Cytotoxic and Pathogenic Properties of Klebsiella oxytoca Isolated from Laboratory Animals

Klebsiella oxytoca is an opportunistic pathogen implicated in various clinical diseases in animals and humans. Studies suggest that in humans K. oxytoca exerts its pathogenicity in part through a cytotoxin. However, cytotoxin production in animal isolates of K. oxytoca and its pathogenic properties have not been characterized. Furthermore, neither the identity of the toxin nor a complete repertoire of genes involved in K. oxytoca pathogenesis have been fully elucidated. Here, we showed that several animal isolates of K. oxytoca, including the clinical isolates, produced secreted products in bacterial culture supernatant that display cytotoxicity on HEp-2 and HeLa cells, indicating the ability to produce cytotoxin. Cytotoxin production appears to be regulated by the environment, and soy based product was found to have a strong toxin induction property. The toxin was identified, by liquid chromatography-mass spectrometry and NMR spectroscopy, as low molecular weight heat labile benzodiazepine, tilivalline, previously shown to cause cytotoxicity in several cell lines, including mouse L1210 leukemic cells. Genome sequencing and analyses of a cytotoxin positive K. oxytoca strain isolated from an abscess of a mouse, identified genes previously shown to promote pathogenesis in other enteric bacterial pathogens including ecotin, several genes encoding for type IV and type VI secretion systems, and proteins that show sequence similarity to known bacterial toxins including cholera toxin. To our knowledge, these results demonstrate for the first time, that animal isolates of K. oxytoca, produces a cytotoxin, and that cytotoxin production is under strict environmental regulation. We also confirmed tilivalline as the cytotoxin present in animal K. oxytoca strains. These findings, along with the discovery of a repertoire of genes with virulence potential, provide important insights into the pathogenesis of K. oxytoca. As a novel diagnostic tool, tilivalline may serve as a biomarker for K oxytoca-induced cytotoxicity in humans and animals through detection in various samples from food to diseased samples using LC-MS/MS. Induction of K. oxytoca cytotoxin by consumption of soy may be in part involved in the pathogenesis of gastrointestinal disease

Oxaliplatin, irinotecan and capecitabine as first-line therapy in metastatic colorectal cancer (mCRC): a dose-finding study and pharmacogenomic analysis

A dose-finding study was performed to evaluate the dose-limiting toxicity (DLT), maximum-tolerated dose (MTD) and the recommended dose (RD) of escalating the doses of capecitabine and fixed doses of irinotecan and oxaliplatin on a biweekly schedule for metastatic colorectal cancer patients (mCRC). A pharmacogenomic analysis was performed to investigate the association between SNPs and treatment outcome. METHODS: Eighty-seven chemotherapy-naive mCRC patients were recruited through a two-step study design; 27 were included in the dose-finding study and 60 in the pharmacogenomic analysis. Oxaliplatin (85 mg m(-2)) and CPT-11 (150 mg m(-2)), both on day 1, and capecitabine doses ranging from 850 to 1500 mg m(-2) bid on days 1-7 were explored. Peripheral blood samples were used to genotype 13 SNPs in 10 genes related to drug metabolism or efficacy. Univariate and multivariate Cox analysis was performed to examine associations between SNPs, ORR and PFS. RESULTS: The capecitabine RD was 1000 mg m(-2) bid. Diarrhoea and neutropenia were the DLTs. After a median follow-up of 52.5 months, the median PFS and OS were 12 (95% CI; 10.6-13.4) and 27 months (95% CI; 17.2-36.8), respectively.The GSTP1-G genotype, the Kohne low-risk category and use of a consolidation approach strongly correlated with decreased risk of progression. Patients with all favourable variables showed a median PFS of 42 months vs 3.4 months in the group with all adverse factors. A superior clinical response was obtained in patients with one GSTP1-G allele as compared with GSTP1-AA carriers (P=0.004). CONCLUSION: First-line therapy with oxaliplatin, irinotecan and capecitabine is efficient and well-tolerated. The GSTP1 polymorphism A>G status was significantly associated with ORR and PFS in mCRC treated with this triplet therapy

NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns

Purpose: Pathogenic variants in the X-linked gene NEXMIF (previously KIAA2022) are associated with intellectual disability (ID), autism spectrum disorder, and epilepsy. We aimed to delineate the female and male phenotypic spectrum of NEXMIF encephalopathy. / Methods: Through an international collaboration, we analyzed the phenotypes and genotypes of 87 patients with NEXMIF encephalopathy. / Results: Sixty-three females and 24 males (46 new patients) with NEXMIF encephalopathy were studied, with 30 novel variants. Phenotypic features included developmental delay/ID in 86/87 (99%), seizures in 71/86 (83%) and multiple comorbidities. Generalized seizures predominated including myoclonic seizures and absence seizures (both 46/70, 66%), absence with eyelid myoclonia (17/70, 24%), and atonic seizures (30/70, 43%). Males had more severe developmental impairment; females had epilepsy more frequently, and varied from unaffected to severely affected. All NEXMIF pathogenic variants led to a premature stop codon or were deleterious structural variants. Most arose de novo, although X-linked segregation occurred for both sexes. Somatic mosaicism occurred in two males and a family with suspected parental mosaicism. / Conclusion: NEXMIF encephalopathy is an X-linked, generalized developmental and epileptic encephalopathy characterized by myoclonic–atonic epilepsy overlapping with eyelid myoclonia with absence. Some patients have developmental encephalopathy without epilepsy. Males have more severe developmental impairment. NEXMIF encephalopathy arises due to loss-of-function variants

Mourning and melancholia revisited: correspondences between principles of Freudian metapsychology and empirical findings in neuropsychiatry

Freud began his career as a neurologist studying the anatomy and physiology of the nervous system, but it was his later work in psychology that would secure his place in history. This paper draws attention to consistencies between physiological processes identified by modern clinical research and psychological processes described by Freud, with a special emphasis on his famous paper on depression entitled 'Mourning and melancholia'. Inspired by neuroimaging findings in depression and deep brain stimulation for treatment resistant depression, some preliminary physiological correlates are proposed for a number of key psychoanalytic processes. Specifically, activation of the subgenual cingulate is discussed in relation to repression and the default mode network is discussed in relation to the ego. If these correlates are found to be reliable, this may have implications for the manner in which psychoanalysis is viewed by the wider psychological and psychiatric communities

Children's and adolescents' rising animal-source food intakes in 1990-2018 were impacted by age, region, parental education and urbanicity

Animal-source foods (ASF) provide nutrition for children and adolescents physical and cognitive development. Here, we use data from the Global Dietary Database and Bayesian hierarchical models to quantify global, regional and national ASF intakes between 1990 and 2018 by age group across 185 countries, representing 93% of the worlds child population. Mean ASF intake was 1.9 servings per day, representing 16% of children consuming at least three daily servings. Intake was similar between boys and girls, but higher among urban children with educated parents. Consumption varied by age from 0.6 at <1 year to 2.5 servings per day at 1519 years. Between 1990 and 2018, mean ASF intake increased by 0.5 servings per week, with increases in all regions except sub-Saharan Africa. In 2018, total ASF consumption was highest in Russia, Brazil, Mexico and Turkey, and lowest in Uganda, India, Kenya and Bangladesh. These findings can inform policy to address malnutrition through targeted ASF consumption programmes. (c) 2023, The Author(s)

Alzheimer disease models and human neuropathology: similarities and differences

Animal models aim to replicate the symptoms, the lesions or the cause(s) of Alzheimer disease. Numerous mouse transgenic lines have now succeeded in partially reproducing its lesions: the extracellular deposits of Aβ peptide and the intracellular accumulation of tau protein. Mutated human APP transgenes result in the deposition of Aβ peptide, similar but not identical to the Aβ peptide of human senile plaque. Amyloid angiopathy is common. Besides the deposition of Aβ, axon dystrophy and alteration of dendrites have been observed. All of the mutations cause an increase in Aβ 42 levels, except for the Arctic mutation, which alters the Aβ sequence itself. Overexpressing wild-type APP alone (as in the murine models of human trisomy 21) causes no Aβ deposition in most mouse lines. Doubly (APP × mutated PS1) transgenic mice develop the lesions earlier. Transgenic mice in which BACE1 has been knocked out or overexpressed have been produced, as well as lines with altered expression of neprilysin, the main degrading enzyme of Aβ. The APP transgenic mice have raised new questions concerning the mechanisms of neuronal loss, the accumulation of Aβ in the cell body of the neurons, inflammation and gliosis, and the dendritic alterations. They have allowed some insight to be gained into the kinetics of the changes. The connection between the symptoms, the lesions and the increase in Aβ oligomers has been found to be difficult to unravel. Neurofibrillary tangles are only found in mouse lines that overexpress mutated tau or human tau on a murine tau −/− background. A triply transgenic model (mutated APP, PS1 and tau) recapitulates the alterations seen in AD but its physiological relevance may be discussed. A number of modulators of Aβ or of tau accumulation have been tested. A transgenic model may be analyzed at three levels at least (symptoms, lesions, cause of the disease), and a reading key is proposed to summarize this analysis

Incident type 2 diabetes attributable to suboptimal diet in 184 countries

The global burden of diet-attributable type 2 diabetes (T2D) is not well established. This risk assessment model estimated T2D incidence among adults attributable to direct and body weight-mediated effects of 11 dietary factors in 184 countries in 1990 and 2018. In 2018, suboptimal intake of these dietary factors was estimated to be attributable to 14.1 million (95% uncertainty interval (UI), 13.814.4 million) incident T2D cases, representing 70.3% (68.871.8%) of new cases globally. Largest T2D burdens were attributable to insufficient whole-grain intake (26.1% (25.027.1%)), excess refined rice and wheat intake (24.6% (22.327.2%)) and excess processed meat intake (20.3% (18.323.5%)). Across regions, highest proportional burdens were in central and eastern Europe and central Asia (85.6% (83.487.7%)) and Latin America and the Caribbean (81.8% (80.183.4%)); and lowest proportional burdens were in South Asia (55.4% (52.160.7%)). Proportions of diet-attributable T2D were generally larger in men than in women and were inversely correlated with age. Diet-attributable T2D was generally larger among urban versus rural residents and higher versus lower educated individuals, except in high-income countries, central and eastern Europe and central Asia, where burdens were larger in rural residents and in lower educated individuals. Compared with 1990, global diet-attributable T2D increased by 2.6 absolute percentage points (8.6 million more cases) in 2018, with variation in these trends by world region and dietary factor. These findings inform nutritional priorities and clinical and public health planning to improve dietary quality and reduce T2D globally. (c) 2023, The Author(s)

A spontaneous ad hoc network to share www access

In this paper, we propose a secure spontaneous ad-hoc network, based on direct peer-to-peer interaction, to grant a quick, easy, and secure access to the users to surf the Web. The paper shows the description of our proposal, the procedure of the nodes involved in the system, the security algorithms implemented, and the designed messages. We have taken into account the security and its performance. Although some people have defined and described the main features of spontaneous ad-hoc networks, nobody has published any design and simulation until today. Spontaneous networking will enable a more natural form of wireless computing when people physically meet in the real world. We also validate the success of our proposal through several simulations and comparisons with a regular architecture, taking into account the optimization of the resources of the devices. Finally, we compare our proposal with other caching techniques published in the related literature. The proposal has been developed with the main objective of improving the communication and integration between different study centers of low-resource communities. That is, it lets communicate spontaneous networks, which are working collaboratively and which have been created on different physical places.Authors want to give thanks to the anonymous reviewers for their valuable suggestions, useful comments, and proofreading of this paper. This work was partially supported by the Ministerio de Educacion y Ciencia, Spain, under Grant no. TIN2008-06441-C02-01, and by the "Ayudas complementarias para proyectos de I+D para grupos de calidad de la Generalitat Valenciana" (ACOMP/2010/005).Lacuesta Gilaberte, R.; Lloret, J.; García Pineda, M.; Peñalver Herrero, ML. (2010). A spontaneous ad hoc network to share www access. EURASIP Journal on Wireless Communications and Networking. 2010:1-16. https://doi.org/10.1155/2010/232083S1162010Preuß S, Cap CH: Overview of spontaneous networking-evolving concepts and technologies. In Rostocker Informatik-Berichte. Volume 24. Fachbereich Informatik der Universit at Rostock; 2000:113-123.Gallo S, Galluccio L, Morabito G, Palazzo S: Rapid and energy efficient neighbor discovery for spontaneous networks. Proceedings of the 7th ACM International Symposium on Modeling, Analysis and Simulation of Wireless and Mobile Systems, October 2004, Venice, ItalyLatvakoski J, Pakkala D, Pääkkönen P: A communication architecture for spontaneous systems. IEEE Wireless Communications 2004, 11(3):36-42. 10.1109/MWC.2004.1308947Zarate Silva VH, De Cruz Salgado EI, Quintana FR: AWISPA: an awareness framework for collaborative spontaneous networks. Proceedings of the 36th ASEE/IEEE Frontiers in Education Conference (FIE '06), October 2006 1-6.Feeney LM, Ahlgren B, Westerlund A: Spontaneous networking: an application-oriented approach to ad hoc networking. IEEE Communications Magazine 2001, 39(6):176-181. 10.1109/35.925687Perkins CE, Bhagwat P: Highly dynamic destination-sequenced distance-vector routing (DSDV) for mobile computers. Proceedings of the Conference on Communications Architectures, Protocols and Applications (SIGCOMM '94), August 1994 234-244.Johnson DB, Maltz DA, Broch J: DSR: The Dynamic Source Routing Protocol for Multihop Wireless Ad Hoc Networks, Ad Hoc Networking. Addison-Wesley Longman Publishing, Boston, Mass, USA; 2001.Perkins C, Belding-Royer E, Das S: Ad hoc on-demand distance vector (AODV) routing. RFC 3561, July 2003Park V, Corson MS: IETF MANET Internet Draft "draft-ietf-MANET-tora-spe03.txt". Novemmer 2000.Viana AC, De Amorim MD, Fdida S, de Rezende JF: Self-organization in spontaneous networks: the approach of DHT-based routing protocols. Ad Hoc Networks 2005, 3(5):589-606.Gilaberte RL, Herrero LP: IP addresses configuration in spontaneous networks. Proceedings of the 9th WSEAS International Conference on Computers, July 2005, Athens, GreeceViana AC, Dias de Amorim M, Fdida S, de Rezende JF: Self-organization in spontaneous networks: the approach of DHT-based routing protocols. Ad Hoc Networks 2005, 3(5):589-606.Alvarez-Hamelin JI, Carneiro Viana A, Dias De Amorim M: Architectural considerations for a self-configuring routing scheme for spontaneous networks.,Tech. Rep. 1 October 2005.Lacuesta R, Peñalver L: Automatic configuration of ad-hoc networks: establishing unique IP link-local addresses. Proceedings of the International Conference on Emerging Security Information, Systems and Technologies (SECURWARE '07), October 2007, Valencia, SpainFoulks EF: Social network therapies and society: an overview. Contemporary Family Therapy 1985, 3(4):316-320.Wang Y, Wu H: DFT-MSN: the delay/fault-tolerant mobile sensor network for pervasive information gathering. Proceedings of the 25th IEEE International Conference on Computer Communications (INFOCOM '06), April 2006Kindberg T, Zhang K: Validating and securing spontaneous associations between wireless devices. In Proceedings of the 6th Information Security Conference (ISC '03), 2003. Springer; 44-53.Al-Jaroodi J: Routing security in open/dynamic mobile ad hoc networks. The International Arab Journal of Information Technology 2007, 4(1):17-25.Stajano F, Anderson RJ: The resurrecting duckling: security issues for ad-hoc wireless networks. Proceedings of the 7th International Workshop on Security Protocols, April 1999 172-194.Zhou L, Haas ZJ: Securing ad hoc networks. IEEE Network 1999, 13(6):24-30. 10.1109/65.806983Hauspie M, Simplot-Ryl I: Cooperation in ad hoc networks: enhancing the virtual currency based models. Proceedings of the 1st International Conference on Integrated Internet Ad Hoc and Sensor Networks (InterSense '06), May 2006, Nice, FranceWang X, Dai F, Qian L, Dong H: A way to solve the threat of selfish and malicious nodes for ad hoc networks. Proceedings of the International Symposium on Information Science and Engieering (ISISE '08), December 2008, Shanghai, China 1: 368-370.Kargl F, Klenk A, Weber M, Schlott S: Sensors for detection of misbehaving nodes in MANETs. Detection of Intrusion and Malware and Vulnerability Assessment (DIMVA '04), July 2004, Dortmund, Germany 83-97.Kargl F, Geiss A, Scholott S, Weber M: Secure dynamic source routing. Proceedings of the 38th Annual Hawaii International Conference on System Sciences (HICSS '05), January 2005, Big Island, Hawaii, USAGokhale S, Dasgupta P: Distributed authentication for peer-to-peer networks. Proceedings of the Symposium on Applications and the Internet Workshops, January 2003 347-353.Capkun S, Buttyán L, Hubaux J-P: Self-organized public-key management for mobile ad hoc networks. IEEE Transactions on Mobile Computing 2003, 2(1):52-64. 10.1109/TMC.2003.1195151Stajano F, Anderson R: The resurrecting duckling security issues for ad-hoc wireless networks. In Proceedings of the 7th International Workshop on Security Protocols, 1999, Berlin, Germany, Lecture Notes in Computer Science. Volume 1796. Springer; 172-194.Balfanz D, Smetters DK, Stewart P, Wong HC: Talking to strangers: authentication in ad-hoc wireless networks. Proceedings of the International Symposium on Network and Distributed Systems Security (NDSS '02), February 2002, San Diego, Calif, USABarbara D, Imielinski T: Sleepers and workaholics: caching strategies in mobile environments. Proceedings of the ACM SIGMOD International Conference on Management of Data, May 1994 1-12.Cao G: A scalable low-latency cache invalidation strategy for mobile environments. IEEE Transactions on Knowledge and Data Engineering 2003, 15(5):1251-1265. 10.1109/TKDE.2003.1232276Hu Q, Lee D: Cache algorithms based on adaptive invalidation reports for mobile environments. Cluster Computing 1998, 1(1):39-50. 10.1023/A:1019012927328Jing J, Elmagarmid A, Helal A, Alonso R: Bit-sequences: an adaptive cache invalidation method in mobile client/server environments. Mobile Networks and Applications 1997, 2(2):115-127. 10.1023/A:1013616213333Kahol A, Khurana S, Gupta S, Srimani P: An efficient cache management scheme for mobile environment. Proceedings of the 20th International Conference on Distributied Computing System (ICDCS '00), April 2000, Taipei, Taiwan 530-537.Kazar M: Synchronization and caching issues in the Andrew file system. Proceedings of USENIX Conference, February 1988, Dallas, Tex, USA 27-36.Roussopoulos M, Baker M: CUP: controlled update propagation in peer-to-peer networks. Proceedings of USENIX Annual Technical Conference, June 2003, San Antonio, Tex, USASandberg S, Kleiman S, Goldberg D, Walsh D, Lyon B: Design and implementation of the sun network file system. Proceedings of USENIX Summer Conference, June 1985, Portland, Ore, USA 119-130.Wu K, Yu PS, Chen M: Energy-efficient caching for wireless mobile computing. Proceedings of the 12th IEEE International Conference on Data Engineering, February-March 1996, New Orleans, La, USA 336-343.Yeung MKH, Kwok Y-K: Wireless cache invalidation schemes with link adaptation and downlink traffic. IEEE Transactions on Mobile Computing 2005, 4(1):68-83.Wessels D, Claffy K: Internet cache protocol (IC) v.2. http://www.ietf.org/rfc/rfc2186.txtFan L, Cao P, Almeida J, Broder AZ: Summary cache: a scalable wide-area web cache sharing protocol. IEEE/ACM Transactions on Networking 2000, 8(3):281-293. 10.1109/90.851975Dykes SG, Robbins KA: A viability analysis of cooperative proxy caching. Proceedings of the 20th Annual Joint Conference of the IEEE Computer and Communications Societies (INFOCOM '01), April 2001, Anchorage, Alaska, USA 3: 1205-1214.Wessels D, Claffy K: RFC 2186: Internet cache protocol (ICP), version 2. The Internet Engineering Taskforce, September 1997Wessels D, Claffy K: RFC 2187: application of internet cache protocol (ICP), version 2. The Internet Engineering Taskforce, September 1997Ren Q, Dunhan MH: Using semantic caching to manage location dependent data in mobile computing. Proceedings of the 6th Annual International Conference on Mobile Computing and Networking, August 2000, Boston, Mass, USA 210-221.Lim S, Lee W-C, Cao G, Das CR: Cache invalidation strategies for internet-based mobile ad hoc networks. Computer Communications 2007, 30(8):1854-1869. 10.1016/j.comcom.2007.02.020Park B-N, Lee W, Lee C: QoS-aware internet access schemes for wireless mobile ad hoc networks. Computer Communications 2007, 30(2):369-384. 10.1016/j.comcom.2006.09.004Hara T: Effective replica allocation in ad hoc networks for improving data accessibility. Proceedings of the 20th Annual Joint Conference of the IEEE Computer and Communications Societies (INFOCOM '01), April 2001, Anchorage, Alaska, USA 1568-1576.Papadopouli M, Schulzrinne H: Effects of power conservation, wireless converage and cooperation on data dissemination among mobile devices. Proceedings of the ACM International Symposium on Mobile Ad Hoc Networking and Computing (MobiHoc '01), October 2001, Long Beach, Calif, USA 117-127.Can P, Irani S: Cost-aware WWW proxy caching algorithms. Proceedings of the USENIX Symposium on lnternet Technology and Systems, December 1997Rizzo L, Vicisano L: Replacement policies for a proxy cache. IEEE/ACM Transactions on Networking 2000, 8(2):158-170. 10.1109/90.842139Williams S, Abrams M, Strandridge CR, Abdulla G, Fox EA: Removal policies in network caches for world-wide web documents. Proceedings of the ACM SIGCOMM Conference on Applications, Technologies, Architectures, and Protocols for Computer Communications, August 1996, Palo Alto, Calif, USA 293-305.Hara T: Replica allocation in ad hoc networks with period data update. Proceedings of the 3rd International Conference on Mobile Data Management (MDM '02), July 2002, Edmonton, Canada 79-86.Papadopouli M, Schulzrinne H: Effects of power conservation, wireless coverage and cooperation on data dissemination among mobile devices. Proceedings of the ACM International Symposium on Mobile Ad Hoc Networking and Computing (MobiHoc '01), October 2001, Long Beach, Calif, USA 117-127.Sailhan F, Issarny V: Cooperative caching in ad hoc networks. Proceedings of the 4th International Conference on Mobile Data Management (MDM '03), January 2003, Melbourne, Australia, Lecture Notes in Computer Science 2574: 13-28.Yin L, Cao G: Supporting cooperative caching in ad hoc networks. IEEE Transactions on Mobile Computing 2006, 5(1):77-89.Karumanchi G, Muralidharan S, Prakash R: Information dissemination in partitionable mobile ad hoc networks. Proceedings of the 18th IEEE Symposium on Reliable Distributed Systems (SRDS '99), October 1999, Lausanne, Switzerland 4-13.Corson MS, Macker JP, Cirincione GH: Internet-based mobile ad hoc networking. IEEE Internet Computing 1999, 3(4):63-70. 10.1109/4236.780962Lim S, Lee W-C, Cao G, Das CR: A novel caching scheme for improving internet-based mobile ad hoc networks performance. Ad Hoc Networks 2006, 4(2):225-239. 10.1016/j.adhoc.2004.04.013Opnet Modeler http://www.opnet.com/solutions/network_rd/modeler_wireless.htmlLacuesta R, Lloret J, Garcia M, Peñalver L: Two secure and energy-saving spontaneous ad-hoc protocol for wireless mesh client networks. Journal of Network and Computer Applications. In pres