Circular RNA (circRNA) is a novel member of the noncoding cancer genome with distinct properties and diverse cellular functions, which is being explored at a steadily increasing pace. The list of ...endogenous circRNAs involved in cancer continues to grow; however, the functional relevance of the vast majority is yet to be discovered. In general, circRNAs are exceptionally stable molecules and some have been shown to function as efficient microRNA sponges with gene-regulatory potential. Many circRNAs are highly conserved and have tissue-specific expression patterns, which often do not correlate well with host gene expression. Here we review the current knowledge on circRNAs in relation to their implications in tumorigenesis as well as their potential as diagnostic and prognostic biomarkers and as possible therapeutic targets in future personalized medicine. Finally, we discuss future directions for circRNA cancer research and current caveats, which must be addressed to facilitate the translation of basic circRNA research into clinical use.
The global emergence of carbapenemase-producing bacteria capable of hydrolyzing the once effective carbapenem antibiotics is considered a contemporary public health concern. Carbapenemase enzymes, ...once constrained to isolates of
Klebsiella pneumoniae
, are now routinely reported in different bacteria within the Enterobacterales order of bacteria, creating the acronym CRE which now defines Carbapenem-Resistant Enterobacterales. CRE harboring different types of enzymes, including the most prevalent types KPC, VIM, IMP, NDM, and OXA-48, are now routinely reported and more importantly, are now frequently present in many infections world-wide. Defining and updating the contemporary epidemiology of both the US and global burden of carbapenem-resistant infections is now more important than ever. This review describes the global distribution and continued evolution of carbapenemases which continue to spread at alarming rates. Informed understanding of the current epidemiology of CRE, coupled with advances in antibiotic options, and the use rapid diagnostics offers the potential for rapid identification and management of carbapenem-resistant infections.
Plain Language Summary
Carbapenems are a subclass of antibiotic used to treat infections caused by Gram-negative bacteria, particularly in resistant and multidrug-resistant (MDR) infections where penicillin and cephalosporins are no longer effective. However, carbapenem-resistant Enterobacterales (CRE) have emerged due to acquisition of carbapenemase enzymes, most prevalent types are KPC, VIM, IMP, NDM, and OXA-48; infections caused by these bacteria have disseminated globally in both the healthcare and community setting. Resulting in a significant public health issue and clinical burden, these CRE infections are associated with increased morbidity and mortality, in part because carbapenems are the last therapeutic line of defense against resistant and MDR bacterial infections. The author wanted to investigate current US and global epidemiology of carbapenem-resistant infections, identify factors driving changes, as well as diagnostic technologies, and reporting or surveillance methods in place to track trends and inform therapeutic protocols and development. Overall, carbapenemase enzymes originally only reported in one country or region in 2006-2007, by 2013 and onwards have spread not only to surrounding countries but to other continents, which has impacted antibiotic resistance patterns and susceptibility. Increasing human travel and environmental factors, such as livestock care, food distribution, sewage, and recreational water, have contributed to global dissemination of CRE. Active surveillance programs are key to tracking resistance in real time, in order to update susceptibility breakpoints and epidemiology, which can inform antibiotic treatment choices, management guidelines, and the development of new therapeutics. Together, these factors will help to identify, control, and treat the spread of carbapenem resistance.
Most strong-interaction resonances have decay channels involving three or more particles, including many of the recently discovered
X
,
Y
, and
Z
resonances. In order to study such resonances from ...first principles using lattice QCD, one must understand finite-volume effects for three particles in the cubic box used in calculations. We review efforts to develop a three-particle quantization condition that relates finite-volume energies to infinite-volume scattering amplitudes. We describe in detail the three approaches that have been followed, and present new results on the relationship between the corresponding results. We show examples of the numerical implementation of all three approaches and point out the important issues that remain to be resolved.
A
bstract
We discuss a method to construct hadronic scattering and decay amplitudes from Euclidean correlators, by combining the approach of a regulated inverse Laplace transform with the work of ...Maiani and Testa 1. Revisiting the original result of ref. 1, we observe that the key observation, i.e. that only threshold scattering information can be extracted at large separations, can be understood by interpreting the correlator as a spectral function,
ρ
(
ω
), convoluted with the Euclidean kernel,
e
−ωt
, which is sharply peaked at threshold. We therefore consider a modification in which a smooth step function, equal to one above a target energy, is inserted in the spectral decomposition. This can be achieved either through Backus-Gilbert-like methods or more directly using the variational approach. The result is a shifted resolution function, such that the large
t
limit projects onto scattering or decay amplitudes above threshold. The utility of this method is highlighted through large
t
expansions of both three- and four-point functions that include leading terms proportional to the real and imaginary parts (separately) of the target observable. This work also presents new results relevant for the un-modified correlator at threshold, including expressions for extracting the
Nπ
scattering length from four-point functions and a new strategy to organize the large
t
expansion that exhibits better convergence than the expansion in powers of 1/
t
.
The natural history for patients with de novo donor‐specific antibodies (dnDSA) and the risk factors for its development have not been well defined. Furthermore, clinical and histologic correlation ...with serologic data is limited. We studied 315 consecutive renal transplants without pretransplant DSA, with a mean follow‐up of 6.2 ± 2.9 years. Protocol (n = 215) and for cause (n = 163) biopsies were analyzed. Solid phase assays were used to screen for dnDSA posttransplant. A total of 47 out of 315 (15%) patients developed dnDSA at a mean of 4.6 ± 3.0 years posttransplant. Independent predictors of dnDSA were HLA‐DRβ1 MM > 0 (OR 5.66, p < 0.006); and nonadherence (OR 8.75, p < 0.001); with a strong trend toward clinical rejection episodes preceding dnDSA (OR 1.57 per rejection episode, p = 0.061). The median 10‐year graft survival for those with dnDSA was lower than the No dnDSA group (57% vs. 96%, p < 0.0001). Pathology consistent with antibody‐mediated injury can occur and progress in patients with dnDSA in the absence of graft dysfunction and furthermore, nonadherence and cellular rejection contribute to dnDSA development and progression to graft loss.
Prospective monitoring for de novo donor‐specific antibody in renal transplantation using clinical, serological and histopathological methods uncovers distinct clinical phenotypes and the pathology associated with them, as well as the independent risk factors for their development. See editorial by Kokko and Colvin on page 1077.
•Proteins produced by ectopic circRNA expression are prone to artefacts by exon concatemerization.•circRNA-specific RiboSeq reads are likely noise and not signal.•circRNA-derived peptides identified ...by mass-spec are typically false discoveries.
Within recent years, circular RNAs (circRNAs) have been an attractive new field of research in RNA biology and disease. Consequently, numerous studies have been published towards the disclosure of circRNA biogenesis and function. Initially, circRNAs were described as a subclass of cytoplasmic non-coding RNA, however, a few recent observations have proposed that circRNAs may instead be templates for protein production. The extent to which this is the case is currently debated, and therefore using rigorous data analysis and proper experimental setups is instrumental to settle the current controversies. Here, the conventional experiments used for detecting circRNA translation are outlined, and guidelines to distinguish signal from the inherent noise are discussed. While these guidelines are specific for circRNA translation, most also apply to other aspects of non-canonical translation.
De novo donor‐specific antibody (dnDSA) develops in 15–25% of renal transplant recipients within 5 years of transplantation and is associated with 40% lower graft survival at 10 years. HLA epitope ...matching is a novel strategy that may minimize dnDSA development. HLAMatchmaker software was used to characterize epitope mismatches at 395 potential HLA‐DR/DQ/DP conformational epitopes for 286 donor–recipient pairs. Epitope specificities were assigned using single antigen HLA bead analysis and correlated with known monoclonal alloantibody epitope targets. Locus‐specific epitope mismatches were more numerous in patients who developed HLA‐DR dnDSA alone (21.4 vs. 13.2, p < 0.02) or HLA‐DQ dnDSA alone (27.5 vs. 17.3, p < 0.001). An optimal threshold for epitope mismatches (10 for HLA‐DR, 17 for HLA‐DQ) was defined that was associated with minimal development of Class II dnDSA. Applying these thresholds, zero and 2.7% of patients developed dnDSA against HLA‐DR and HLA‐DQ, respectively, after a median of 6.9 years. Epitope specificity analysis revealed that 3 HLA‐DR and 3 HLA‐DQ epitopes were independent multivariate predictors of Class II dnDSA. HLA‐DR and DQ epitope matching outperforms traditional low‐resolution antigen‐based matching and has the potential to minimize the risk of de novo Class II DSA development, thereby improving long‐term graft outcome.
This article provides a comprehensive evaluation of HLA Class II epitope mismatch load and epitope immunogenicity as predictors for de novo Class II donor‐specific antibody development in renal transplant recipients. See editorial by Tambur and Claas on page 3059.
A
bstract
We present a generalization of the relativistic, finite-volume, three-particle quantization condition for non-identical pions in isosymmetric QCD. The resulting formalism allows one to use ...discrete finite-volume energies, determined using lattice QCD, to constrain scattering amplitudes for all possible values of two- and three-pion isospin. As for the case of identical pions considered previously, the result splits into two steps: the first defines a non-perturbative function with roots equal to the allowed energies,
E
n
(
L
), in a given cubic volume with side-length
L
. This function depends on an intermediate three-body quantity, denoted
K
df
,
3
,
which can thus be constrained from lattice QCD in- put. The second step is a set of integral equations relating
K
df
,
3
to the physical scattering amplitude, ℳ
3
. Both of the key relations,
E
n
(
L
)
↔
K
df
,
3
and
K
df
,
3
↔
ℳ
3
,
are shown to be block-diagonal in the basis of definite three-pion isospin,
I
πππ
, so that one in fact recovers four independent relations, corresponding to
I
πππ
= 0
,
1
,
2
,
3. We also provide the generalized threshold expansion of
K
df
,
3
for all channels, as well as parameterizations for all three-pion resonances present for
I
πππ
= 0 and
I
πππ
= 1. As an example of the utility of the generalized formalism, we present a toy implementation of the quantization condition for
I
πππ
= 0, focusing on the quantum numbers of the
ω
and
h
1
resonances.
A
bstract
The leading finite-volume and thermal effects, arising in numerical lattice QCD calculations of
a
μ
HVP
,
LO
≡
g
−
2
μ
HVP
,
LO
/
2
, are determined to all orders with respect to the ...interactions of a generic, relativistic effective field theory of pions. In contrast to earlier work 1 based in the finite-volume Hamiltonian, the results presented here are derived by formally summing all Feynman diagrams contributing to the Euclidean electromagnetic-current two-point function, with any number of internal pion loops and interaction vertices. As was already found in ref. 1, the leading finite-volume corrections to
a
μ
HVP
,
LO
scale as exp
−mL
where
m
is the pion mass and
L
is the length of the three periodic spatial directions. In this work we additionally control the two sub-leading exponentials, scaling as exp
−
2
mL
and exp
−
3
mL
. As with the leading term, the coefficient of these is given by the forward Compton amplitude of the pion, meaning that all details of the effective theory drop out of the final result. Thermal effects are additionally considered, and found to be sub-percent-level for typical lattice calculations. All finite-volume corrections are presented both for
a
μ
HVP
,
LO
and for each time slice of the two-point function, with the latter expected to be particularly useful in correcting small to intermediate current separations, for which the series of exponentials exhibits good convergence.
A
bstract
This work employs the spectral reconstruction approach of ref.
1
to determine an inclusive rate in the 1 + 1 dimensional O(3) non-linear
σ
-model, analogous to the QCD part of
e
+
e
−
→ ...hadrons. The Euclidean two-point correlation function of the conserved current
j
is computed using Monte Carlo lattice field theory simulations for a variety of spacetime volumes and lattice spacings. The spectral density of this correlator is related to the inclusive rate for
j
→ X in which all final states produced by the external current are summed. The ill-posed inverse problem of determining the spectral density from the correlation function is made tractable through the determination of smeared spectral densities in which the desired density is convolved with a set of known smearing kernels of finite width
ϵ
. The smooth energy dependence of the underlying spectral density enables a controlled
ϵ
→ 0 extrapolation in the inelastic region, yielding the real-time inclusive rate without reference to individual finite-volume energies or matrix elements. Systematic uncertainties due to cutoff effects and residual finite-volume effects are estimated and taken into account in the final error budget. After taking the continuum limit, the results are consistent with the known analytic rate to within the combined statistical and systematic errors. Above energies where 20-particle states contribute, the overall precision is sufficient to discern the four-particle contribution to the spectral density.
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