Whole-genome sequencing has opened the way for investigating the dynamics and genomic evolution of bacterial pathogens during the colonization and infection of humans. The application of this ...technology to the longitudinal study of adaptation in an infected host--in particular, the evolution of drug resistance and host adaptation in patients who are chronically infected with opportunistic pathogens--has revealed remarkable patterns of convergent evolution, suggestive of an inherent repeatability of evolution. In this Review, we describe how these studies have advanced our understanding of the mechanisms and principles of within-host genome evolution, and we consider the consequences of findings such as a potent adaptive potential for pathogenicity. Finally, we discuss the possibility that genomics may be used in the future to predict the clinical progression of bacterial infections and to suggest the best option for treatment.
Targeted alpha therapy is an emerging strategy for the treatment of disseminated cancer.
223
RaRaCl
2
is the only clinically approved alpha particle-emitting drug, and it is used to treat ...castrate-resistant prostate cancer bone metastases, to which
223
RaRa
2+
localizes. To specifically direct
223
RaRa
2+
to non-osseous disease sites, chelation and conjugation to a cancer-targeting moiety is necessary. Although previous efforts to stably chelate
223
RaRa
2+
for this purpose have had limited success, here we report a biologically stable radiocomplex with the 18-membered macrocyclic chelator macropa. Quantitative labeling of macropa with
223
RaRa
2+
was accomplished within 5 min at room temperature with a radiolabeling efficiency of >95%, representing a significant advancement over conventional chelators such as DOTA and EDTA, which were unable to completely complex
223
RaRa
2+
under these conditions.
223
RaRa(macropa) was highly stable in human serum and exhibited dramatically reduced bone and spleen uptake in mice in comparison to bone-targeted
223
RaRaCl
2
, signifying that
223
RaRa(macropa) remains intact
in vivo
. Upon conjugation of macropa to a single amino acid β-alanine as well as to the prostate-specific membrane antigen-targeting peptide DUPA, both constructs retained high affinity for
223
Ra, complexing >95% of Ra
2+
in solution. Furthermore,
223
RaRa(macropa-β-alanine) was rapidly cleared from mice and showed low
223
Ra bone absorption, indicating that this conjugate is stable under biological conditions. Unexpectedly, this stability was lost upon conjugation of macropa to DUPA, which suggests a role of targeting vectors in complex stability
in vivo
for this system. Nonetheless, our successful demonstration of efficient radiolabeling of the β-alanine conjugate with
223
Ra and its subsequent stability
in vivo
establishes for the first time the possibility of delivering
223
RaRa
2+
to metastases outside of the bone using functionalized chelators, marking a significant expansion of the therapeutic utility of this radiometal in the clinic.
The therapeutic alpha-emitter
223
Ra can be stably complexed
in vivo
, creating opportunities for the development of targeted radiopharmaceutical agents with this radionuclide.
Bacterial pathogens impose a heavy burden of disease on human populations worldwide. The gravest threats are posed by highly virulent respiratory pathogens, enteric pathogens, and HIV-associated ...infections. Tuberculosis alone is responsible for the deaths of 1.5 million people annually. Treatment options for bacterial pathogens are being steadily eroded by the evolution and spread of drug resistance. However, population-level whole genome sequencing offers new hope in the fight against pathogenic bacteria. By providing insights into bacterial evolution and disease etiology, these approaches pave the way for novel interventions and therapeutic targets. Sequencing populations of bacteria across the whole genome provides unprecedented resolution to investigate (i) within-host evolution, (ii) transmission history, and (iii) population structure. Moreover, advances in rapid benchtop sequencing herald a new era of real-time genomics in which sequencing and analysis can be deployed within hours in response to rapidly changing public health emergencies. The purpose of this review is to highlight the transformative effect of population genomics on bacteriology, and to consider the prospects for answering abiding questions such as why bacteria cause disease.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
How massive early-type galaxies (ETGs) assembled their mass, on which timescales the star formation quenched, and when their supersolar metallicity has been established are still open and ...debated issues. Thanks to very deep spectroscopic observations carried out at the Large Binocular Telescope, we simultaneously measured stellar age, metallicity, and velocity dispersion for C1-23152, an ETG at redshift
z
= 3.352, corresponding to an epoch when the universe was ∼1.8 Gyr old. The analysis of its spectrum shows that this galaxy, hosting an active galactic nucleus (AGN), formed and assembled ∼2 × 10
11
M
⊙
, shaping its morphology within the ∼600 Myr preceding the observations, since
z
∼ 4.6. The stellar population has a mean mass-weighted age of
Myr, and it is formed between ∼600 and ∼150 Myr before the observed epoch, the latter being the time since quenching. Its high stellar velocity dispersion,
σ
e
= 409 ± 60 km s
−1
, confirms the high mass (
M
dyn
= 2.2 (±0.4) × 10
11
M
⊙
) and the high mass density (
= Σ
1kpc
= 3.2 (±0.7) × 10
10
M
⊙
kpc
−2
), suggesting a fast dissipative process at its origin. The analysis points toward a supersolar metallicity, Z/H = 0.25
, in agreement with the above picture, suggesting a star formation efficiency much higher than the replenishment time. However, subsolar-metallicity values cannot be firmly ruled out by our analysis. Quenching must have been extremely efficient to reduce the star formation to SFR < 6.5
M
⊙
yr
−1
in less than 150 Myr. This could be explained by the presence of the AGN, even if a causal relation cannot be established from the data. C1-23152 has the same stellar and physical properties of the densest ETGs in the local universe of comparable mass, suggesting that they are C1-23152-like galaxies that evolved to
z
= 0 unperturbed.
Pathogen genome sequencing can reveal details of transmission histories and is a powerful tool in the fight against infectious disease. In particular, within-host pathogen genomic variants identified ...through heterozygous nucleotide base calls are a potential source of information to identify linked cases and infer direction and time of transmission. However, using such data effectively to model disease transmission presents a number of challenges, including differentiating genuine variants from those observed due to sequencing error, as well as the specification of a realistic model for within-host pathogen population dynamics. Here we propose a new Bayesian approach to transmission inference, BadTrIP (BAyesian epiDemiological TRansmission Inference from Polymorphisms), that explicitly models evolution of pathogen populations in an outbreak, transmission (including transmission bottlenecks), and sequencing error. BadTrIP enables the inference of host-to-host transmission from pathogen sequencing data and epidemiological data. By assuming that genomic variants are unlinked, our method does not require the computationally intensive and unreliable reconstruction of individual haplotypes. Using simulations we show that BadTrIP is robust in most scenarios and can accurately infer transmission events by efficiently combining information from genetic and epidemiological sources; thanks to its realistic model of pathogen evolution and the inclusion of epidemiological data, BadTrIP is also more accurate than existing approaches. BadTrIP is distributed as an open source package (https://bitbucket.org/nicofmay/badtrip) for the phylogenetic software BEAST2. We apply our method to reconstruct transmission history at the early stages of the 2014 Ebola outbreak, showcasing the power of within-host genomic variants to reconstruct transmission events.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
SARS-CoV-2 uses the human ACE2 (hACE2) receptor for cell attachment and entry, with mouse ACE2 (mACE2) unable to support infection. Herein we describe an ACE2-lentivirus system and illustrate its ...utility for
in vitro
and
in vivo
SARS-CoV-2 infection models. Transduction of non-permissive cell lines with hACE2 imparted replication competence, and transduction with mACE2 containing N30D, N31K, F83Y and H353K substitutions, to match hACE2, rescued SARS-CoV-2 replication. Intrapulmonary hACE2-lentivirus transduction of C57BL/6J mice permitted significant virus replication in lung epithelium. RNA-Seq and histological analyses illustrated that this model involved an acute inflammatory disease followed by resolution and tissue repair, with a transcriptomic profile similar to that seen in COVID-19 patients. hACE2-lentivirus transduction of IFNAR
-/-
and IL-28RA
-/-
mouse lungs was used to illustrate that loss of type I or III interferon responses have no significant effect on virus replication. However, their importance in driving inflammatory responses was illustrated by RNA-Seq analyses. We also demonstrate the utility of the hACE2-lentivirus transduction system for vaccine evaluation in C57BL/6J mice. The ACE2-lentivirus system thus has broad application in SARS-CoV-2 research, providing a tool for both mutagenesis studies and mouse model development.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Expansion of anthropogenic noise and night lighting across our planet
is of increasing conservation concern
. Despite growing knowledge of physiological and behavioural responses to these stimuli ...from single-species and local-scale studies, whether these pollutants affect fitness is less clear, as is how and why species vary in their sensitivity to these anthropic stressors. Here we leverage a large citizen science dataset paired with high-resolution noise and light data from across the contiguous United States to assess how these stimuli affect reproductive success in 142 bird species. We find responses to both sensory pollutants linked to the functional traits and habitat affiliations of species. For example, overall nest success was negatively correlated with noise among birds in closed environments. Species-specific changes in reproductive timing and hatching success in response to noise exposure were explained by vocalization frequency, nesting location and diet. Additionally, increased light-gathering ability of species' eyes was associated with stronger advancements in reproductive timing in response to light exposure, potentially creating phenological mismatches
. Unexpectedly, better light-gathering ability was linked to reduced clutch failure and increased overall nest success in response to light exposure, raising important questions about how responses to sensory pollutants counteract or exacerbate responses to other aspects of global change, such as climate warming. These findings demonstrate that anthropogenic noise and light can substantially affect breeding bird phenology and fitness, and underscore the need to consider sensory pollutants alongside traditional dimensions of the environment that typically inform biodiversity conservation.
SIRT2 is a member of NAD+-dependent sirtuins and its inhibition has been proposed as a promising therapeutic approach for treating human diseases, including neurodegenerative diseases, cancer, and ...infections. Expanding SIRT2 inhibitors based on the 3-aminobenzyloxy nicotinamide core structure, we have synthesized and evaluated constrained analogs and selected stereoisomers. Our structure-activity relationship (SAR) study has revealed that 2,3-constrained (S)-isomers possess enhanced in vitro enzymatic inhibitory activity against SIRT2 and retain excellent selectivity over SIRT1 and SIRT3, provided that a suitable ring A is used. This current study further explores SIRT2 inhibitors based on the 3-aminobenzyloxy nicotinamide scaffold and contributes to the discovery of potent, selective SIRT2 inhibitors that have been actively pursued for their potential therapeutic applications.
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