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Head-fixation is widely used in neuroscience for stimulus control, behavioral monitoring, and neural recording and perturbation experiments, because it minimizes motion between the subject’s head and the recording or stimulating equipment.

Autotaxin (ATX) converts lysophosphatidylcholine and sphingosyl-phosphorylcholine into lysophosphatidic acid and sphingosine 1-phosphate, respectively. Despite the pivotal function of ATX in lipid metabolism, mechanisms by which ATX regulates immune and inflammatory disorders remain elusive. Here, using myeloid cell lineage-restricted Atx knockout mice, we show that Atx deficiency disrupts membrane microdomains and lipid rafts, resulting in the inhibition of Toll-like receptor 4 (TLR4) complex formation and the suppression of adaptor recruitment, thereby inhibiting TLR4-mediated responses in macrophages. Accordingly, TLR4-induced innate immune functions, including phagocytosis and iNOS expression, are attenuated in Atx-deficient macrophages. Consequently, Atx-/- mice exhibit a higher bacterial prevalence in the intestinal mucosa compared to controls. When combined with global Il10-/- mice, which show spontaneous colitis due to the translocation of luminal commensal microbes into the mucosa, myeloid cell lineage-restricted Atx knockout accelerates colitis development compared to control littermates. Collectively, our data reveal that Atx deficiency compromises innate immune responses, thereby promoting microbe-associated gut inflammation.

Il-Gyu Ko,1 Jun-Jang Jin,1 Lakkyong Hwang,1 Sang-Hoon Kim,1 Chang-Ju Kim,1 Kyu Yeoun Won,2 Yong Gil Na,3 Khae Hawn Kim,3 Su Jin Kim4 1Department of Physiology, College of Medicine, Kyung Hee University, Seoul, 02447, Republic of Korea; 2Department of Pathology, Kyung Hee University Hospital at Gangdong, College of Medicine, Kyung Hee University, Seoul, 05278, Korea; 3Department of Urology, Chungnam National University Sejong Hospital, College of Medicine, Chungnam National University, Sejong-si, 30099, Republic of Korea; 4Department of Urology, Yonsei University Wonju College of Medicine, Wonju, 26426, Republic of KoreaCorrespondence: Su Jin KimDepartment of Urology, Yonsei University Wonju College of Medicine, 20 Ilsanro, Wonju, Gangwon-do, 26426, Republic of KoreaTel +82-10-3287-0615Email hygeiasujin@naver.comBackground: Interstitial cystitis (IC) is a chronic disorder that indicates bladder-related pain or discomfort. Patients with IC often experience urination problems, such as urinary frequency and urgency, along with pain or discomfort in the bladder area. Therefore, new treatments based on IC etiology are needed. Polydeoxyribonucleotide (PDRN) is a biologic agonist of the adenosine A2A receptor, and PDRN has anti-inflammatory effect and inhibits apoptosis. In the current study, the effect of PDRN on cyclophosphamide-induced IC animal model was investigated using rats.Methodology: To induce the IC animal model, 75 mg/kg of cyclophosphamide was injected intraperitoneally once every 3 days for 10 days. The rats in the PDRN-treated groups were intraperitoneally injected with 0.5 mL physiological saline containing 8 mg/kg PDRN, once a day for 10 days after IC induction.Results: Induction of IC by cyclophosphamide injection caused voiding dysfunction, bladder edema, and histological damage. Cyclophosphamide injection increased secretion of pro-inflammatory cytokines and enhanced apoptosis. In contrast, PDRN treatment alleviated voiding dysfunction, bladder edema, a

This thesis presents an assessment of the effects of climate change in reservoir inflow and hydropower generation potential across the Lower Nelson River Basin. A hydrologic-operations model coupling framework was developed and two coupled models, WATFLOOD-MODSIM and HEC-HMS-MODSIM, were set up to simulate both basin water balance and hydropower generation. The coupled models were driven by nineteen climate simulations from CMIP5 to compute historical (1981-2010) and future (2021-2070) reservoir inflow and hydropower generation potential. This work aimed to identify changes in the annual and seasonal reservoir inflow quantity and distribution and to evaluate the likelihood of future hydropower generation exceedance (relative to a historical threshold). Results show that it is about as likely as not or unlikely to be a statistically significant trend (neither increase nor decrease) in annual and seasonal reservoir inflow and hydropower generation potential over 30-year periods on Lower Nelson River. There is a large variability in projected changes in both annual and seasonal reservoir inflow and hydropower generation potential due to dry scenarios becoming drier and wet scenarios becoming wetter over the years. Winter is identified as the season with the greatest possible reduction in reservoir inflow and hydropower generation potential and the least possible increase in the 30-year mean over time. Increases in reservoir inflow did not always translate to an increase in hydropower generation potential on the Lower Nelson River due to limits on system generation capacity for storing water. Therefore, a reduction in inflow directly translated to a reduction in hydropower generation potential, while an increase in inflow only contributed to a limited increase in hydropower generation potential.

This thesis presents an assessment of the effects of climate change in reservoir inflow and hydropower generation potential across the Lower Nelson River Basin. A hydrologic-operations model coupling framework was developed and two coupled models, WATFLOOD-MODSIM and HEC-HMS-MODSIM, were set up to simulate both basin water balance and hydropower generation. The coupled models were driven by nineteen climate simulations from CMIP5 to compute historical (1981-2010) and future (2021-2070) reservoir inflow and hydropower generation potential. This work aimed to identify changes in the annual and seasonal reservoir inflow quantity and distribution and to evaluate the likelihood of future hydropower generation exceedance (relative to a historical threshold). Results show that it is about as likely as not or unlikely to be a statistically significant trend (neither increase nor decrease) in annual and seasonal reservoir inflow and hydropower generation potential over 30-year periods on Lower Nelson River. There is a large variability in projected changes in both annual and seasonal reservoir inflow and hydropower generation potential due to dry scenarios becoming drier and wet scenarios becoming wetter over the years. Winter is identified as the season with the greatest possible reduction in reservoir inflow and hydropower generation potential and the least possible increase in the 30-year mean over time. Increases in reservoir inflow did not always translate to an increase in hydropower generation potential on the Lower Nelson River due to limits on system generation capacity for storing water. Therefore, a reduction in inflow directly translated to a reduction in hydropower generation potential, while an increase in inflow only contributed to a limited increase in hydropower generation potential.

This thesis presents an assessment of the effects of climate change in reservoir inflow and hydropower generation potential across the Lower Nelson River Basin. A hydrologic-operations model coupling framework was developed and two coupled models, WATFLOOD-MODSIM and HEC-HMS-MODSIM, were set up to simulate both basin water balance and hydropower generation. The coupled models were driven by nineteen climate simulations from CMIP5 to compute historical (1981-2010) and future (2021-2070) reservoir inflow and hydropower generation potential. This work aimed to identify changes in the annual and seasonal reservoir inflow quantity and distribution and to evaluate the likelihood of future hydropower generation exceedance (relative to a historical threshold). Results show that it is about as likely as not or unlikely to be a statistically significant trend (neither increase nor decrease) in annual and seasonal reservoir inflow and hydropower generation potential over 30-year periods on Lower Nelson River. There is a large variability in projected changes in both annual and seasonal reservoir inflow and hydropower generation potential due to dry scenarios becoming drier and wet scenarios becoming wetter over the years. Winter is identified as the season with the greatest possible reduction in reservoir inflow and hydropower generation potential and the least possible increase in the 30-year mean over time. Increases in reservoir inflow did not always translate to an increase in hydropower generation potential on the Lower Nelson River due to limits on system generation capacity for storing water. Therefore, a reduction in inflow directly translated to a reduction in hydropower generation potential, while an increase in inflow only contributed to a limited increase in hydropower generation potential.

This thesis presents an assessment of the effects of climate change in reservoir inflow and hydropower generation potential across the Lower Nelson River Basin. A hydrologic-operations model coupling framework was developed and two coupled models, WATFLOOD-MODSIM and HEC-HMS-MODSIM, were set up to simulate both basin water balance and hydropower generation. The coupled models were driven by nineteen climate simulations from CMIP5 to compute historical (1981-2010) and future (2021-2070) reservoir inflow and hydropower generation potential. This work aimed to identify changes in the annual and seasonal reservoir inflow quantity and distribution and to evaluate the likelihood of future hydropower generation exceedance (relative to a historical threshold). Results show that it is about as likely as not or unlikely to be a statistically significant trend (neither increase nor decrease) in annual and seasonal reservoir inflow and hydropower generation potential over 30-year periods on Lower Nelson River. There is a large variability in projected changes in both annual and seasonal reservoir inflow and hydropower generation potential due to dry scenarios becoming drier and wet scenarios becoming wetter over the years. Winter is identified as the season with the greatest possible reduction in reservoir inflow and hydropower generation potential and the least possible increase in the 30-year mean over time. Increases in reservoir inflow did not always translate to an increase in hydropower generation potential on the Lower Nelson River due to limits on system generation capacity for storing water. Therefore, a reduction in inflow directly translated to a reduction in hydropower generation potential, while an increase in inflow only contributed to a limited increase in hydropower generation potential.

BackgroundPhosphatase and tensin homolog (Pten) is capable of mediating microbe-induced immune responses in the gut. Thus, Pten deficiency in the intestine accelerates colitis development in Il10-/- mice. As some ambient pollutants inhibit Pten function and exposure to ambient pollutants may increase inflammatory bowel disease (IBD) incidence, it is of interest to examine how Pten inhibition could affect colitis development in genetically susceptible hosts.MethodsWith human colonic mucosa biopsies from pediatric ulcerative colitis and non-IBD control subjects, we assessed the mRNA levels of the PTEN gene and the gene involved in IL10 responses. The data from the human tissues were corroborated by treating Il10-/-, Il10rb-/-, and wild-type C57BL/6 mice with Pten-specific inhibitor VO-OHpic. We evaluated the severity of mouse colitis by investigating the tissue histology and cytokine production. The gut microbiome was investigated by analyzing the 16S ribosomal RNA gene sequence with mouse fecal samples.ResultsPTEN and IL10RB mRNA levels were reduced in the human colonic mucosa of pediatric ulcerative colitis compared with non-IBD subjects. Intracolonic treatment of the Pten inhibitor induced colitis in Il10-/- mice, characterized by reduced body weight, marked colonic damage, and increased production of inflammatory cytokines, whereas Il10rb-/- and wild-type C57BL/6 mice treated with the inhibitor did not develop colitis. Pten inhibitor treatment changed the fecal microbiome, with increased abundance of colitogenic bacteria Bacteroides and Akkermansia in Il10-/- mice.ConclusionsLoss of Pten function increases the levels of colitogenic bacteria in the gut, thereby inducing deleterious colitis in an Il10-deficient condition.

The recognition of lysine-type peptidoglycans (PG) by the PG recognition complex has been suggested to cause activation of the serine protease cascade leading to the processing of Spätzle and subsequent activation of the Toll signaling pathway. So far, two serine proteases involved in the lysine-type PG Toll signaling pathway have been identified. One is a modular serine protease functioning as an initial enzyme to be recruited into the lysine-type PG recognition complex. The other is the Drosophila Spätzle processing enzyme (SPE), a terminal enzyme that converts Spätzle pro-protein to its processed form capable of binding to the Toll receptor. However, it remains unclear how the initial PG recognition signal is transferred to Spätzle resulting in Toll pathway activation. Also, the biochemical characteristics and mechanism of action of a serine protease linking the modular serine protease and SPE have not been investigated. Here, we purified and cloned a novel upstream serine protease of SPE that we named SAE, SPE-activating enzyme, from the hemolymph of a large beetle, Tenebrio molitor larvae. This enzyme was activated by Tenebrio modular serine protease and in turn activated the Tenebrio SPE. The biochemical ordered functions of these three serine proteases were determined in vitro, suggesting that the activation of a three-step proteolytic cascade is necessary and sufficient for lysine-type PG recognition signaling. The processed Spätzle by this cascade induced antibacterial activity in vivo. These results demonstrate that the three-step proteolytic cascade linking the PG recognition complex and Spätzle processing is essential for the PG-dependent Toll signaling pathway.