Modeling of Surface Microtopography and its Impacts on Hydrologic Processes

Understanding the impacts of surface microtopography on hydrologic processes is critical. The objectives of this thesis research are: (1) to evaluate the effects of DEM resolution on microtopographic characteristics, hydrologic connectivity, and modeling of hydrologic processes; and (2) to assess the influences of multiple rainfall events on surface and subsurface hydrologic processes with the use of a puddle-to-puddle (P2P) modeling system. The change in DEM resolution has a significant effect on how surface microtopography is depicted, which in turn alters the hydrologic response of a topographic surface. The smoothing of reduced DEM resolution tends to enhance hydrologic connectivity, reduce the depression storage and infiltration, and increase surface runoff. Temporal rainfall distribution results in spatio-temporal variations in soil water dynamics, depression storage, infiltration, hydrologic connectivity, and surface runoff. The reduction in ponding time and infiltration, and the enhancement of hydrologic connectivity further caused earlier and greater surface runoff generation

THE DECADENCE OF THE BET-ʾASGÄDÄ ARISTOCRATIC SYSTEM AND THE EMANCIPATION OF THE TǝGRÄ (1890-1948)

Per secoli gli altopiani settentrionali dell'Eritrea hanno ospitato gruppi di immigrati di diversa origine. Nel sedicesimo secolo ci fu il reinsediamento della famiglia di Bʾǝmnät (ብእምነት), in seguito noto come Bet-ʾAsgädä (ቤት ኣስገደ) dopo una delle migrazioni di suo figlio a Sahǝl (ሳሕል). Partirono da ʿAdi-Nǝfas (ዓዲ ንፋስ), di Ḥamasen (ሓማሴን) insieme a numerose famiglie e persone di varie professioni e si stabilirono negli altopiani del Sahǝl. A causa della geografia e del clima, i vari antichi abitanti dell'area del Sahǝl conducevano una vita pastorale. Si spostavano stagionalmente dagli altopiani alle pianure costiere a est, e dalle pianure occidentali fino all’attuale Sudan. La piccole dimensioni e la natura mobile dell'organizzazione sociale nomade avevano reso i clan vittime di qualsiasi forza bellica organizzata. La lotta per il potere della famiglia Bʾǝmnät e l'economia sedentaria in patria diedero loro una relativa superiorità guerriera e organizzativa sui clan ospitanti Tǝgrä (ትግረ). In nessun momento i Bet-ʾAsgädä si sono imposti come signori della terra e del popolo nella regione, con la responsabilità di difendere eventuali incursioni e diritti di pascolo, in cambio i sudditi offrivano gabelle e servizi. Tale fornitura di imposte e di servizi fece sì che i signori noti anche come i Šumaglä (ሹማግለ) abbandonassero la loro tradizione agricola e dipendessero interamente dai doni Tǝgrä. La consolidata aristocrazia Tǝgrä-Šumaglä dei Bet-ʾAsgädä continuò con un'economia nomade predominante. Tale classificazione e relazione binaria tra proprietari terrieri e pastori fu quasi un'esperienza unica nel suo genere rispetto alle pratiche feudali convenzionali fino a quando non crollò definitivamente alla fine degli anni '40. Pertanto, questa dissertazione cerca di scoprire l'indebolimento e il declino del rapporto aristocratico. Di fronte al diverso dinamismo politico della regione, l'ordine aristocratico ha resistito fino al XX secolo. Numerose forze politiche e movimenti religiosi si aggirarono e si stabilirono nella regione di Bet-ʾAsgädä, numerosi imperi regionali e viceré assoggettarono la regione ma senza alcun cambiamento fondamentale nella natura del legame aristocratico. Quindi, questa tesi si sforza di investigare sul perché la fine dell’aristocrazia, che ha preannunciato l'emancipazione del Tǝgrä è avvenuta nel periodo britannico piuttosto che prima o dopo? Infine, i risultati della tesi sostengono che, analogamente alla natura debole e 2 Sahǝl (ሳሕል) è la parte settentrionale dell'Eritrea. Confina con il Sudan e il Mar Rosso, rispettivamente a nord-ovest e ad est. Gli altopiani settentrionali o it territorio di Bet-ʾAsgädä in esame si trovano all’interno di questa regione. Disorganizzata dei Tǝgrä che mettevano in soggezione, la loro emanicipazione fu raggiunta grazie agli elementi che causarono l’inevitabile decadenza del Sistema aristocratico. Questi includevano; l'intervento capitalista formale e informale del sistema coloniale italiano, la forte resistenza e unità del Tǝgrä sotto la guida di individui coscienti e istruiti e la buona volontà dell'amministrazione britannica. Come indagine storica, questo lavoro seguirà gli sviluppi cronologici per dimostrare una relativa veridicità di spiegazione e ricostruzione del processo del declino dell'aristocrazia Bet-ʾAsgädä e della successiva emancipazione delle comunità Tǝgrä

Alternatively activated macrophages promote pancreatic fibrosis in chronic pancreatitis.

Chronic pancreatitis (CP) is a progressive and irreversible inflammatory and fibrotic disease with no cure. Unlike acute pancreatitis (AP), we find that alternatively activated macrophages (AAMs) are dominant in mouse and human CP. AAMs are dependent on interleukin (IL)-4 and IL-13 signalling, and we show that mice lacking IL-4Rα, myeloid-specific IL-4Rα and IL-4/IL-13 were less susceptible to pancreatic fibrosis. Furthermore, we demonstrate that mouse and human pancreatic stellate cells (PSCs) are a source of IL-4/IL-13. Notably, we show that pharmacologic inhibition of IL-4/IL-13 in human ex vivo studies as well as in established mouse CP decreases pancreatic AAMs and fibrosis. We identify a critical role for macrophages in pancreatic fibrosis and in turn PSCs as important inducers of macrophage-alternative activation. Our study challenges and identifies pathways involved in crosstalk between macrophages and PSCs that can be targeted to reverse or halt pancreatic fibrosis progression

Absence of keratin 8 or 18 promotes antimitochondrial autoantibody formation in aging male mice

Human mutations in keratin 8 (K8) and keratin 18 (K18), the intermediate filament proteins of hepatocytes, predispose to several liver diseases. K8‐null mice develop chronic liver injury and fragile hepatocytes, dysfunctional mitochondria, and Th2‐type colitis. We tested the hypothesis that autoantibody formation accompanies the liver damage that associates with K8/K18 absence. Sera from wild‐type control, K8‐null, and K18‐null mice were analyzed by immunoblotting and immunofluorescence staining of cell and mouse tissue homogenates. Autoantibodies to several antigens were identified in 81 % of K8‐null male mice 8 mo or older. Similar autoantibodies were detected in aging K18‐null male mice that had a related liver phenotype but normal colon compared with K8‐null mice, suggesting that the autoantibodies are linked to liver rather than colonic disease. However, these autoantibodies were not observed in nontransgenic mice subjected to 4 chronic injury models. The autoantigens are ubiquitous and partition with mitochondria. Mass spectrometry and purified protein analysis identified, mitochondrial HMG‐CoA synthase, aldehyde dehydrogenase, and catalase as the primary autoantigens, and glutamate dehydrogenase and epoxide hydrolase‐2 as additional autoantigens. Therefore, absence of the hepatocyte keratins results in production of anti‐mitochondrial autoantibodies (AMA) that recognize proteins involved in energy metabolism and oxidative stress, raising the possibility that AMA may be found in patients with keratin mutations that associate with liver and other diseases.—Toivola, D. M., Habtezion, A., Misiorek, J. O., Zhang, L., Nyström, J. H., Sharpe, O., Robinson, W. H., Kwan, R., Omary, M. B. Absence of keratin 8 or 18 promotes antimitochondrial autoantibody formation in aging male mice. FASEB J. 29, 5081–5089 (2015). www.fasebj.orgPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154363/1/fsb2029012032.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154363/2/fsb2029012032-sup-0002.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154363/3/fsb2029012032-sup-0003.pd

Accelerating the Drug Delivery Pipeline for Acute and Chronic Pancreatitis: Summary of the Working Group on Drug Development and Trials in Chronic Pancreatitis at the National Institute of Diabetes and Digestive and Kidney Diseases Workshop

The lack of effective therapeutic agents specifically tailored for chronic pancreatitis (CP) has hampered clinical care and negatively impacted patients' lives. New mechanistic insights now point to novel therapies, which involve both recently developed and/or repurposed agents. This working group focused on 2 main outcomes for CP: pain and progression of disease. The goal is to frame the essential aspects of trial design including patient-centered outcomes, proposed methods to measure the outcomes of pain and progression, and study design considerations for future trials to facilitate rapid drug development for patients with CP

Diabetes Mellitus and Obesity as Risk Factors for Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest types of cancer. The worldwide estimates of its incidence and mortality in the general population are eight cases per 100,000 person-years and seven deaths per 100,000 person-years, and they are significantly higher in the United States than in the rest of the world. The incidence of this disease in the United States is more than 50,000 new cases in 2017. Indeed, total deaths due to PDAC are projected to increase dramatically to become the second leading cause of cancer-related deaths before 2030. Considering the failure to date to efficiently treat existing PDAC, increased effort should be undertaken to prevent this disease. A better understanding of the risk factors leading to PDAC development is of utmost importance to identify and formulate preventive strategies. Large epidemiologic and cohort studies have identified risk factors for the development of PDAC, including obesity and type 2 diabetes mellitus. This review highlights the current knowledge of obesity and type 2 diabetes as risk factors for PDAC development and progression, their interplay and underlying mechanisms, and the relation to diet. Research gaps and opportunities to address this deadly disease are also outlined

Alternative p38MAPKs as biomarkers in the interplay of colon cancer and inflammatory bowel diseases

Trabajo presentado en el 44º Congreso Nacional de la Sociedad Española de Bioquímica y Biología Molecular (SEBBM), celebrado en Málaga (España) del 06 al 09 de septiembre de 2022.Chronic inflammation in inflammatory bowel disease (IBD) is a risk factor for Colorectal cancer (CRC) development, but our understanding of this interplay at a molecular level is still limited. p38γ and p38δ, are central in the development of mouse colitis-associated CRC (CAC) by modulating the inflammatory immune response. However, their implication in human CRC and IBD is not well defined. In this study we perform an integrative analysis of p38γ and p38δ mRNA and protein expression and activation in human patients; using human CRC derived organoids and plasma samples, as well as data from different human CRC and IBD mRNA databases. We found that, p38δ levels were decreased, whereas p38γ expression and phosphorylation were significantly increased in CRC compared to normal colon samples. This increase correlated with the expression of genes implicated in inflammation. Examine of p38γ/p38δ in IBD patients showed that p38γ mRNA and protein levels were increased in Crohn’s disease and ulcerative colitis patients. Contrary, p38δ mRNA was significantly decreased. We also investigated the expression of miRNAs, miR-128-2, miR133a and miR-155, implicated in inflammation and cancer development. In mouse model of colitis and CAC, miR128-2 level was regulated by p38γ/p38δ. In the plasma of IBD and CRC patients, miR128-2 was increased compared to healthy donors, and this correlated with p38γ and p38δ levels. Our results show an opposite regulation of p38γ and p38δ in both CRC and IBD; and suggest that p38γ acts as a link between colitis and CRC by favouring an inflammatory environment that promotes tumour development. We provided evidence that p38γ/p38δ, together with miR-128-2, can be useful as biomarkers, and as potential treatment targets, for colitis and early-stage CRC

p38γ and p38δ as biomarkers in the interplay of colon cancer and inflammatory bowel diseases

descripción no proporcionada por scopusThis research was funded by the MCIN/AEI/10.13039/501100011033 (PID2019-108349RB100 and SAF2016-79792R) to AC and JJSE; Villum Foundation, grant no. 13152 to KA; by Agencia Estatal de Investigación (PID2019-104867RBI00/AEI/10.13039/501100011033) and the Instituto de Salud Carlos III- Fondo Europeo de Desarrollo Regional (CIBERONC/CB16/12/00273 and ICI20/00057) to AM and AB. PF received MCIN FPI fellowship (BES-2017-080139)