Abstract
Pairs of nucleotides within functional nucleic acid secondary structures often display evidence of coevolution that is consistent with the maintenance of base-pairing. Here, we introduce a ...sequence evolution model, MESSI (Modeling the Evolution of Secondary Structure Interactions), that infers coevolution associated with base-paired sites in DNA or RNA sequence alignments. MESSI can estimate coevolution while accounting for an unknown secondary structure. MESSI can also use graphics processing unit parallelism to increase computational speed. We used MESSI to infer coevolution associated with GC, AU (AT in DNA), GU (GT in DNA) pairs in noncoding RNA alignments, and in single-stranded RNA and DNA virus alignments. Estimates of GU pair coevolution were found to be higher at base-paired sites in single-stranded RNA viruses and noncoding RNAs than estimates of GT pair coevolution in single-stranded DNA viruses. A potential biophysical explanation is that GT pairs do not stabilize DNA secondary structures to the same extent that GU pairs do in RNA. Additionally, MESSI estimates the degrees of coevolution at individual base-paired sites in an alignment. These estimates were computed for a SHAPE-MaP-determined HIV-1 NL4-3 RNA secondary structure. We found that estimates of coevolution were more strongly correlated with experimentally determined SHAPE-MaP pairing scores than three nonevolutionary measures of base-pairing covariation. To assist researchers in prioritizing substructures with potential functionality, MESSI automatically ranks substructures by degrees of coevolution at base-paired sites within them. Such a ranking was created for an HIV-1 subtype B alignment, revealing an excess of top-ranking substructures that have been previously identified as having structure-related functional importance, among several uncharacterized top-ranking substructures.
Abstract
Previous positive selection analyses on primate host restriction factors have helped to elucidate differences in primate adaptation to viral infection. However, many of these studies have ...been focused on small gene families and genes known or suspected to play a role as primate host restriction factors. With the genome sequencing of numerous primate species, we are now capable of comparing the evolutionary profiles of primate genes across the whole genome. Using these evolutionary profiles as guides, we characterize evolutionary similarities and differences between known primate restriction factors and sets of other genes with diverse functions to provide insight on new candidate restriction factors and the biological pressures that affect them.
Well-ordered HIV-1 envelope glycoprotein (Env) trimers are prioritized for clinical evaluation, and there is a need for an improved understanding about how elicited B cell responses evolve following ...immunization. To accomplish this, we prime-boosted rhesus macaques with clade C NFL trimers and identified 180 unique Ab lineages from ∼1,000 single-sorted Env-specific memory B cells. We traced all lineages in high-throughput heavy chain (HC) repertoire (Rep-seq) data generated from multiple immune compartments and time points and expressed several as monoclonal Abs (mAbs). Our results revealed broad dissemination and high levels of somatic hypermutation (SHM) of most lineages, including tier 2 virus neutralizing lineages, following boosting. SHM was highest in the Ab complementarity determining regions (CDRs) but also surprisingly high in the framework regions (FRs), especially FR3. Our results demonstrate the capacity of the immune system to affinity-mature large numbers of Env-specific B cell lineages simultaneously, supporting the use of regimens consisting of repeated boosts to improve each Ab, even those belonging to less expanded lineages.
Living and non-living active matter consumes energy at the microscopic scale to drive emergent, macroscopic behavior including traveling waves and coherent oscillations. Recent work has characterized ...non-equilibrium systems by their total energy dissipation, but little has been said about how dissipation manifests in distinct spatiotemporal patterns. We introduce a measure of irreversibility we term the entropy production factor to quantify how time reversal symmetry is broken in field theories across scales. We use this scalar, dimensionless function to characterize a dynamical phase transition in simulations of the Brusselator, a prototypical biochemically motivated non-linear oscillator. We measure the total energetic cost of establishing synchronized biochemical oscillations while simultaneously quantifying the distribution of irreversibility across spatiotemporal frequencies.
Conventional immunization strategies will likely be insufficient for the development of a broadly neutralizing antibody (bnAb) vaccine for HIV or other difficult pathogens because of the ...immunological hurdles posed, including B cell immunodominance and germinal center (GC) quantity and quality. We found that two independent methods of slow delivery immunization of rhesus monkeys (RMs) resulted in more robust T follicular helper (TFH) cell responses and GC B cells with improved Env-binding, tracked by longitudinal fine needle aspirates. Improved GCs correlated with the development of >20-fold higher titers of autologous nAbs. Using a new RM genomic immunoglobulin locus reference, we identified differential IgV gene use between immunization modalities. Ab mapping demonstrated targeting of immunodominant non-neutralizing epitopes by conventional bolus-immunized animals, whereas slow delivery-immunized animals targeted a more diverse set of epitopes. Thus, alternative immunization strategies can enhance nAb development by altering GCs and modulating the immunodominance of non-neutralizing epitopes.
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•Slow delivery immunization enhances HIV neutralizing antibody development in monkeys•Slow delivery immunization alters immunodominance of the responding B cells•Weekly longitudinal germinal center (GC) B and TFH analyses provides new GC insights•High-resolution rhesus immunoglobulin locus genomic reference sequence
An integrated immunological, bioinformatic and imaging approach demonstrates how slow delivery immunization enhances neutralizing antibody and germinal center reactions over conventional strategies in response to HIV Env protein immunization in non-human primates.
Understanding how multiple co‐occurring environmental stressors combine to affect biodiversity and ecosystem services is an on‐going grand challenge for ecology. Currently, progress has been made ...through accumulating large numbers of smaller‐scale empirical studies that are then investigated by meta‐analyses to detect general patterns. There is particular interest in detecting, understanding and predicting ‘ecological surprises’ where stressors interact in a non‐additive (e.g. antagonistic or synergistic) manner, but so far few general results have emerged. However, the ability of the statistical tools to recover non‐additive interactions in the face of data uncertainty is unstudied, so crucially, we do not know how well the empirical results reflect the true stressor interactions. Here, we investigate the performance of the commonly implemented additive null model. A meta‐analysis of a large (545 interactions) empirical dataset for the effects of pairs of stressors on freshwater communities reveals additive interactions dominate individual studies, whereas pooling the data leads to an antagonistic summary interaction class. However, analyses of simulated data from food chain models, where the underlying interactions are known, suggest both sets of results may be due to observation error within the data. Specifically, we show that the additive null model is highly sensitive to observation error, with non‐additive interactions being reliably detected at only unrealistically low levels of data uncertainty. Similarly, plausible levels of observation error lead to meta‐analyses reporting antagonistic summary interaction classifications even when synergies co‐dominate. Therefore, while our empirical results broadly agree with those of previous freshwater meta‐analyses, we conclude these patterns may be driven by statistical sampling rather than any ecological mechanisms. Further investigation of candidate null models used to define stressor‐pair interactions is essential, and once any artefacts are accounted for, the so‐called ‘ecological surprises’ may be more frequent than was previously assumed.
Ecosystems often face multiple stressors that act simultaneously; hence, understanding how stressors interact is an important goal. We perform a meta‐analysis of 545 freshwater stressor‐pair interactions and find that most individual experiment results cannot be distinguished from additive (i.e., the sum of the effects of both stressors acting individually), whilst the summary effect computed across all interactions is antagonistic (i.e., less than additive). However, computer models show these results are expected under plausible levels of measurement error, even if non‐additive interactions dominate the data, questioning our ability to reliably detect the true ways in which ecosystem stressors interact.
Dupilumab is a first-in-class biologic approved by the European Medicines Agency and the US Food and Drug Administration for the treatment of multiple atopic diseases, including atopic dermatitis, ...asthma, and chronic rhinosinusitis with nasal polyposis. Since gaining traction as an effective treatment modality, multiple reports have highlighted the many ocular side effects associated with dupilumab usage. These range from mild diseases, such as conjunctivitis, dry eyes, and blepharitis, to more severe manifestations such as intraocular inflammation and cicatrizing conjunctivitis. The pathogenesis behind these manifestations remains controversial, but are likely multi-factorial. We review the current evidence surrounding ocular manifestations of dupilumab-associated disease and proposed treatments to provide an overview of this unique disease entity. With increasing usage of dupilumab, formal recommendations regarding the treatment of dupilumab-associated ocular disease are warranted to provide standardized clinical guidance. Furthermore, it is important for health care practitioners to remain abreast with existing literature to counsel and empower patients with the knowledge surrounding contemporary treatments for atopic diseases and their associated sideeffects.
: A retrospective case-controlled study was performed to evaluate the outcomes of shoulder arthroplasty performed as a day case in carefully selected patients, compared to the traditional inpatient ...approach.
: Patients who had total or hemiarthroplasty of the shoulder performed as a day case or inpatient procedure were recruited. The primary outcome compared rates of uneventful recovery, defined by the absence of complications or readmission to the hospital within six months of surgery, between the inpatient and outpatient groups. Secondary outcomes included examiner-determined functional and patient-determined pain scores at one, six, twelve, and twenty-four weeks post-surgery. A further assessment of patient-determined pain scores was carried out at least two years post-surgery (5.8 ± 3.2).
: 73 patients (36 inpatients and 37 outpatients) were included in the study. Within this time frame, 25/36 inpatients (69%) had uneventful recoveries compared to 24/37 outpatients (65%) (
= 0.17). Outpatients showed significant improvement over pre-operative baseline levels in more secondary outcomes (strength and passive range-of-motion) by six months post-operation. Outpatients also performed significantly better than inpatients in external rotation (
< 0.05) and internal rotation (
= 0.05) at six weeks post-surgery. Both groups showed significant improvement compared to pre-operative baselines in all patient-determined secondary outcomes except the activity level at work and sports. Inpatients, however, experienced less severe pain at rest at six weeks (
= 0.03), significantly less frequent pain at night (
= 0.03), and extreme pain (
= 0.04) at 24 weeks, and less severe pain at night at 24 weeks (
< 0.01). By a minimum of two years post-operation, inpatients were more comfortable repeating their treatment setting for future arthroplasty (16/18) compared to outpatients (7/22) (
= 0.0002).
: At a minimum of two years of follow-up, there were no significant differences in rates of complications, hospitalizations, or revision surgeries between patients that underwent shoulder arthroplasty as an inpatient versus an outpatient. Outpatients demonstrated superior functional outcomes but reported more pain at six months post-surgery. Patients in both groups preferred inpatient treatment for any future shoulder arthroplasty.
Shoulder arthroplasty is a complex procedure and has traditionally been performed on an inpatient basis, with patients admitted for six to seven days post-surgery. One of the primary reasons for this is the high level of post-operative pain, usually treated with hospital-based opioid therapy. Two studies demonstrated outpatient TSA to have a similar rate of complications as inpatient TSA; however, these studies only examined patients within a shorter-term 90-day post-operative period and did not evaluate functional outcomes between the two groups or in the longer term.
This study provides evidence supporting the longer-term results of shoulder arthroplasty done as a day case in carefully selected patients, which are comparable to outcomes in patients that are admitted to the hospital post-surgery.
Vitiligo is an autoimmune skin disorder resulting in the depigmentation of skin characterised by patches of varying sizes and shapes. A common disorder of pigmentation that affects 0.5%–2% of the ...global population. Despite its well‐understood autoimmune pathogenesis, the targets for effective cytokine intervention remain unclear. Current first‐line treatments include oral or topical corticosteroids, calcineurin inhibitors and phototherapy. These treatments are limited, have varying efficacies, and are associated with significant adverse events or can be time‐consuming. Therefore, biologics should be explored as a potential treatment for vitiligo. There are currently limited data for the use of JAK and IL‐23 inhibitors for vitiligo. A total of 25 studies were identified in the review. There is promising evidence regarding the use of JAK and IL‐23 inhibitors for the treatment of vitiligo.
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