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        Novel KCNQ4 variants in different functional domains confer genotype- and mechanism-based therapeutics in patients with nonsyndromic hearing loss

        Sang-Yeon Lee,Hyun Been Choi,Mina Park,Il Soon Choi,Jieun An,Ami Kim,Eunku Kim,Nahyun Kim,Jin Hee Han,Min young Kim,Seung min Lee,Doo-Yi Oh,Bong Jik Kim,Nayoung Yi,Nayoung, K. D. Kim,Chung Lee,Woong-Y 생화학분자생물학회 2021 Experimental and molecular medicine Vol.53 No.-

        Loss-of-function variant in the gene encoding the KCNQ4 potassium channel causes autosomal dominant nonsyndromic hearing loss (DFNA2), and no effective pharmacotherapeutics have been developed to reverse channel activity impairment. Phosphatidylinositol 4,5-bisphosphate (PIP2), an obligatory phospholipid for maintaining KCNQ channel activity, confers differentialpharmacological sensitivity of channels to KCNQ openers. Through whole-exome sequencing of DFNA2 families, we identified three novel KCNQ4 variants related to diverse auditory phenotypes in the proximal C-terminus (p.Arg331Gln), the C-terminus of the S6 segment (p.Gly319Asp), and the pore region (p.Ala271_Asp272del). Potassium currents in HEK293T cells expressing each KCNQ4 variant were recorded by patch-clamp, and functional recovery by PIP2 expression or KCNQ openers was examined. In the homomeric expression setting, the three novel KCNQ4 mutant proteins lost conductance and were unresponsive to KCNQ openers or PIP2 expression. Loss of p.Arg331Gln conductance was slightly restored by a tandem concatemer channel (WT-p.R331Q), and increased PIP2 expression further increased the concatemer current to the level of the WT channel. Strikingly, an impaired homomeric p.Gly319Asp channel exhibited hyperactivity when a concatemer (WT-p.G319D), with a negative shift in the voltage dependence of activation. Correspondingly, a KCNQ inhibitor and chelation of PIP2 effectively downregulated the hyperactive WTp. G319D concatemer channel. Conversely, the pore-region variant (p.Ala271_Asp272del) was nonrescuable under any condition. Collectively, these novel KCNQ4 variants may constitute therapeutic targets that can be manipulated by the PIP2 level and KCNQregulating drugs under the physiological context of heterozygous expression. Our research contributes to the establishment of a genotype/mechanism-based therapeutic portfolio for DFNA2.

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        줄눈 채움재 크기에 따른 투수 블록 포장의 표면 침투율

        이은구(Lee, Eunku),김 건(Kim, Geon),안재훈(Ahn, Jaehun),신현석(Shin, Hyunsuk) 한국방재학회 2017 한국방재학회논문집 Vol.17 No.1

        도시화로 인한 불투수 면적의 증가와 기후변화로 인한 강우 패턴 변화는, 도심 홍수의 발생빈도를 높이는 주요한 원인으로 파악되고 있다. 이러한 문제를 극복하기 위한 방안으로, 국제적으로 저영향개발 시설의 적용이 확산되고 있는 추세이며, 저영향개발 시설의 대표적인 예로 투수성 포장을 들 수 있다. 본 연구에서는 줄눈 채움재의 직경에 따른 투수 블록 포장의 현장 표면 침투율을 평가하기 위하여, 실증 규모의 블록 포장 주차장을 대상으로, ASTM C 1701 표준 시험법을 사용하여 침투율을 산정하였다. 줄눈 채움재의 직경이 1.5~2.5 mm인 블록 포장의 평균 침투율은 0.98 mm/s, 줄눈 채움재의 직경이 4~8 mm인 경우는 평균 침투율이 2.62 mm/s로 측정되어, 조립 줄눈 채움채를 사용한 투수 블록은 세립 줄눈 채움재를 사용한 블록과 비교해 약 2.7배의 평균 침투율을 가지는 것을 확인하였다. 블록을 제거한 상태에서의 침투율은 하부구조와 관계없이약 13.5 mm/s으로 측정되어, 측정된 블록 포장 침투율 보다 크게 커서, 시험에 사용된 블록 주차장의 경우, 하부 구조는 블록 포장의 ASTM C 1701 시험법으로 계측한 표면 침투율에 큰 영향을 미치지 못하고, 침투율은 블록과 줄눈 채움재 층의 특성에 지배되는 것으로 평가되었다. Urbanization increased the impervious coverage rapidly and the rainfall pattern changed much due to the global weather change. As such, the peak flood discharge was raised and the travel time reduced. In order to overcome these problems, Low Impact Development (LID) techniques have been widely applied internationally, and the permeable pavement is one of notable examples of LID. In an attempt to evaluate field infiltration performance of permeable block pavement systems, the surface infiltration rate of two block parking lot testbeds which have different layer systems and sizes of filling material was investigated by using ASTM C 1701 procedure. A number of tests showed that the average surface infiltration rate was 0.98 mm/s for filler diameter 1.5~2.5 mm and 2.62 mm/s for 4~8 mm, respectively, which means that when the average diameter of the filler was increased three times, the average surface infiltration rate increased about 2.7 times. After removing blocks on the surface of pavement systems, the average surface infiltration rate was 13.5 mm/s that was much higher than the surface infiltration rate on block layer, so it was indicated that the understructure of pavement systems did not have an effect on surface infiltration rate.

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