Consequences of Brief Periods of Sleep Loss on Hippocampus-Dependent Memory and Synaptic Plasticity

Hippocampal cellular and molecular processes critical for memory consolidation are affected by the amount and quality of sleep attained. Questions remain with regard to how sleep enhances memory, what parameters of sleep after learning are optimal for memory consolidation, and what underlying hippocampal molecular players are dysregulated by sleep deprivation to impair memory consolidation and plasticity. In this dissertation, I describe experiments that we performed to identify the time window where memory consolidation is sensitive to sleep loss as well as to characterize two potential molecular players targeted by sleep deprivation. Because consolidation appears to have a particular window where it is sensitive to sleep loss, we explore the parameters of this time window in Chapter 2. Our results suggest that a specific 3-hour period of sleep loss during consolidation disrupts both memory and plasticity. In the second portion of this dissertation, I examine the mechanisms by which sleep deprivation impairs hippocampus-dependent memory consolidation. In Chapter 3, we show that loss of the phosphodiesterase (PDE) 4A, an enzyme responsible for decreasing cAMP signaling, rescues spatial memory disrupted by sleep loss. These results further implicate cAMP signaling with the negative effects of sleep deprivation on memory. Obtaining adequate sleep is challenging in a society that values work around the clock. Therefore, the development of interventions to combat the negative cognitive effects of sleep deprivation is critical. However, a limited number of therapeutics exists that are able to enhance cognition in the face of insufficient sleep. The identification of the temporal characteristics of sleep loss and the molecular pathways implicated in the deleterious effects of sleep deprivation on memory could potentially yield new targets for the development of more effective drugs

A new class of sum rules for products of Bessel functions

In this paper we derive a new class of sum rules for products of the Bessel functions of first kind. Using standard algebraic manipulations we extend some of the well known properties of $J_n$. Some physical applications of the results are also discussed. A comparison with the Newberger[J. Math. Phys. \textbf{23} (1982) 1278] sum rules is performed on a typical example.Comment: Published in Journal of Mathematical Physics, 9 pages, no picture

Gene Duplication and Gain in the Trematode Atriophallophorus winterbourni Contributes to Adaptation to Parasitism.

Gene duplications and novel genes have been shown to play a major role in helminth adaptation to a parasitic lifestyle because they provide the novelty necessary for adaptation to a changing environment, such as living in multiple hosts. Here we present the de novo sequenced and annotated genome of the parasitic trematode Atriophallophorus winterbourni and its comparative genomic analysis to other major parasitic trematodes. First, we reconstructed the species phylogeny, and dated the split of A. winterbourni from the Opisthorchiata suborder to approximately 237.4 Ma (±120.4 Myr). We then addressed the question of which expanded gene families and gained genes are potentially involved in adaptation to parasitism. To do this, we used hierarchical orthologous groups to reconstruct three ancestral genomes on the phylogeny leading to A. winterbourni and performed a GO (Gene Ontology) enrichment analysis of the gene composition of each ancestral genome, allowing us to characterize the subsequent genomic changes. Out of the 11,499 genes in the A. winterbourni genome, as much as 24% have arisen through duplication events since the speciation of A. winterbourni from the Opisthorchiata, and as much as 31.9% appear to be novel, that is, newly acquired. We found 13 gene families in A. winterbourni to have had more than ten genes arising through these recent duplications; all of which have functions potentially relating to host behavioral manipulation, host tissue penetration, and hiding from host immunity through antigen presentation. We identified several families with genes evolving under positive selection. Our results provide a valuable resource for future studies on the genomic basis of adaptation to parasitism and point to specific candidate genes putatively involved in antagonistic host-parasite adaptation

Personalized Cytokine-Directed Therapy With Tocilizumab for Refractory Immune Checkpoint Inhibitor-Related Cholangiohepatitis.

For patients with corticosteroid (CS)-refractory immune checkpoint inhibitor-related cholangiohepatitis (irCH), no consensus exists regarding treatment, and outcomes remain poor. We evaluated the possibility of personalized treatment according to the patient's cytokine profile and the immunohistopathologic assessment of the predominant immune infiltrate type of liver tissue. NSCLCs with CS-refractory irCH were analyzed by immunohistochemistry of liver biopsy specimen, serum cytokine panel, and assessment of peripheral blood mononuclear cell immune cell monitoring by mass cytometry. A total of three consecutive patients with irCH were identified. We found a predominant T-cell infiltrate and an interferon-gamma or T helper 1 proinflammatory cytokine profile. Here, we report for the first time that a T-cell-targeted therapy with the interleukin (IL)-6 receptor-neutralizing antibody tocilizumab, which inhibits signaling downstream of interferon-gamma and several other Janus kinase-dependent cytokines, is an effective single cytokine-directed therapy for CS-refractory irCH. Three patients with severe, CS-refractory irCH who were treated with tocilizumab were found to have persistent clinical and biological remission. Dysregulation of the IL-6/T-cell axis may contribute to the pathogenesis of CS-refractory irCH. Our observations suggest that IL-6 blockade seems to have promise in the treatment of CS-refractory irCH. The results from our three patients need to be confirmed in a larger patient population

Artificial intelligence for automated detection of diabetic foot ulcers: A real-world proof-of-concept clinical evaluation

Objective: Conduct a multicenter proof-of-concept clinical evaluation to assess the accuracy of an artificial intelligence system on a smartphone for automated detection of diabetic foot ulcers. Methods: The evaluation was undertaken with patients with diabetes (n = 81) from September 2020 to January 2021. A total of 203 foot photographs were collected using a smartphone, analysed using the artificial intelligence system, and compared against expert clinician judgement, with 162 images showing at least one ulcer, and 41 showing no ulcer. Sensitivity and specificity of the system against clinician decisions was determined and inter- and intra-rater reliability analysed. Results: Predictions/decisions made by the system showed excellent sensitivity (0.9157) and high specificity (0.8857). Merging of intersecting predictions improved specificity to 0.9243. High levels of inter- and intra-rater reliability for clinician agreement on the ability of the artificial intelligence system to detect diabetic foot ulcers was also demonstrated (Kα > 0.8000 for all studies, between and within raters). Conclusions: We demonstrate highly accurate automated diabetic foot ulcer detection using an artificial intelligence system with a low-end smartphone. This is the first key stage in the creation of a fully automated diabetic foot ulcer detection and monitoring system, with these findings underpinning medical device development

Dengue Virus Infection-Enhancing Activity in Serum Samples with Neutralizing Activity as Determined by Using FcγR-Expressing Cells

Dengue has become a major international public health concern in recent decades. There are four dengue virus serotypes. Recovery from infection with one serotype confers life-long protection to the homologous serotype but only partial protection to subsequent infection with other serotypes. Secondary infection with a serotype different from that in primary infection increases the risk of development of severe complications. Antibodies may play two competing roles during infection: virus neutralization that leads to protection and recovery, or infection-enhancement that may cause severe complications. Progress in vaccine development has been hampered by limited understanding on protective immunity against dengue virus infection. We report the neutralization activity and infection-enhancement activity in individuals with dengue in Malaysia. We show that infection-enhancement activity is present when neutralizing activity is absent or low, and cross-reactive neutralizing activity may be hampered by infection-enhancing activity. Conventional assays for titration of neutralizing antibody do not consider infection-enhancement activity. We used an alternative assay that determines the sum of neutralizing and infection-enhancement activity in sera from dengue patients. In addition to providing insights into antibody responses during infection, the alternative assay provides a new platform for the study of immune responses to vaccine

NRF2-driven miR-125B1 and miR-29B1 transcriptional regulation controls a novel anti-apoptotic miRNA regulatory network for AML survival

Transcription factor NRF2 is an important regulator of oxidative stress. It is involved in cancer progression, and has abnormal constitutive expression in acute myeloid leukaemia (AML). Posttranscriptional regulation by microRNAs (miRNAs) can affect the malignant phenotype of AML cells. In this study, we identified and characterised NRF2-regulated miRNAs in AML. An miRNA array identified miRNA expression level changes in response to NRF2 knockdown in AML cells. Further analysis of miRNAs concomitantly regulated by knockdown of the NRF2 inhibitor KEAP1 revealed the major candidate NRF2-mediated miRNAs in AML. We identified miR-125B to be upregulated and miR-29B to be downregulated by NRF2 in AML. Subsequent bioinformatic analysis identified putative NRF2 binding sites upstream of the miR-125B1 coding region and downstream of the mir-29B1 coding region. Chromatin immunoprecipitation analyses showed that NRF2 binds to these antioxidant response elements (AREs) located in the 5′ untranslated regions of miR-125B and miR-29B. Finally, primary AML samples transfected with anti-miR-125B antagomiR or miR-29B mimic showed increased cell death responsiveness either alone or co-treated with standard AML chemotherapy. In summary, we find that NRF2 regulation of miR-125B and miR-29B acts to promote leukaemic cell survival, and their manipulation enhances AML responsiveness towards cytotoxic chemotherapeutics

TIPS MEMILIH DAN MENYIMPAN TELUR YANG AMAN UNTUK DIKONSUSMI

Eggs are perfect foodstuffs because they contain nutrients such as protein, fat, vitamins, and minerals in sufficient quantities. Under certain conditions, the complete nutritional content in eggs can be a good growth medium for microorganisms. It is important to educate the community about how to differentiate egg quality and how to store eggs properly so that people can choose and get eggs of good quality in the long term. The benefit is that they can be more careful in choosing the eggs to buy, and know-how to store eggs properly so that the egg's shelf life can last longer. This education was carried out online during the Covid-19 pandemic Work From Home (WFH) period using the Zoom meet application. The participants in this counseling consisted of housewives and students