically supports people living with dementia and their families

The use of deception in dementia-care robots: Should robots tell "white lies" to limit emotional distress?

With projections of ageing populations and increasing rates of dementia, there is need for professional caregivers. Assistive robots have been proposed as a solution to this, as they can assist people both physically and socially. However, caregivers often need to use acts of deception (such as misdirection or white lies) in order to ensure necessary care is provided while limiting negative impacts on the cared-for such as emotional distress or loss of dignity. We discuss such use of deception, and contextualise their use within robotics.Comment: 3 pages, to be published in Proceedings of the 11th International Conference on Human-Agent Interaction (ACM HAI'23

Law and Morality in the Han Fei Zi

Master'sMASTER OF ART