Production of extracellular aspartic protease in submerged fermentation with Mucor mucedo DSM 809

Fungal milk-clotting enzymes have gained value as bovine Chymosin substitutes in the cheese industry. In this work, the effects of culture conditions on the production of extracellular milk clotting enzymes from Mucor mucedo DSM 809 in submerged fermentation were studied. The maximum activity was observed after 48 h of cultivation at 24°C in Erlenmeyer flasks. The optimized initial pH and shaking speed for enzyme production were 4.5 and 220 rpm, respectively. Glucose at a concentration of 1% (w/v) was the best carbon source for the production of enzyme among the carbohydrates examined (glucose, fructose, lactose, maltodextrin). On the other hand casein at a concentration of 0.5% (w/v) was the selected nitrogen source in the media formulation. Under optimized conditions enzyme levels reached 130 SU per ml fermentation broth. The inoculum type and size has also affected biomass production and the biosynthesis of the enzyme. The preferred method was the inoculation of the culture media with spores at a total load of 6x105 spores per flask.Key words: Milk clotting enzyme, Aspartic protease, Mucor mucedo, Sub-merged fermentation

JUNO Conceptual Design Report

The Jiangmen Underground Neutrino Observatory (JUNO) is proposed to determine the neutrino mass hierarchy using an underground liquid scintillator detector. It is located 53 km away from both Yangjiang and Taishan Nuclear Power Plants in Guangdong, China. The experimental hall, spanning more than 50 meters, is under a granite mountain of over 700 m overburden. Within six years of running, the detection of reactor antineutrinos can resolve the neutrino mass hierarchy at a confidence level of 3-4$\sigma$, and determine neutrino oscillation parameters $\sin^2\theta_{12}$, $\Delta m^2_{21}$, and $|\Delta m^2_{ee}|$ to an accuracy of better than 1%. The JUNO detector can be also used to study terrestrial and extra-terrestrial neutrinos and new physics beyond the Standard Model. The central detector contains 20,000 tons liquid scintillator with an acrylic sphere of 35 m in diameter. $\sim$17,000 508-mm diameter PMTs with high quantum efficiency provide $\sim$75% optical coverage. The current choice of the liquid scintillator is: linear alkyl benzene (LAB) as the solvent, plus PPO as the scintillation fluor and a wavelength-shifter (Bis-MSB). The number of detected photoelectrons per MeV is larger than 1,100 and the energy resolution is expected to be 3% at 1 MeV. The calibration system is designed to deploy multiple sources to cover the entire energy range of reactor antineutrinos, and to achieve a full-volume position coverage inside the detector. The veto system is used for muon detection, muon induced background study and reduction. It consists of a Water Cherenkov detector and a Top Tracker system. The readout system, the detector control system and the offline system insure efficient and stable data acquisition and processing.Comment: 328 pages, 211 figure

The European internet-based patient and research database for primary immunodeficiencies: results 2006-2008

Primary immunodeficiencies (PID) are rare diseases; therefore transnational studies are essential to maximize the scientific outcome and to improve diagnosis and therapy. In order to estimate the prevalence of PID in Europe as well as to establish and evaluate harmonized guidelines for the diagnosis and treatment of PID, the European Society for Immunodeficiencies (ESID) has developed an internet-based database for clinical and research data on patients with PID. This database is a platform for epidemiological analyses as well as the development of new diagnostic and therapeutic strategies and the identification of novel disease-associated genes. Within 4 years, 7430 patients from 39 countries have been documented in the ESID database. Common variable immunodeficiency (CVID) represents the most common entity, with 1540 patients or 20.7% of all entries, followed by isolated immunoglobulin (Ig)G subclass deficiency (546 patients, 7.4%). Evaluations show that the average life expectancy for PID patients varies from 1 to 49 years (median), depending on the type of PID. The prevalence and incidence of PID remains a key question to be answered. As the registration progress is far from finished we can only calculate minimum values for PID, with e.g. France currently showing a minimum prevalence of 3.72 patients per 100,000 inhabitants. The most frequently documented permanent treatment is immunoglobulin replacement; 2819 patients (42% of all patients alive) currently receive this form of treatment

Radioactivity control strategy for the JUNO detector

602siopenJUNO is a massive liquid scintillator detector with a primary scientific goal of determining the neutrino mass ordering by studying the oscillated anti-neutrino flux coming from two nuclear power plants at 53 km distance. The expected signal anti-neutrino interaction rate is only 60 counts per day (cpd), therefore a careful control of the background sources due to radioactivity is critical. In particular, natural radioactivity present in all materials and in the environment represents a serious issue that could impair the sensitivity of the experiment if appropriate countermeasures were not foreseen. In this paper we discuss the background reduction strategies undertaken by the JUNO collaboration to reduce at minimum the impact of natural radioactivity. We describe our efforts for an optimized experimental design, a careful material screening and accurate detector production handling, and a constant control of the expected results through a meticulous Monte Carlo simulation program. We show that all these actions should allow us to keep the background count rate safely below the target value of 10 Hz (i.e. ∼1 cpd accidental background) in the default fiducial volume, above an energy threshold of 0.7 MeV. [Figure not available: see fulltext.]openAbusleme A.; Adam T.; Ahmad S.; Ahmed R.; Aiello S.; Akram M.; An F.; An Q.; Andronico G.; Anfimov N.; Antonelli V.; Antoshkina T.; Asavapibhop B.; de Andre J.P.A.M.; Auguste D.; Babic A.; Baldini W.; Barresi A.; Basilico D.; Baussan E.; Bellato M.; Bergnoli A.; Birkenfeld T.; Blin S.; Blum D.; Blyth S.; Bolshakova A.; Bongrand M.; Bordereau C.; Breton D.; Brigatti A.; Brugnera R.; Bruno R.; Budano A.; Buscemi M.; Busto J.; Butorov I.; Cabrera A.; Cai H.; Cai X.; Cai Y.; Cai Z.; Cammi A.; Campeny A.; Cao C.; Cao G.; Cao J.; Caruso R.; Cerna C.; Chang J.; Chang Y.; Chen P.; Chen P.-A.; Chen S.; Chen X.; Chen Y.-W.; Chen Y.; Chen Y.; Chen Z.; Cheng J.; Cheng Y.; Chetverikov A.; Chiesa D.; Chimenti P.; Chukanov A.; Claverie G.; Clementi C.; Clerbaux B.; Conforti Di Lorenzo S.; Corti D.; Cremonesi O.; Dal Corso F.; Dalager O.; De La Taille C.; Deng J.; Deng Z.; Deng Z.; Depnering W.; Diaz M.; Ding X.; Ding Y.; Dirgantara B.; Dmitrievsky S.; Dohnal T.; Dolzhikov D.; Donchenko G.; Dong J.; Doroshkevich E.; Dracos M.; Druillole F.; Du S.; Dusini S.; Dvorak M.; Enqvist T.; Enzmann H.; Fabbri A.; Fajt L.; Fan D.; Fan L.; Fang J.; Fang W.; Fargetta M.; Fedoseev D.; Fekete V.; Feng L.-C.; Feng Q.; Ford R.; Formozov A.; Fournier A.; Gan H.; Gao F.; Garfagnini A.; Giammarchi M.; Giaz A.; Giudice N.; Gonchar M.; Gong G.; Gong H.; Gornushkin Y.; Gottel A.; Grassi M.; Grewing C.; Gromov V.; Gu M.; Gu X.; Gu Y.; Guan M.; Guardone N.; Gul M.; Guo C.; Guo J.; Guo W.; Guo X.; Guo Y.; Hackspacher P.; Hagner C.; Han R.; Han Y.; Hassan M.S.; He M.; He W.; Heinz T.; Hellmuth P.; Heng Y.; Herrera R.; Hor Y.K.; Hou S.; Hsiung Y.; Hu B.-Z.; Hu H.; Hu J.; Hu J.; Hu S.; Hu T.; Hu Z.; Huang C.; Huang G.; Huang H.; Huang W.; Huang X.; Huang X.; Huang Y.; Hui J.; Huo L.; Huo W.; Huss C.; Hussain S.; Ioannisian A.; Isocrate R.; Jelmini B.; Jen K.-L.; Jeria I.; Ji X.; Ji X.; Jia H.; Jia J.; Jian S.; Jiang D.; Jiang X.; Jin R.; Jing X.; Jollet C.; Joutsenvaara J.; Jungthawan S.; Kalousis L.; Kampmann P.; Kang L.; Karaparambil R.; Kazarian N.; Khan W.; Khosonthongkee K.; Korablev D.; Kouzakov K.; Krasnoperov A.; Kruth A.; Kutovskiy N.; Kuusiniemi P.; Lachenmaier T.; Landini C.; Leblanc S.; Lebrin V.; Lefevre F.; Lei R.; Leitner R.; Leung J.; Li D.; Li F.; Li F.; Li H.; Li H.; Li J.; Li M.; Li M.; Li N.; Li N.; Li Q.; Li R.; Li S.; Li T.; Li W.; Li W.; Li X.; Li X.; Li X.; Li Y.; Li Y.; Li Z.; Li Z.; Li Z.; Liang H.; Liang H.; Liao J.; Liebau D.; Limphirat A.; Limpijumnong S.; Lin G.-L.; Lin S.; Lin T.; Ling J.; Lippi I.; Liu F.; Liu H.; Liu H.; Liu H.; Liu H.; Liu H.; Liu J.; Liu J.; Liu M.; Liu Q.; Liu Q.; Liu R.; Liu S.; Liu S.; Liu S.; Liu X.; Liu X.; Liu Y.; Liu Y.; Lokhov A.; Lombardi P.; Lombardo C.; Loo K.; Lu C.; Lu H.; Lu J.; Lu J.; Lu S.; Lu X.; Lubsandorzhiev B.; Lubsandorzhiev S.; Ludhova L.; Luo F.; Luo G.; Luo P.; Luo S.; Luo W.; Lyashuk V.; Ma B.; Ma Q.; Ma S.; Ma X.; Ma X.; Maalmi J.; Malyshkin Y.; Mantovani F.; Manzali F.; Mao X.; Mao Y.; Mari S.M.; Marini F.; Marium S.; Martellini C.; Martin-Chassard G.; Martini A.; Mayer M.; Mayilyan D.; Mednieks I.; Meng Y.; Meregaglia A.; Meroni E.; Meyhofer D.; Mezzetto M.; Miller J.; Miramonti L.; Montini P.; Montuschi M.; Muller A.; Nastasi M.; Naumov D.V.; Naumova E.; Navas-Nicolas D.; Nemchenok I.; Nguyen Thi M.T.; Ning F.; Ning Z.; Nunokawa H.; Oberauer L.; Ochoa-Ricoux J.P.; Olshevskiy A.; Orestano D.; Ortica F.; Othegraven R.; Pan H.-R.; Paoloni A.; Parmeggiano S.; Pei Y.; Pelliccia N.; Peng A.; Peng H.; Perrot F.; Petitjean P.-A.; Petrucci F.; Pilarczyk O.; Pineres Rico L.F.; Popov A.; Poussot P.; Pratumwan W.; Previtali E.; Qi F.; Qi M.; Qian S.; Qian X.; Qian Z.; Qiao H.; Qin Z.; Qiu S.; Rajput M.U.; Ranucci G.; Raper N.; Re A.; Rebber H.; Rebii A.; Ren B.; Ren J.; Ricci B.; Robens M.; Roche M.; Rodphai N.; Romani A.; Roskovec B.; Roth C.; Ruan X.; Ruan X.; Rujirawat S.; Rybnikov A.; Sadovsky A.; Saggese P.; Sanfilippo S.; Sangka A.; Sanguansak N.; Sawangwit U.; Sawatzki J.; Sawy F.; Schever M.; Schwab C.; Schweizer K.; Selyunin A.; Serafini A.; Settanta G.; Settimo M.; Shao Z.; Sharov V.; Shaydurova A.; Shi J.; Shi Y.; Shutov V.; Sidorenkov A.; Simkovic F.; Sirignano C.; Siripak J.; Sisti M.; Slupecki M.; Smirnov M.; Smirnov O.; Sogo-Bezerra T.; Sokolov S.; Songwadhana J.; Soonthornthum B.; Sotnikov A.; Sramek O.; Sreethawong W.; Stahl A.; Stanco L.; Stankevich K.; Stefanik D.; Steiger H.; Steinmann J.; Sterr T.; Stock M.R.; Strati V.; Studenikin A.; Sun S.; Sun X.; Sun Y.; Sun Y.; Suwonjandee N.; Szelezniak M.; Tang J.; Tang Q.; Tang Q.; Tang X.; Tietzsch A.; Tkachev I.; Tmej T.; Treskov K.; Triossi A.; Troni G.; Trzaska W.; Tuve C.; Ushakov N.; van den Boom J.; van Waasen S.; Vanroyen G.; Vassilopoulos N.; Vedin V.; Verde G.; Vialkov M.; Viaud B.; Vollbrecht M.C.; Volpe C.; Vorobel V.; Voronin D.; Votano L.; Walker P.; Wang C.; Wang C.-H.; Wang E.; Wang G.; Wang J.; Wang J.; Wang K.; Wang L.; Wang M.; Wang M.; Wang M.; Wang R.; Wang S.; Wang W.; Wang W.; Wang W.; Wang X.; Wang X.; Wang Y.; Wang Y.; Wang Y.; Wang Y.; Wang Y.; Wang Y.; Wang Y.; Wang Z.; Wang Z.; Wang Z.; Wang Z.; Waqas M.; Watcharangkool A.; Wei L.; Wei W.; Wei W.; Wei Y.; Wen L.; Wiebusch C.; Wong S.C.-F.; Wonsak B.; Wu D.; Wu F.; Wu Q.; Wu Z.; Wurm M.; Wurtz J.; Wysotzki C.; Xi Y.; Xia D.; Xie X.; Xie Y.; Xie Z.; Xing Z.; Xu B.; Xu C.; Xu D.; Xu F.; Xu H.; Xu J.; Xu J.; Xu M.; Xu Y.; Xu Y.; Yan B.; Yan T.; Yan W.; Yan X.; Yan Y.; Yang A.; Yang C.; Yang C.; Yang H.; Yang J.; Yang L.; Yang X.; Yang Y.; Yang Y.; Yao H.; Yasin Z.; Ye J.; Ye M.; Ye Z.; Yegin U.; Yermia F.; Yi P.; Yin N.; Yin X.; You Z.; Yu B.; Yu C.; Yu C.; Yu H.; Yu M.; Yu X.; Yu Z.; Yu Z.; Yuan C.; Yuan Y.; Yuan Z.; Yuan Z.; Yue B.; Zafar N.; Zambanini A.; Zavadskyi V.; Zeng S.; Zeng T.; Zeng Y.; Zhan L.; Zhang A.; Zhang F.; Zhang G.; Zhang H.; Zhang H.; Zhang J.; Zhang J.; Zhang J.; Zhang J.; Zhang J.; Zhang P.; Zhang Q.; Zhang S.; Zhang S.; Zhang T.; Zhang X.; Zhang X.; Zhang X.; Zhang Y.; Zhang Y.; Zhang Y.; Zhang Y.; Zhang Y.; Zhang Y.; Zhang Z.; Zhang Z.; Zhao F.; Zhao J.; Zhao R.; Zhao S.; Zhao T.; Zheng D.; Zheng H.; Zheng M.; Zheng Y.; Zhong W.; Zhou J.; Zhou L.; Zhou N.; Zhou S.; Zhou T.; Zhou X.; Zhu J.; Zhu K.; Zhu K.; Zhu Z.; Zhuang B.; Zhuang H.; Zong L.; Zou J.Abusleme, A.; Adam, T.; Ahmad, S.; Ahmed, R.; Aiello, S.; Akram, M.; An, F.; An, Q.; Andronico, G.; Anfimov, N.; Antonelli, V.; Antoshkina, T.; Asavapibhop, B.; de Andre, J. P. A. M.; Auguste, D.; Babic, A.; Baldini, W.; Barresi, A.; Basilico, D.; Baussan, E.; Bellato, M.; Bergnoli, A.; Birkenfeld, T.; Blin, S.; Blum, D.; Blyth, S.; Bolshakova, A.; Bongrand, M.; Bordereau, C.; Breton, D.; Brigatti, A.; Brugnera, R.; Bruno, R.; Budano, A.; Buscemi, M.; Busto, J.; Butorov, I.; Cabrera, A.; Cai, H.; Cai, X.; Cai, Y.; Cai, Z.; Cammi, A.; Campeny, A.; Cao, C.; Cao, G.; Cao, J.; Caruso, R.; Cerna, C.; Chang, J.; Chang, Y.; Chen, P.; Chen, P. -A.; Chen, S.; Chen, X.; Chen, Y. -W.; Chen, Y.; Chen, Y.; Chen, Z.; Cheng, J.; Cheng, Y.; Chetverikov, A.; Chiesa, D.; Chimenti, P.; Chukanov, A.; Claverie, G.; Clementi, C.; Clerbaux, B.; Conforti Di Lorenzo, S.; Corti, D.; Cremonesi, O.; Dal Corso, F.; Dalager, O.; De La Taille, C.; Deng, J.; Deng, Z.; Deng, Z.; Depnering, W.; Diaz, M.; Ding, X.; Ding, Y.; Dirgantara, B.; Dmitrievsky, S.; Dohnal, T.; Dolzhikov, D.; Donchenko, G.; Dong, J.; Doroshkevich, E.; Dracos, M.; Druillole, F.; Du, S.; Dusini, S.; Dvorak, M.; Enqvist, T.; Enzmann, H.; Fabbri, A.; Fajt, L.; Fan, D.; Fan, L.; Fang, J.; Fang, W.; Fargetta, M.; Fedoseev, D.; Fekete, V.; Feng, L. -C.; Feng, Q.; Ford, R.; Formozov, A.; Fournier, A.; Gan, H.; Gao, F.; Garfagnini, A.; Giammarchi, M.; Giaz, A.; Giudice, N.; Gonchar, M.; Gong, G.; Gong, H.; Gornushkin, Y.; Gottel, A.; Grassi, M.; Grewing, C.; Gromov, V.; Gu, M.; Gu, X.; Gu, Y.; Guan, M.; Guardone, N.; Gul, M.; Guo, C.; Guo, J.; Guo, W.; Guo, X.; Guo, Y.; Hackspacher, P.; Hagner, C.; Han, R.; Han, Y.; Hassan, M. S.; He, M.; He, W.; Heinz, T.; Hellmuth, P.; Heng, Y.; Herrera, R.; Hor, Y. K.; Hou, S.; Hsiung, Y.; Hu, B. -Z.; Hu, H.; Hu, J.; Hu, J.; Hu, S.; Hu, T.; Hu, Z.; Huang, C.; Huang, G.; Huang, H.; Huang, W.; Huang, X.; Huang, X.; Huang, Y.; Hui, J.; Huo, L.; Huo, W.; Huss, C.; Hussain, S.; Ioannisian, A.; Isocrate, R.; Jelmini, B.; Jen, K. -L.; Jeria, I.; Ji, X.; Ji, X.; Jia, H.; Jia, J.; Jian, S.; Jiang, D.; Jiang, X.; Jin, R.; Jing, X.; Jollet, C.; Joutsenvaara, J.; Jungthawan, S.; Kalousis, L.; Kampmann, P.; Kang, L.; Karaparambil, R.; Kazarian, N.; Khan, W.; Khosonthongkee, K.; Korablev, D.; Kouzakov, K.; Krasnoperov, A.; Kruth, A.; Kutovskiy, N.; Kuusiniemi, P.; Lachenmaier, T.; Landini, C.; Leblanc, S.; Lebrin, V.; Lefevre, F.; Lei, R.; Leitner, R.; Leung, J.; Li, D.; Li, F.; Li, F.; Li, H.; Li, H.; Li, J.; Li, M.; Li, M.; Li, N.; Li, N.; Li, Q.; Li, R.; Li, S.; Li, T.; Li, W.; Li, W.; Li, X.; Li, X.; Li, X.; Li, Y.; Li, Y.; Li, Z.; Li, Z.; Li, Z.; Liang, H.; Liang, H.; Liao, J.; Liebau, D.; Limphirat, A.; Limpijumnong, S.; Lin, G. -L.; Lin, S.; Lin, T.; Ling, J.; Lippi, I.; Liu, F.; Liu, H.; Liu, H.; Liu, H.; Liu, H.; Liu, H.; Liu, J.; Liu, J.; Liu, M.; Liu, Q.; Liu, Q.; Liu, R.; Liu, S.; Liu, S.; Liu, S.; Liu, X.; Liu, X.; Liu, Y.; Liu, Y.; Lokhov, A.; Lombardi, P.; Lombardo, C.; Loo, K.; Lu, C.; Lu, H.; Lu, J.; Lu, J.; Lu, S.; Lu, X.; Lubsandorzhiev, B.; Lubsandorzhiev, S.; Ludhova, L.; Luo, F.; Luo, G.; Luo, P.; Luo, S.; Luo, W.; Lyashuk, V.; Ma, B.; Ma, Q.; Ma, S.; Ma, X.; Ma, X.; Maalmi, J.; Malyshkin, Y.; Mantovani, F.; Manzali, F.; Mao, X.; Mao, Y.; Mari, S. M.; Marini, F.; Marium, S.; Martellini, C.; Martin-Chassard, G.; Martini, A.; Mayer, M.; Mayilyan, D.; Mednieks, I.; Meng, Y.; Meregaglia, A.; Meroni, E.; Meyhofer, D.; Mezzetto, M.; Miller, J.; Miramonti, L.; Montini, P.; Montuschi, M.; Muller, A.; Nastasi, M.; Naumov, D. V.; Naumova, E.; Navas-Nicolas, D.; Nemchenok, I.; Nguyen Thi, M. T.; Ning, F.; Ning, Z.; Nunokawa, H.; Oberauer, L.; Ochoa-Ricoux, J. P.; Olshevskiy, A.; Orestano, D.; Ortica, F.; Othegraven, R.; Pan, H. -R.; Paoloni, A.; Parmeggiano, S.; Pei, Y.; Pelliccia, N.; Peng, A.; Peng, H.; Perrot, F.; Petitjean, P. -A.; Petrucci, F.; Pilarczyk, O.; Pineres Rico, L. F.; Popov, A.; Poussot, P.; Pratumwan, W.; Previtali, E.; Qi, F.; Qi, M.; Qian, S.; Qian, X.; Qian, Z.; Qiao, H.; Qin, Z.; Qiu, S.; Rajput, M. U.; Ranucci, G.; Raper, N.; Re, A.; Rebber, H.; Rebii, A.; Ren, B.; Ren, J.; Ricci, B.; Robens, M.; Roche, M.; Rodphai, N.; Romani, A.; Roskovec, B.; Roth, C.; Ruan, X.; Ruan, X.; Rujirawat, S.; Rybnikov, A.; Sadovsky, A.; Saggese, P.; Sanfilippo, S.; Sangka, A.; Sanguansak, N.; Sawangwit, U.; Sawatzki, J.; Sawy, F.; Schever, M.; Schwab, C.; Schweizer, K.; Selyunin, A.; Serafini, A.; Settanta, G.; Settimo, M.; Shao, Z.; Sharov, V.; Shaydurova, A.; Shi, J.; Shi, Y.; Shutov, V.; Sidorenkov, A.; Simkovic, F.; Sirignano, C.; Siripak, J.; Sisti, M.; Slupecki, M.; Smirnov, M.; Smirnov, O.; Sogo-Bezerra, T.; Sokolov, S.; Songwadhana, J.; Soonthornthum, B.; Sotnikov, A.; Sramek, O.; Sreethawong, W.; Stahl, A.; Stanco, L.; Stankevich, K.; Stefanik, D.; Steiger, H.; Steinmann, J.; Sterr, T.; Stock, M. R.; Strati, V.; Studenikin, A.; Sun, S.; Sun, X.; Sun, Y.; Sun, Y.; Suwonjandee, N.; Szelezniak, M.; Tang, J.; Tang, Q.; Tang, Q.; Tang, X.; Tietzsch, A.; Tkachev, I.; Tmej, T.; Treskov, K.; Triossi, A.; Troni, G.; Trzaska, W.; Tuve, C.; Ushakov, N.; van den Boom, J.; van Waasen, S.; Vanroyen, G.; Vassilopoulos, N.; Vedin, V.; Verde, G.; Vialkov, M.; Viaud, B.; Vollbrecht, M. C.; Volpe, C.; Vorobel, V.; Voronin, D.; Votano, L.; Walker, P.; Wang, C.; Wang, C. -H.; Wang, E.; Wang, G.; Wang, J.; Wang, J.; Wang, K.; Wang, L.; Wang, M.; Wang, M.; Wang, M.; Wang, R.; Wang, S.; Wang, W.; Wang, W.; Wang, W.; Wang, X.; Wang, X.; Wang, Y.; Wang, Y.; Wang, Y.; Wang, Y.; Wang, Y.; Wang, Y.; Wang, Y.; Wang, Z.; Wang, Z.; Wang, Z.; Wang, Z.; Waqas, M.; Watcharangkool, A.; Wei, L.; Wei, W.; Wei, W.; Wei, Y.; Wen, L.; Wiebusch, C.; Wong, S. C. -F.; Wonsak, B.; Wu, D.; Wu, F.; Wu, Q.; Wu, Z.; Wurm, M.; Wurtz, J.; Wysotzki, C.; Xi, Y.; Xia, D.; Xie, X.; Xie, Y.; Xie, Z.; Xing, Z.; Xu, B.; Xu, C.; Xu, D.; Xu, F.; Xu, H.; Xu, J.; Xu, J.; Xu, M.; Xu, Y.; Xu, Y.; Yan, B.; Yan, T.; Yan, W.; Yan, X.; Yan, Y.; Yang, A.; Yang, C.; Yang, C.; Yang, H.; Yang, J.; Yang, L.; Yang, X.; Yang, Y.; Yang, Y.; Yao, H.; Yasin, Z.; Ye, J.; Ye, M.; Ye, Z.; Yegin, U.; Yermia, F.; Yi, P.; Yin, N.; Yin, X.; You, Z.; Yu, B.; Yu, C.; Yu, C.; Yu, H.; Yu, M.; Yu, X.; Yu, Z.; Yu, Z.; Yuan, C.; Yuan, Y.; Yuan, Z.; Yuan, Z.; Yue, B.; Zafar, N.; Zambanini, A.; Zavadskyi, V.; Zeng, S.; Zeng, T.; Zeng, Y.; Zhan, L.; Zhang, A.; Zhang, F.; Zhang, G.; Zhang, H.; Zhang, H.; Zhang, J.; Zhang, J.; Zhang, J.; Zhang, J.; Zhang, J.; Zhang, P.; Zhang, Q.; Zhang, S.; Zhang, S.; Zhang, T.; Zhang, X.; Zhang, X.; Zhang, X.; Zhang, Y.; Zhang, Y.; Zhang, Y.; Zhang, Y.; Zhang, Y.; Zhang, Y.; Zhang, Z.; Zhang, Z.; Zhao, F.; Zhao, J.; Zhao, R.; Zhao, S.; Zhao, T.; Zheng, D.; Zheng, H.; Zheng, M.; Zheng, Y.; Zhong, W.; Zhou, J.; Zhou, L.; Zhou, N.; Zhou, S.; Zhou, T.; Zhou, X.; Zhu, J.; Zhu, K.; Zhu, K.; Zhu, Z.; Zhuang, B.; Zhuang, H.; Zong, L.; Zou, J

Theories of schizophrenia: a genetic-inflammatory-vascular synthesis

BACKGROUND: Schizophrenia, a relatively common psychiatric syndrome, affects virtually all brain functions yet has eluded explanation for more than 100 years. Whether by developmental and/or degenerative processes, abnormalities of neurons and their synaptic connections have been the recent focus of attention. However, our inability to fathom the pathophysiology of schizophrenia forces us to challenge our theoretical models and beliefs. A search for a more satisfying model to explain aspects of schizophrenia uncovers clues pointing to genetically mediated CNS microvascular inflammatory disease. DISCUSSION: A vascular component to a theory of schizophrenia posits that the physiologic abnormalities leading to illness involve disruption of the exquisitely precise regulation of the delivery of energy and oxygen required for normal brain function. The theory further proposes that abnormalities of CNS metabolism arise because genetically modulated inflammatory reactions damage the microvascular system of the brain in reaction to environmental agents, including infections, hypoxia, and physical trauma. Damage may accumulate with repeated exposure to triggering agents resulting in exacerbation and deterioration, or healing with their removal. There are clear examples of genetic polymorphisms in inflammatory regulators leading to exaggerated inflammatory responses. There is also ample evidence that inflammatory vascular disease of the brain can lead to psychosis, often waxing and waning, and exhibiting a fluctuating course, as seen in schizophrenia. Disturbances of CNS blood flow have repeatedly been observed in people with schizophrenia using old and new technologies. To account for the myriad of behavioral and other curious findings in schizophrenia such as minor physical anomalies, or reported decreased rates of rheumatoid arthritis and highly visible nail fold capillaries, we would have to evoke a process that is systemic such as the vascular and immune/inflammatory systems. SUMMARY: A vascular-inflammatory theory of schizophrenia brings together environmental and genetic factors in a way that can explain the diversity of symptoms and outcomes observed. If these ideas are confirmed, they would lead in new directions for treatments or preventions by avoiding inducers of inflammation or by way of inflammatory modulating agents, thus preventing exaggerated inflammation and consequent triggering of a psychotic episode in genetically predisposed persons