Theory predicts that intraspecific competition should be stronger than interspecific competition for any pair of stably coexisting species, yet previous literature reviews found little support for ...this pattern. We screened over 5400 publications and identified 39 studies that quantified phenomenological intraspecific and interspecific interactions in terrestrial plant communities. Of the 67% of species pairs in which both intra‐ and interspecific effects were negative (competitive), intraspecific competition was, on average, four to five‐fold stronger than interspecific competition. Of the remaining pairs, 93% featured intraspecific competition and interspecific facilitation, a situation that stabilises coexistence. The difference between intra‐ and interspecific effects tended to be larger in observational than experimental data sets, in field than greenhouse studies, and in studies that quantified population growth over the full life cycle rather than single fitness components. Our results imply that processes promoting stable coexistence at local scales are common and consequential across terrestrial plant communities.
•Adaptive R&D contract for urgently needed drugs is analyzed.•Impact of urgent policies such as EUA on the client’s and the agent’s decisions.•We contribute to the understanding of the public-private ...state-emergency contracts under pandemic situation such as COVID-19.
This paper analyzes an incentive contract for new vaccine research and development (R&D) under pandemic situations such as COVID-19, considering the R&D contract’s adaptability to the pandemic. We study how the public sector (government) designs the adaptive R&D contract and offers it to pharmaceutical enterprises. An agency-theoretic model is employed to explore the contract whose terms are an upfront grant as a fixed fee and a sales tax credit as an incentive tool, examining how the values of related parameters affect contract term determinations. We found that the adaptability factor derived from urgent policies such as emergency use authorization (EUA) as well as tax credits, can be utilized as practical incentive tools that lead vaccine developers to increase their effort levels for R&D success. We also found that public-private state-emergency contracts may not follow the conventional wisdom. Counterintuitively, dependency on tax credits (incentive part) decrease as the client’s degree of risk averseness increases in the emergency contract.
Although chromoendoscopy is currently the recommended mode of surveillance in patients with long-standing ulcerative colitis, it is technically challenging and requires a long procedure time. The aim ...of this study was to compare the dysplasia detection rate of high-definition white light endoscopy with random biopsy (HDWL-R) vs high-definition chromoendoscopy with targeted biopsy (HDCE-T).
This was a multicenter, prospective randomized controlled trial involving 9 tertiary teaching hospitals in South Korea. A total of 210 patients with long-standing ulcerative colitis were randomized to undergo either the HDWL-R group (n = 102) or HDCE-T group (n = 108). The detection rates of colitis-associated dysplasia (CAD) or all colorectal neoplasia from each trial arm were compared.
There was no significant difference in the CAD detection rate between HDCE-T and HDWL-R groups (4/102, 3.9% vs 6/108, 5.6%, P = 0.749). However, HDCE-T showed a trend toward improved colorectal neoplasia detection compared with HDWL-R (21/102, 20.6% vs 13/108, 12.0%, P = 0.093). The median (range) time for colonoscopy withdrawal between the 2 groups was similar (17.6 7.0-43.3 minutes vs 16.5 6.3-38.1 minutes; P=0.212; for HDWL-R and HDCE-T, respectively). The total number of biopsies was significantly larger in the HDWL-R group (34 12-72) compared with the HDCE-T group (9 1-20; P < 0.001).
On the basis of our prospective randomized controlled trial, HDCE-T was not superior to HDWL-R for detecting CADs.
ObjectiveUlcerative colitis (UC) is a dynamic disease with its severity continuously changing over time. We hypothesised that the risk of colorectal neoplasia (CRN) in UC closely follows an actuarial ...accumulative inflammatory burden, which is inadequately represented by current risk stratification strategies.DesignThis was a retrospective single-centre study. Patients with extensive UC who were under colonoscopic surveillance between 2003 and 2012 were studied. Each surveillance episode was scored for a severity of microscopic inflammation (0=no activity; 1=mild; 2=moderate; 3=severe activity). The cumulative inflammatory burden (CIB) was defined as sum of: average score between each pair of surveillance episodes multiplied by the surveillance interval in years. Potential predictors were correlated with CRN outcome using time-dependent Cox regression.ResultsA total of 987 patients were followed for a median of 13 years (IQR, 9-18), 97 (9.8%) of whom developed CRN. Multivariate analysis showed that the CIB was significantly associated with CRN development (HR, 2.1 per 10-unit increase in CIB (equivalent of 10, 5 or 3.3 years of continuous mild, moderate or severe active microscopic inflammation); 95% CI 1.4 to 3.0; P<0.001). Reflecting this, while inflammation severity based on the most recent colonoscopy alone was not significant (HR, 0.9 per-1-unit increase in severity; 95% CI 0.7 to 1.2; P=0.5), a mean severity score calculated from all colonoscopies performed in preceding 5 years was significantly associated with CRN risk (HR, 2.2 per-1-unit increase; 95% CI 1.6 to 3.1; P<0.001).ConclusionThe risk of CRN in UC is significantly associated with accumulative inflammatory burden. An accurate CRN risk stratification should involve assessment of multiple surveillance episodes to take this into account.
Understanding interactions among biogeochemical cycles is increasingly important as anthropogenic alterations of global climate and of carbon (C), nitrogen (N), and phosphorus (P) cycles ...interactively affect the Earth system. Ecosystem processes in the dryland biome, which makes up over 40% of Earth's terrestrial surface, are often distinctively sensitive to small changes in resource availability, likely because levels of many resources are low. However, data also suggest that simultaneous changes in the availability of multiple resources may be necessary to affect a response in these low‐resource systems, offering an opportunity to test patterns and controls of co‐limitation, serial limitation, and individual limitation in soil environments. While drylands may play a governing role in key aspects of Earth's C cycle, and while an improved understanding of resource limitation could substantially improve our forecasts of dryland responses to change, our understanding of interacting controls on soil C cycle processes remains notably poor in these dry systems. Here, we address multiple fundamental hypotheses of resource controls over ecosystem function to test how water, C, N, and P regulate soil C cycling individually and interactively in a dryland ecosystem on the Colorado Plateau. Using a series of laboratory incubations, we found that, while water, C, and N limited C cycling through serial limitation, water alone resulted in an extremely small respiratory response from target organisms, whereas water + C resulted in a dramatic increase in soil C cycling, suggesting a degree of functional co‐limitation. Nitrogen additions alone resulted in no changes to soil C cycling, but when N was added in concert with water and C, N greatly increased soil C cycling rates relative to additions of water and C without N. Phosphorus additions had no effect on the C cycle either alone or synergistically. These patterns were consistent with the stoichiometry of the system and interactions among resources were surprising in ways that inform our understanding of critical theories in ecology, such as the Transient Maxima Hypothesis, supporting the suggestion that multiple resource limitation explains pulse‐dynamic C cycling in drylands better than water limitation alone.
This study provides an overview of the largest and longest-running colonoscopic surveillance program for colorectal cancer (CRC) in patients with long-standing ulcerative colitis (UC).
Data were ...obtained from medical records, endoscopy, and histology reports. Primary end points were defined as death, colectomy, withdrawal from surveillance, or censor date (1 January 2013).
A total of 1,375 UC patients were followed up for 15,234 patient-years (median, 11 years per patient). CRC was detected in 72 patients (incidence rate (IR), 4.7 per 1,000 patient-years). Time-trend analysis revealed that although there was significant decrease in incidence of colectomy performed for dysplasia (linear regression, R=-0.43; P=0.007), IR of advanced CRC and interval CRC have steadily decreased over past four decades (Pearson's correlation, -0.99; P=0.01 for both trends). The IR of early CRC has increased 2.5-fold in the current decade compared with past decade (χ(2), P=0.045); however, its 10-year survival rate was high (79.6%). The IR of dysplasia has similarly increased (χ(2), P=0.01), potentially attributable to the recent use of chromoendoscopy that was twice more effective at detecting dysplasia compared with white-light endoscopy (χ(2), P<0.001). CRCs were frequently accompanied by synchronous CRC or spatially distinct dysplasia (37.5%). Finally, the risk of CRC was not significantly different between "indefinite" or low-grade dysplasia (log-rank, P=0.78).
Colonoscopic surveillance may have a significant role in reducing the risk of advanced and interval CRC while allowing more patients to retain their colon for longer. Given the ongoing risk of early CRC, patients with any grade of dysplasia who are managed endoscopically should be monitored closely with advanced techniques.
ObjectiveIBD confers an increased lifetime risk of developing colorectal cancer (CRC), and colitis-associated CRC (CA-CRC) is molecularly distinct from sporadic CRC (S-CRC). Here we have dissected ...the evolutionary history of CA-CRC using multiregion sequencing.DesignExome sequencing was performed on fresh-frozen multiple regions of carcinoma, adjacent non-cancerous mucosa and blood from 12 patients with CA-CRC (n=55 exomes), and key variants were validated with orthogonal methods. Genome-wide copy number profiling was performed using single nucleotide polymorphism arrays and low-pass whole genome sequencing on archival non-dysplastic mucosa (n=9), low-grade dysplasia (LGD; n=30), high-grade dysplasia (HGD; n=13), mixed LGD/HGD (n=7) and CA-CRC (n=19). Phylogenetic trees were reconstructed, and evolutionary analysis used to reveal the temporal sequence of events leading to CA-CRC.Results10/12 tumours were microsatellite stable with a median mutation burden of 3.0 single nucleotide alterations (SNA) per Mb, ~20% higher than S-CRC (2.5 SNAs/Mb), and consistent with elevated ageing-associated mutational processes. Non-dysplastic mucosa had considerable mutation burden (median 47 SNAs), including mutations shared with the neighbouring CA-CRC, indicating a precancer mutational field. CA-CRCs were often near triploid (40%) or near tetraploid (20%) and phylogenetic analysis revealed that copy number alterations (CNAs) began to accrue in non-dysplastic bowel, but the LGD/HGD transition often involved a punctuated ‘catastrophic’ CNA increase.ConclusionsEvolutionary genomic analysis revealed precancer clones bearing extensive SNAs and CNAs, with progression to cancer involving a dramatic accrual of CNAs at HGD. Detection of the cancerised field is an encouraging prospect for surveillance, but punctuated evolution may limit the window for early detection.
ABSTRACT
Intense media scrutiny and public backlash stimulate consumers to be conscientious about sustainability issues from the supply chain (SC) perspective. Accordingly, our focus in this article ...is on joint sustainability issues in a manufacturer–supplier relationship under a contract that possibly shares sustainability‐related costs, when there exists a supplier's potentially deficient sustainability effort. We find that the manufacturer may prefer indirect (i.e., paying a higher component price to its supplier) rather than direct support (i.e., increasing subsidies for a supplier's sustainability expenditures) when consumers are sensitive to the supplier's sustainability. We further find that as consumers' sensitivity to the supplier's sustainability increases, an uncoordinated SC will gradually approach the coordinated SC. This occurs because the increased sensitivity encourages greater cooperation among SC members. Our findings will help establish a better understanding of the joint sustainability development issues in an SC.
The aim of this study was to identify risk factors associated with development of high-grade dysplasia (HGD) or colorectal cancer (CRC) in ulcerative colitis (UC) patients diagnosed with low-grade ...dysplasia (LGD).
Patients with histologically confirmed extensive UC, who were diagnosed with LGD between 1993 and 2012 at St Mark's Hospital, were identified and followed up to 1 July 2013. Demographic, endoscopic, and histological data were collected and correlated with the development of HGD or CRC.
A total of 172 patients were followed for a median of 48 months from the date of initial LGD diagnosis (interquartile range (IQR), 15-87 months). Overall, 33 patients developed HGD or CRC (19.1% of study population; 20 CRCs) during study period. Multivariate Cox proportional hazard analysis revealed that macroscopically non-polypoid (hazard ratio (HR), 8.6; 95% confidence interval (CI), 3.0-24.8; P<0.001) or invisible (HR, 4.1; 95% CI, 1.3-13.4; P=0.02) dysplasia, dysplastic lesions ≥1 cm in size (HR, 3.8; 95% CI, 1.5-13.4; P=0.01), and a previous history of "indefinite for dysplasia" (HR, 2.8; 95% CI, 1.2-6.5; P=0.01) were significant contributory factors for HGD or CRC development. Multifocal dysplasia (HR, 3.9; 95% CI, 1.9-7.8; P<0.001), metachronous dysplasia (HR, 3.5; 95% CI, 1.6-7.5; P=0.001), or a colonic stricture (HR, 7.4; 95% CI, 2.5-22.1; P<0.001) showed only univariate correlation to development of HGD or CRC.
Lesions that are non-polypoid or endoscopically invisible, large (≥1 cm), or preceded by indefinite dysplasia are independent risk factors for developing HGD or CRC in UC patients diagnosed with LGD.
SARS-CoV-2, the etiologic agent of the COVID-19 pandemic, has had an enduring impact on global public health. However, SARS-CoV-2 is only one of multiple pathogenic human coronaviruses (CoVs) to have ...emerged since the turn of the century. CoVs encode for several nonstructural proteins (nsps) that are essential for viral replication and pathogenesis. Among them is nsp15, a uridine-specific viral endonuclease that is important in evading the host immune response and promoting viral replication. Despite the established endonuclease function of nsp15, little is known about other determinants of its cleavage specificity. In this study we investigate the role of RNA secondary structure in SARS-CoV-2 nsp15 endonuclease activity. Using a series of in vitro endonuclease assays, we observed that thermodynamically stable RNA structures were protected from nsp15 cleavage relative to RNAs lacking stable structure. We leveraged the s2m RNA from the SARS-CoV-1 3'UTR as a model for our structural studies as it adopts a well-defined structure with several uridines, two of which are unpaired and thus highly probable targets for nsp15 cleavage. We found that SARS-CoV-2 nsp15 specifically cleaves s2m at the unpaired uridine within the GNRNA pentaloop of the RNA. Further investigation revealed that the position of uridine within the pentaloop also impacted nsp15 cleavage efficiency suggesting that positioning within the pentaloop is necessary for optimal presentation of the scissile uridine and alignment within the nsp15 catalytic pocket. Our findings indicate that RNA secondary structure is an important determinant of nsp15 cleavage and provides insight into the molecular mechanisms of RNA recognition by nsp15.
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