Robust Model Selection for Classification of Microarrays

Recently, microarray-based cancer diagnosis systems have been increasingly investigated. However, cost reduction and reliability assurance of such diagnosis systems are still remaing problems in real clinical scenes. To reduce the cost, we need a supervised classifier involving the smallest number of genes, as long as the classifier is sufficiently reliable. To achieve a reliable classifier, we should assess candidate classifiers and select the best one. In the selection process of the best classifier, however, the assessment criterion must involve large variance because of limited number of samples and non-negligible observation noise. Therefore, even if a classifier with a very small number of genes exhibited the smallest leave-one-out cross-validation (LOO) error rate, it would not necessarily be reliable because classifiers based on a small number of genes tend to show large variance. We propose a robust model selection criterion, the min-max criterion, based on a resampling bootstrap simulation to assess the variance of estimation of classification error rates. We applied our assessment framework to four published real gene expression datasets and one synthetic dataset. We found that a state-of-the-art procedure, weighted voting classifiers with LOO criterion, had a non-negligible risk of selecting extremely poor classifiers and, on the other hand, that the new min-max criterion could eliminate that risk. These finding suggests that our criterion presents a safer procedure to design a practical cancer diagnosis system

精巣上体炎におけるindoleamine 2,3-dioxygenase（IDO）の役割に関する検討

　Indoleamine 2,3-dioxygenase（IDO）は，必須アミノ酸であるトリプトファンのキヌレニン代謝経路における律速酵素であり，免疫反応への関連性が示唆されている．これまでに我々は，IDO が精巣上体頭部に高く発現すると報告している．しかし，その役割について明らかにされていない．今回，我々は精巣上体炎におけるIDO の役割について検討した．　実験動物は12週齢，雄性，C57BL/6マウス，野生型マウス（Ido+ /+）およびIDO ノックアウトマウス（Ido- /-）を用いた．精管側から精巣上体へlipopolysaccharide（LPS）を投与することで，精巣上体炎モデルを作成し，LPS 投与後に精巣上体を摘出した．精巣上体におけるIDO の経時的な発現についてIDO 定量検査（ELISA 法）を用いて解析した．また，精巣上体における炎症性変化について，網羅的サイトカイン/ ケモカイン定量検査により代表マーカーを選出し，免疫染色を行うことで，精巣上体炎におけるIDO の働きについて生化学的および免疫組織学的に検討した．　HE 染色では，Ido- /- はIdo+ /+ と比較して，リンパ球優位の炎症細胞浸潤および精巣上体内の腺管構造破壊が抑制されていた．IDO 定量検査（ELISA 法）では，Ido+ /+ はIdo+ /+ sham と比較して，LPS 投与後１日目，３日目において，精巣上体内におけるIDO 発現の有意な上昇を認めた．Ido- /- では全ての観察期間においてIDO の発現を認めなかった．網羅的サイトカイン/ ケモカイン定量検査では，Ido- /- においてIdo+ /+ と比較して，炎症促進性サイトカイン（IL-1α，IL-6）およびケモカイン（CCL3，CXCL1）の発現が抑制され，炎症抑制性サイトカイン（IL-4，IL-10）の発現が促進されていた．各種マーカーを用いた免疫染色においても同様に，炎症促進性サイトカイン（IL-1α，IL-6）およびケモカイン（CCL3，CXCL1）の発現が抑制され，炎症抑制性サイトカイン（IL-4，IL-10）の発現が促進されていた．　精巣上体では，IDO を介したサイトカイン/ケモカインの調節が行われている可能性がある．IDO を阻害することにより，精巣上体炎に対して精巣上体内の組織保護作用を有すると推測され，抗菌薬に加えてIDO 阻害薬が新規治療薬となる可能性があると考えられる．　Indoleamine 2,3-dioxygenase (IDO) catalyzes the first and rate-limiting step of tryptophan catabolism and has been implicated in immune tolerance. IDO is induced in various tissues during systematic bacterial infection and plays a key role in immune response. In a previous study, we showed that epididymal IDO expression in mouse is restricted to the caput region. We hypothesize that IDO plays a central role in local immunological reactions in the epididymis. To examine this hypothesis, we investigated several cytokines in an epididymitis model in an IDO knockout mouse (Ido- /- ).　Twelve-week-old male mice were used in the study. Wild type mice (Ido+ /+ ) and Ido- /- were injected with lipopolysaccharide (LPS 100 μg) in the epididymis on the side of the vas deferens. After LPS injection, the epididymis was removed in a time-dependent manner. Expression of IDO in the epididymis was chronologically analyzed using ELISA methods. Inflammatory changes were analyzed using a comprehensive cytokine/chemokine assay to identify representative candidates, and immunohistological changes were then analyzed separately for each of these candidates.　Histological analysis showed invasion of lymphocyte-predominant inflammatory cells and destruction of epididymal ductal structure in the epididymitis model in Ido+ /+ compared with Ido- /- . IDO assay showed significant up-regulation of IDO were observed in Ido+ /+ compared with Ido+ /+ sham at day1 and day3. On the other hand, there were not observed the expression of IDO in Ido- /- anytime in time series. The comprehensive cytokine/chemokine assay identified six significant markers: pro-inflammatory cytokines (IL-1α, IL-6) and chemokines (CCL3, CXCL1) were downregulated and anti-inflammatory cytokines (IL-4, IL-10) were up-regulated in Ido- /- compared with Ido+ /+ . Similar results were obtained from immunohistochemical staining for these molecules.　IDO is involved in epididymal immunological reactions via cytokines/chemokines, and inhibition of IDO may contribute to protection of epididymis tissue when inflammation occurs in this tissue. Therefore, IDO might be a novel target for therapy for epididymitis, in addition to antimicrobial agents

Fetal Goitrous Hypothyroidism due to Maternal Thyroid Stimulation-Blocking Antibody: A Case Report

Most fetal goitrous hypothyroidisms are reportedly caused by the maternal use of an antithyroid drug or fetal dyshormonogenesis. However, fetal goitrous hypothyroidism due to the transplacental passage of maternal thyroid stimulation-blocking antibody (TSBAb) is extremely rare. A woman at 28 weeks of gestation was found to have a fetal goiter by ultrasonography. Because the maternal serum showed hypothyroidism with an elevated titer of TSBAb, levothyroxine sodium was administered. The patient delivered a male infant, 3,412 g, with a goiter at term. Umbilical blood revealed primary hypothyroidism with increased TSBAb, and the infant was given levothyroxine sodium. After a month, neonatal thyroid function and TSBAb levels became normal. Attention should be paid to possible fetal hypothyroidism when a fetal goiter is observed to avoid impaired mental development of the neonate.ArticleFETAL DIAGNOSIS AND THERAPY. 28(4):220-224 (2010)journal articl

Natural dimethyl sulfide gradients would lead marine predators to higher prey biomass

© The Author(s), 2021. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Owen, K., Saeki, K., Warren, J. D., Bocconcelli, A., Wiley, D. N., Ohira, S., Bombosch, A., Toda, K., & Zitterbart, D. P. Natural dimethyl sulfide gradients would lead marine predators to higher prey biomass. Communications Biology, 4(1), (2021): 149, https://doi.org/10.1038/s42003-021-01668-3.Finding prey is essential to survival, with marine predators hypothesised to track chemicals such as dimethyl sulfide (DMS) while foraging. Many predators are attracted to artificially released DMS, and laboratory experiments have shown that zooplankton grazing on phytoplankton accelerates DMS release. However, whether natural DMS concentrations are useful for predators and correlated to areas of high prey biomass remains a fundamental knowledge gap. Here, we used concurrent hydroacoustic surveys and in situ DMS measurements to present evidence that zooplankton biomass is spatially correlated to natural DMS concentration in air and seawater. Using agent simulations, we also show that following gradients of DMS would lead zooplankton predators to areas of higher prey biomass than swimming randomly. Further understanding of the conditions and scales over which these gradients occur, and how they are used by predators, is essential to predicting the impact of future changes in the ocean on predator foraging success.Open Access funding enabled and organized by Projekt DEAL. This study was funded by the Herrington Fitch Family Foundation, by the Woods Hole Oceanographic Institution Joint Initiative Awards Fund from the Andrew W. Mellon Foundation and The President’s Investment Fund, and by KAKENHI, Grants-in-Aid for Basic Research (B) (Grant no. 16H04168) and Bilateral Programs Joint Research Projects (open partnership), both from the Japan Society for the Promotion of Science. The authors thank Mrs. Norio Hayashi, Takanori Nagahata, and Ms. Mihoko Asano (Mitsubishi Chemical Analytech Co.) for their support with the SGV-CL device. The research was conducted under Scientific Research Permit number 18059, issued by the National Oceanic and Atmospheric Administration under the Marine Mammal Protection Act

Interference of High Degrees Salt on Spectrophotometric Flow Injection Analysis : Quantitative Error of Nitrite from Schlieren Effect and Salt Effect

Interference of high salt concentrations in spectrophotometric flow injection analysis is described. The spectrophotometric determination of nitrite with Griess reagent was used as a test model. Several percentage concentrations of sodium chloride, magnesium chloride, or magnesium sulfate solutions caused more than 10% positive interference in determining 0.040 mg L-1 nitrite. This interference was attributed not only to the schlieren effect but to the salt effect, i.e., the accelerated reaction of nitrite with the Griess reagent

Mobile monitoring along a street canyon and stationary forest air monitoring of formaldehyde by means of a micro gas analysis system

A micro-gas analysis system (μGAS) was developed for mobile monitoring and continuous measurements of atmospheric HCHO. HCHO gas was trapped into an absorbing/reaction solution continuously using a microchannel scrubber in which the microchannels were patterned in a honeycomb structure to form a wide absorbing area with a thin absorbing solution layer. Fluorescence was monitored after reaction of the collected HCHO with 2,4-pentanedione (PD) in the presence of acetic acid/ammonium acetate. The system was portable, battery-driven, highly sensitive (limit of detection = 0.01 ppbv) and had good time resolution (response time 50 s). The results revealed that the PD chemistry was subject to interference from O3. The mechanism of this interference was investigated and the problem was addressed by incorporating a wet denuder. Mobile monitoring was performed along traffic roads, and elevated HCHO levels in a street canyon were evident upon mapping of the obtained data. The system was also applied to stationary monitoring in a forest in which HCHO formed naturally via reaction of biogenic compounds with oxidants. Concentrations of a few ppbv-HCHO and several-tens of ppbv of O3 were then simultaneously monitored with the μGAS in forest air monitoring campaigns. The obtained 1 h average data were compared with those obtained by 1 h impinger collection and offsite GC-MS analysis after derivatization with o-(2,3,4,5,6-pentafluorobenzyl)hydroxylamine (PFBOA). From the obtained data in the forest, daily variations of chemical HCHO production and loss are discussed

Pathological analysis of spermatic dysfunction following testicular ischemia-reperfusion injury\n

　Introduction & Objectives: Torsion, which may result in testicular ischemia, requires emergency surgery to restore testicular blood flow. However, the risk of spermatic dysfunction remains even if surgery is performed. The pathology of spermatic dysfunction in testicular ischemia-reperfusion injury (TIRI) remains unclear. A previous study showed the relevance of inflammation and oxidative stress in the other organs of ischemia-reperfusion injury. We hypothesized that inflammation and oxidative stress play key roles in causing spermatic dysfunction following TIRI. We investigated the pathophysiology of spermatic dysfunction in TIRI focusing on inflammatory changes using TIRI model mice.　Materials and Methods: The study used C57BL/6J male mice aged 10 to 15 weeks. To create TIRI model mice, the unilateral (left side) testicular vessels were clamped using Dieffenbach clamps (Bulldog clamps) for 1 hour and de-clamped. The bilateral testes were removed at 0 (ischemic state), 1, 3, and 5 weeks after creating the TIRI model mice. Spermatic changes following TIRI were investigated by analyzing the histology of the testes and semen and assessing levels of inflammation and oxidative stress. Semen was collected from the bilateral cauda epididymites and investigated using the sperm motility analysis system (SMAS).　Results: Histological analysis after hematoxylin-eosin staining showed tissue thickening in interstitial tissues at week 1 and 3 on the left (affected) testis, and week 1, 3 and 5 on the right (unaffected) testis. The infiltration of lymphocytes-predominant inflammatory cells were observed at week 1 and week 3 on the left (affected) testis. The destruction of ductal structures and giant cells were observed at weeks 3 and 5 on the left (affected) testis and week 5 on the right (unaffected) testis. SMAS showed significantly decreased spermatic concentration and motility in both testes of TIRI model mice compared with those of sham-operated mice at weeks 1, 3 and 5. Inflammation analysis using an inflammation-related proteome assay showed significantly increased levels of cytokines (IL-2, IL-3, IL-17A, and IL-23) and chemokines (CCL2, CCL5, CXCL1, and CX3CL1) at weeks 1, 3, and 5 in both testes of TIRI model mice. For the assessment of oxidative stress, enzyme-linked immuno-sorbent assay (ELISA) for 8-hydroxy-2’-deoxyguanosine (8-OHdG) was performed, which showed that levels of 8-OHdG were significantly increased in the left (affected) testis of TIRI model mice compared with that of sham-operated mice at all observation periods. Meanwhile, ELISA showed that levels of 8-OHdG in the right (unaffected) testis were significantly increased in TIRI model mice at weeks 3 and 5 compared with that of sham-operated mice.　Conclusions: Spermatic dysfunction following TIRI is induced by inflammation and oxidative stress. Inflammation and oxidative stress may be novel regulatory factors to prevent spermatic dysfunction following TIRI

Fetal Goitrous Hypothyroidism due to Maternal Thyroid Stimulation-Blocking Antibody: A Case Report

Most fetal goitrous hypothyroidisms are reportedly caused by the maternal use of an antithyroid drug or fetal dyshormonogenesis. However, fetal goitrous hypothyroidism due to the transplacental passage of maternal thyroid stimulation-blocking antibody (TSBAb) is extremely rare. A woman at 28 weeks of gestation was found to have a fetal goiter by ultrasonography. Because the maternal serum showed hypothyroidism with an elevated titer of TSBAb, levothyroxine sodium was administered. The patient delivered a male infant, 3,412 g, with a goiter at term. Umbilical blood revealed primary hypothyroidism with increased TSBAb, and the infant was given levothyroxine sodium. After a month, neonatal thyroid function and TSBAb levels became normal. Attention should be paid to possible fetal hypothyroidism when a fetal goiter is observed to avoid impaired mental development of the neonate.ArticleFETAL DIAGNOSIS AND THERAPY. 28(4):220-224 (2010)journal articl