How free-ranging ungulates with differing water dependencies cope with seasonal variation in temperature and aridity

Large mammals respond to seasonal changes in temperature and precipitation by behavioural and physiological flexibility. These responses are likely to differ between species with differing water dependencies. We used biologgers to contrast the seasonal differences in activity patterns, microclimate selection, distance to potential water source and body temperature of the water-independent gemsbok (Oryx gazella gazella) and water-dependent blue wildebeest (Connochaetes taurinus), free-living in the arid Kalahari region of Botswana. Gemsbok were more active nocturnally during the hot seasons than in the cold-dry season, while wildebeest showed no seasonal difference in their nocturnal activity level. Both species similarly selected shaded microclimates during the heat of the day, particularly during the hot seasons. Wildebeest were further than 10 km from surface water 30% or more of the time, while gemsbok were frequently recorded >20 km from potential water sources. In general, both species showed similar body temperature variation with high maximum 24-h body temperature when conditions were hot and low minimum 24-h body temperatures when conditions were dry, resulting in the largest amplitude of 24-h body temperature rhythm during the hot-dry period. Wildebeest thus coped almost as well as gemsbok with the fairly typical seasonal conditions that occurred during our study period. They do need to access surface water and may travel long distances to do so when local water sources become depleted during drought conditions. Thus, perennial water sources should be provided judiciously and only where essential

MicroRNA inhibition using antimiRs in acute human brain tissue sections

Antisense inhibition of microRNAs is an emerging preclinical approach to pharmacoresistant epilepsy. A leading candidate is an "antimiR" targeting microRNA-134 (ant-134), but testing to date has used rodent models. Here, we develop an antimiR testing platform in human brain tissue sections. Brain specimens were obtained from patients undergoing resective surgery to treat pharmacoresistant epilepsy. Neocortical specimens were submerged in modified artificial cerebrospinal fluid (ACSF) and dissected for clinical neuropathological examination, and unused material was transferred for sectioning. Individual sections were incubated in oxygenated ACSF, containing either ant-134 or a nontargeting control antimiR, for 24 h at room temperature. RNA integrity was assessed using BioAnalyzer processing, and individual miRNA levels were measured using quantitative reverse transcriptase polymerase chain reaction. Specimens transported in ACSF could be used for neuropathological diagnosis and had good RNA integrity. Ant-134 mediated a dose-dependent knockdown of miR-134, with approximately 75% reduction of miR-134 at 1 μmol L-1 and 90% reduction at 3 μmol L-1 . These doses did not have off-target effects on expression of a selection of three other miRNAs. This is the first demonstration of ant-134 effects in live human brain tissues. The findings lend further support to the preclinical development of a therapy that targets miR-134 and offer a flexible platform for the preclinical testing of antimiRs, and other antisense oligonucleotide therapeutics, in human brain

Rare occurrence of pseudomyxoma peritonei (PMP) syndrome arising from a malignant transformed ovarian primary mature cystic teratoma treated by cytoreductive surgery and HIPEC: a case report

Background: Pseudomyxoma peritonei (PMP) syndrome is a disease process that typically occurs from ruptured appendiceal mucocele neoplasms. PMP syndrome arising from malignant transformation of an ovarian primary mature cystic teratoma (MCT) is a pathogenesis rarely encountered. Case presentation: Herein, we report a 28-year-old patient evaluated and treated for a right ovarian mass and large volume symptomatic abdominopelvic mucinous ascites. Molecular profiling and genetic analysis revealed mutations in ATM, GNAS, and KRAS proteins while IHC demonstrated gastrointestinal-specific staining for CK20, CDX2, CK7, and SATB2. Peritoneal cytology showed paucicellular mucin. Diffuse peritoneal adenomucinosis (DPAM) variant of PMP arising from a ruptured ovarian primary MCT after malignant transformation to a low-grade appendiceal-like mucinous neoplasm was ultimately confirmed. Treatment included staged therapeutic tumor debulking and right salpingo-oophorectomy followed by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). Conclusions: Our report builds upon the existing literature supporting this aggressive treatment option reserved for advanced abdominal malignancies utilized in this patient with a rare clinical entity

A stromal lysolipid-autotaxin signaling axis promotes pancreatic tumor progression

Pancreatic ductal adenocarcinoma (PDAC) develops a pronounced stromal response reflecting an aberrant wound-healing process. This stromal reaction features transdifferentiation of tissue-resident pancreatic stellate cells (PSC) into activated cancer-associated fibroblasts, a process induced by PDAC cells but of unclear significance for PDAC progression. Here, we show that PSCs undergo a dramatic lipid metabolic shift during differentiation in the context of pancreatic tumorigenesis, including remodeling of the intracellular lipidome and secretion of abundant lipids in the activated, fibroblastic state. Specifically, stroma-derived lysophosphatidylcholines support PDAC cell synthesis of phosphatidylcholines, key components of cell membranes, and also facilitate production of the potent wound-healing mediator lysophosphatidic acid (LPA) by the extracellular enzyme autotaxin, which is overexpressed in PDAC. The autotaxin–LPA axis promotes PDAC cell proliferation, migration, and AKT activation, and genetic or pharmacologic autotaxin inhibition suppresses PDAC growth in vivo. Our work demonstrates how PDAC cells exploit the local production of wound-healing mediators to stimulate their own growth and migration. Significance: Our work highlights an unanticipated role for PSCs in producing the oncogenic LPA signaling lipid and demonstrates how PDAC tumor cells co-opt the release of wound-healing mediators by neighboring PSCs to promote their own proliferation and migration

Neglected Tropical Diseases outside the Tropics

Neglected Tropical Diseases (NTDs) have been targeted due to their prevalence and the burden of disease they cause globally, but there has been no significant focus in the literature on the subject of NTDs as a group in immigrants and travelers, and no specific studies on the emerging phenomenon of imported NTDs. We present the experience of a Tropical Medicine Unit in a major European city, over a 19-year period, describing and comparing NTDs diagnosed amongst immigrants, travelers and travelers visiting friends and relatives (VFRs). NTDs were diagnosed outside tropical areas and occurred more frequently in immigrants, followed by VFR travelers and then by other travelers. The main NTDs diagnosed in immigrants were onchocerciasis, Chagas disease and ascariasis; most frequent NTDs in travelers were schistosomiasis, onchocerciasis and ascariasis, and onchocerciasis and schistosomiasis in VFRs. Issues focusing on modes of transmission outside endemic areas and how eradication programs for some NTDs in endemic countries may have an impact in non-tropical Western countries by decreasing disease burden in immigrants, are addressed. Adherence to basic precautions such as safe consumption of food/water and protection against arthropod bites could help prevent many NTDs in travelers

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis

Management and Outcome of Cardiac and Endovascular Cystic Echinococcosis

Cardiac and vascular involvement are infrequent in classical cystic echinococcosis (CE), but when they occur they tend to present earlier and are associated with complications that may be life threatening. Cardiovascular CE usually requires complex surgery, so in low-income countries the outcome is frequently fatal. This case series describes the characteristics of cardiovascular CE in patients diagnosed and treated at a Tropical Medicine & Clinical Parasitology Center in Spain. A retrospective case series of 11 patients with cardiac and/or endovascular CE, followed-up over a period of 15 years (1995–2009) is reported. The main clinical manifestations included thoracic pain or dyspnea, although 2 patients were asymptomatic. The clinical picture and complications vary according to cyst location. Isolated cardiac CE may be cured after surgery, while endovascular extracardiac involvement is associated with severe chronic complications. CE should be included in the differential diagnosis of cardiovascular disease in patients from endemic areas. CE is a neglected disease and further studies are necessary in order to make more definite management recommendations for this rare and severe form of the disease. The authors propose a general approach based on cyst location: exclusively cardiac, endovascular or both

The polymorphism L412F in TLR3 inhibits autophagy and is a marker of severe COVID-19 in males

The polymorphism L412F in TLR3 has been associated with several infectious diseases. However, the mechanism underlying this association is still unexplored. Here, we show that the L412F polymorphism in TLR3 is a marker of severity in COVID-19. This association increases in the sub-cohort of males. Impaired macroautophagy/autophagy and reduced TNF/TNFα production was demonstrated in HEK293 cells transfected with TLR3L412F-encoding plasmid and stimulated with specific agonist poly(I:C). A statistically significant reduced survival at 28 days was shown in L412F COVID-19 patients treated with the autophagy-inhibitor hydroxychloroquine (p = 0.038). An increased frequency of autoimmune disorders such as co-morbidity was found in L412F COVID-19 males with specific class II HLA haplotypes prone to autoantigen presentation. Our analyses indicate that L412F polymorphism makes males at risk of severe COVID-19 and provides a rationale for reinterpreting clinical trials considering autophagy pathways. Abbreviations: AP: autophagosome; AUC: area under the curve; BafA1: bafilomycin A1; COVID-19: coronavirus disease-2019; HCQ: hydroxychloroquine; RAP: rapamycin; ROC: receiver operating characteristic; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TLR: toll like receptor; TNF/TNF-α: tumor necrosis factor

Inferring causal molecular networks: empirical assessment through a community-based effort

Inferring molecular networks is a central challenge in computational biology. However, it has remained unclear whether causal, rather than merely correlational, relationships can be effectively inferred in complex biological settings. Here we describe the HPN-DREAM network inference challenge that focused on learning causal influences in signaling networks. We used phosphoprotein data from cancer cell lines as well as in silico data from a nonlinear dynamical model. Using the phosphoprotein data, we scored more than 2,000 networks submitted by challenge participants. The networks spanned 32 biological contexts and were scored in terms of causal validity with respect to unseen interventional data. A number of approaches were effective and incorporating known biology was generally advantageous. Additional sub-challenges considered time-course prediction and visualization. Our results constitute the most comprehensive assessment of causal network inference in a mammalian setting carried out to date and suggest that learning causal relationships may be feasible in complex settings such as disease states. Furthermore, our scoring approach provides a practical way to empirically assess the causal validity of inferred molecular networks

Inferring causal molecular networks: empirical assessment through a community-based effort

It remains unclear whether causal, rather than merely correlational, relationships in molecular networks can be inferred in complex biological settings. Here we describe the HPN-DREAM network inference challenge, which focused on learning causal influences in signaling networks. We used phosphoprotein data from cancer cell lines as well as in silico data from a nonlinear dynamical model. Using the phosphoprotein data, we scored more than 2,000 networks submitted by challenge participants. The networks spanned 32 biological contexts and were scored in terms of causal validity with respect to unseen interventional data. A number of approaches were effective, and incorporating known biology was generally advantageous. Additional sub-challenges considered time-course prediction and visualization. Our results suggest that learning causal relationships may be feasible in complex settings such as disease states. Furthermore, our scoring approach provides a practical way to empirically assess inferred molecular networks in a causal sense