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Objective: To evaluate the completeness and reliability of recurrence data from an institutional cancer registry for patients with head and neck cancer. Patients and Methods: Recurrence information was collected by radiation oncology and otolaryngology researchers. This was compared with the institutional cancer registry for continuous patients treated with radiation therapy for head and neck cancer at a tertiary cancer center. The sensitivity and specificity of institutional cancer registry data was calculated using manual review as the gold standard. False negative recurrences were compared to true positive recurrences to assess for differences in patient characteristics. Results: A total of 1338 patients who were treated from January 1, 2010, through December 31, 2017, were included in a cancer registry and underwent review. Of them, 375 (30%) had confirmed cancer recurrences, 45 (3%) had concern for recurrence without radiologic or pathologic confirmation, and 31 (2%) had persistent disease. Most confirmed recurrences were distant (37%) or distant plus locoregional (29%), whereas few were local (11%), regional (9%), or locoregional (14%) alone. The cancer registry accuracy was 89.4%, sensitivity 61%, and specificity 99%. Time to recurrence was associated with registry accuracy. True positives had recurrences at a median of 414 days vs 1007 days for false negatives. Conclusion: Currently, institutional cancer registry recurrence data lacks the required accuracy for implementation into studies without manual confirmation. Longer follow-up of cancer status will likely improve sensitivity. No identified differences in patients accounted for differences in sensitivity. New, ideally automated, data abstraction tools are needed to improve detection of cancer recurrences and minimize manual chart review.

BACKGROUND: The evolving landscape of application processes for obstetrics and gynecology residency applicants poses many challenges for applicants and advisors. The lack of data coordination among national groups creates crucial gaps in information for stakeholder groups. OBJECTIVE: This study aimed to identify the current state of the advising milieu for obstetrics and gynecology residency applicants and their career advisors, the annual Association of Professors of Gynecology and Obstetrics survey focused on US clerkship directors’ experiences advising students through these processes. STUDY DESIGN: A 23-item anonymous survey was developed that asked respondents about demographics and outcomes for the students that they advised through the 2021 application process and their experiences with dual applicants and students not matching. The survey was sent electronically to all obstetrics and gynecology clerkship directors with active Association of Professors of Gynecology and Obstetrics memberships in April 2021. RESULTS: Of 224 total clerkship directors, 143 (63.8%) responded to the survey, Of the 143 respondents, almost all (136 [95.1%]) served as career advisors, and 50 (35.0%) were aware of students dual applying. Furthermore, obstetrics and gynecology was rarely the backup to a more competitive specialty. For the 2021 application cycle, 79 of 143 respondents (55.2%) reported having students not successfully match into obstetrics and gynecology, with “academic concerns” followed by “poor communication skills” as the primary reasons cited for students not matching. CONCLUSION: This snapshot of clerkship directors’ experiences advising students in the residency application process reveals notably high rates of dual applicants and students not matching into obstetrics and gynecology. This work fills key gaps in our knowledge of current processes and highlights the importance of career advising at multiple points during the application process.

BACKGROUND: Given the increasing complexities of the residency application processes, there is an ever-increasing need for faculty to serve in the role of fourth-year medical student career advisors. OBJECTIVE: This study aimed to investigate obstetrics and gynecology clerkship directors’ confidence and fulfillment with serving in the role of faculty career advisors. STUDY DESIGN: A 25-item electronic survey was developed and distributed to the 225 US obstetrics and gynecology clerkship directors in university-based and community-based medical schools with active memberships in the Association of Professors of Gynecology and Obstetrics. Items queried respondents on demographics, confidence in fourth-year advising, satisfaction with this aspect of their career, and resources used for advising. RESULTS: Of 225 clerkship directors, 143 (63.6%) responded to the survey. Nearly all clerkship directors (136/143 [95%]) reported advising fourth-year students. A median of 5.0 hours (interquartile range, 3.0–10.0) was spent per student in this advisory role, with 29 of 141 clerkship directors (20.5%) reporting some form of compensation for advising. Confidence in the ability to advise fourth-year medical students correlated significantly with number of years as a faculty, number of years as a clerkship director, and a higher full-time equivalent allotted as clerkship director. Fulfillment as a faculty career advisor was correlated with number of years as a clerkship director and a higher number of students advised. CONCLUSION: Obstetrics and gynecology clerkship directors regularly serve in the crucial role of faculty career advisor. Confidence in advising fourth-year students, advising fulfillment, and satisfaction with advising resources were all significantly correlated. We recommend that clerkship directors review resources available for advising and that they be provided academic time to serve as career advisors.

Background: Accurate glenoid component placement in shoulder arthroplasty is often difficult even with the use of preoperative planning. Computer navigation and patient-specific guides increase component placement accuracy, but which patients benefit most is unknown. Our purpose was to assess surgeons' accuracy in placing a glenoid component in vivo using 3-dimensional preoperative planning and standard instruments among various glenoid wear patterns. Methods: We conducted a retrospective review of 170 primary anatomic total shoulder arthroplasty (aTSA) and reverse total shoulder arthroplasty (rTSA) performed at a single institution. Commercially available preoperative planning software was used in all arthroplasties with multiplanar 2-dimensional computed tomography and a 3-dimensional implant overlay. After registration of intraoperative bony landmarks to the navigation system, participating surgeons with knowledge of the preoperative plan were blinded to the computer screen and attempted to implement their preoperative plan by simulating placement of a central-axis glenoid guide pin. Two hundred thirty-three screenshots of surgeon's simulated guide pin placement were included. Glenoid displacement, error in version and inclination, and overall malposition from the preoperatively planned target point were stratified by posterior wear status (with [Walch B2 or B3] or without [A1, A2, or B1]) and Walch classification (A1, A2, B1, B2, or B3). The glenoid component was considered malpositioned when version or inclination errors exceeded 10° or the starting point displacement exceeded 4 mm. Results: For rTSA, errors in version were greater for glenoids with posterior wear compared with those without (8.1° ± 5.6° vs. 4.7° ± 4.0°; P 10° compared with those without (31% vs. 8%; P

Background: Instability remains the most common complication after revision total hip arthroplasty (THA). The purpose of this study was to determine whether there was a difference in aseptic revision rates and survivorship between dual-mobility (DM) and constrained liners (CL) in revision THA. Methods: We reviewed a consecutive series of 2432 revision THA patients from 2008 to 2019 at our institution and identified all patients who received either a CL or DM bearing. We compared demographics, comorbidities, indications, dislocations, and aseptic failure rates between the two groups. Bivariate and multivariate regression analyses were used to determine risk factors for failure, and a Kaplan-Meier survivorship analysis was performed with an aseptic re-revision as the endpoint. Results: Of the 191 patients, 139 (72%) received a DM bearing, and 52 (28%) had a CL. At a mean follow-up of 14.3 months, there was no statistically significant difference in rates of dislocation (10.4% vs 14.0%, P = .667), aseptic revision (30.9% vs 46.2%, P = .073), or time to revision (3.78 vs 6 months, P = .565) between the two groups. The multivariate analysis revealed CL had no difference in aseptic re-revision rates when compared with DM (odds ratio 1.47, 95% confidence interval 0.84-2.52, P = .177). The survivorship analysis found no difference in aseptic failure between the groups at 12 months (P = .059). Conclusion: Both CL and DM bearings have high aseptic failure rates at intermediate term follow-up after revision THA. CL did show a higher risk of failure than DM bearings, but it was not statistically significant with the numbers available for this study. Further prospective studies are needed to determine the optimal treatment for recurrent instability.

Background: Patellar tendon ruptures are the third-most common injury involving the knee extensor mechanism. They typically occur in men under 40 years old as a result of eccentric quadriceps contraction while the knee is flexed and the foot is planted. 1 The optimal treatment is surgical repair within 2 weeks of injury to prevent scar formation, degeneration, and loss of tendon excursion. Indications: Operative management is generally indicated for patellar tendon ruptures. In this case, a physically active, healthy 24-year-old man presented with acute pain, extensor lag, and patella alta related to a basketball injury. He was diagnosed with acute patellar tendon rupture/extensor mechanism disruption and indicated for surgery. Technique description: We describe a technique for primary patellar tendon repair which uses both knot-based and knotless suture anchor fixation. Using a pulley effect, sutures in the inferior patellar anchors are used to reduce and repair the patellar tendon back to its bony origin. Patellar anchor-based tapes and a suprapatellar traction suture are affixed with knotless anchors to the proximal tibia to reinforce the repair. Anchor-based suture limbs are used to repair the medial and lateral retinacula. Results: The senior authors’ experience with this technique has been excellent restoration of extensor mechanism function, with rehabilitation permitting early range of motion and no major complications or failures. This patient returned to unassisted activities of daily living between 8 and 12 weeks and had returned to gym workouts and recreational sports at 12 months. Discussion/conclusion: Biomechanical studies have demonstrated that compared with transosseous repair, suture anchor repair decreases gap formation and improves ultimate load to failure. Advantages of suture anchor repair include smaller incision, less tissue dissection, shorter operative time, and improved repair biomechanics. Our technique follows a principle of tendon repair using a high number of suture and tape limbs to span the repair. In addition, this technique incorporates a “double row” of suture anchors and spans the primary repair with a suture and tape “internal brace.” The author(s) attests that consent has been obtained from any patient(s) appearing in this publication. If the individual may be identifiable, the author(s) has included a statement of release or other written form of approval from the patient(s) with this submission for publication.

In this study, we report the case of a pediatric neurology stroke patient who was ultimately diagnosed with Takayasu's Arteritis. Our case describes a 14-year-old Hispanic female with no significant past medical history who presented to an outside hospital for acute onset of confusion and right sided weakness. She was given tissue plasminogen activator (TPA) at the outside hospital and transferred as a stroke alert. Initial The NIH stroke scale (NIHSS) was 12 with primarily right sided symptoms. Physical exam was also significant for asymmetric pulses and blood pressures. Imaging was significant for multifocal stenosis. She was ultimately diagnosed with Takayasu's arteritis and treated with a multidisciplinary approach including pediatrics, neurology and rheumatology. This case represents an important differential diagnosis for pediatric stroke patients including those who have stroke as the presenting symptom of this systemic disease. Keywords: Takayasu's arteritis, Stroke, Pediatric

Objective: To examine HIV viral suppression during/after pregnancy. Design: Prospective observational cohort. Methods: We identified pregnancies from 1996 to 2015. We examined HIV RNA viral load (VL), VL suppression (≤500 copies/mL), and antiretroviral therapy (ART) status at pregnancy start, end, and 6 months postpartum. We estimated risk ratios (RRs) and 95% confidence intervals (CIs) for VL nonsuppression. Results: Among 253 pregnancies analyzed, 34.8% of women exhibited VL suppression at pregnancy start, 60.1% at pregnancy end, and 42.7% at 6 months postpartum. Median VL (log 10 copies/mL) was 2.80 (interquartile range [IQR]: 1.40-3.85) at pregnancy start, 1.70 (IQR: 1.40-2.82) at pregnancy end, and 2.30 (IQR: 1.40-3.86) at postpartum. Risk of postpartum VL nonsuppression was also lower among women on ART and with VL suppression at pregnancy end (versus those not; adjusted RR = 0.30, 95% CI: 0.17-0.53). Conclusions: Maintaining VL suppression among US women remains a challenge, particularly during postpartum. Achieving VL suppression earlier during pregnancy benefits women subsequently.

Objectives: The proliferation of metallo-β-lactamase (MBL)-producing Pseudomonas aeruginosa represents a significant public health threat. P. aeruginosa undergoes significant phenotypic changes that drastically impair antibiotic efficacy. The objectives of this study were (1) to quantify the time-course of killing of VIM-2-producing P. aeruginosa in response to aztreonam-based therapies (including avibactam for coverage of AmpC), and (2) to document the capacity of P. aeruginosa to undergo morphological transformations that facilitate persistence., Methods: A well-characterised, clinical VIM-2-producing P. aeruginosa was studied in the hollow fibre infection model (HFIM) over 9 days (7 days of active antibiotic therapy, 2 days of treatment withdrawal) at a 10 7.5 CFU/mL starting inoculum. HFIM treatment arms included: growth control, aztreonam, ceftazidime/avibactam, aztreonam/ceftazidime/avibactam, polymyxin B, and aztreonam/ceftazidime/avibactam/polymyxin B. In addition, real-time imaging studies were conducted under static conditions to determine the time course of the reversion of persister cells., Results: There was a pronounced discrepancy between OD 620 and bacterial counts obtained from plating methods (hereafter referred to as 'OD-count discrepancy'). For aztreonam monotherapy, observed counts were 0 CFU/mL by 120 h. Despite this, there was a significant OD-count discrepancy compared with the pre-treatment 0 h. Between therapy withdrawal at 168 h and 216 h, all arms with suppressed counts had regrown to the system-carrying capacity. Real-time imaging of the P. aeruginosa filaments after drug removal showed rapid reversion from a long, filamentous phenotype to many individual rods within 2 h., Conclusion: Managing MBL-producing P. aeruginosa requires a multifaceted approach, focused on maximising killing and minimising proliferation of resistant and persistent subpopulations, which will involve eliminating drug-induced phenotypic transformers., (Copyright © 2024 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)

Ostracod crustaceans originated at least 500 Ma ago. Their tiny bivalved shells represent the most species-abundant fossil arthropods, and ostracods are omnipresent in a wide array of freshwater and marine environments today and in the past. Derima paparme gen. et sp. nov. from the Herefordshire Silurian Lagerstätte (~430 Ma) in the Welsh Borderland, UK, is one of only a handful of exceptionally preserved ostracods (with soft parts as well as the shell) known from the Palaeozoic. A male specimen provides the first evidence of the appendages of Binodicopina, a major group of Palaeozoic ostracods comprising some 135 Ordovician to Permian genera. The appendage morphology of D. paparme , but not its shell, indicates that binodicopes belong to Podocopa. The discovery that the soft-part morphology of binodicopes allies them with podocopes affirms that using the shell alone is an unreliable basis for classifying certain fossil ostracods, and knowledge of soft-part morphology is critical for the task. Current assignment of many fossil ostracods to higher taxa, and therefore the evolutionary history of the group, may require reconsideration.

The Msh2-Msh3 mismatch repair (MMR) complex in Saccharomyces cerevisiae recognizes and directs repair of insertion/deletion loops (IDLs) up to ∼17 nucleotides. Msh2-Msh3 also recognizes and binds distinct looped and branched DNA structures with varying affinities, thereby contributing to genome stability outside post-replicative MMR through homologous recombination, double-strand break repair (DSBR) and the DNA damage response. In contrast, Msh2-Msh3 promotes genome instability through trinucleotide repeat (TNR) expansions, presumably by binding structures that form from single-stranded (ss) TNR sequences. We previously demonstrated that Msh2-Msh3 binding to 5' ssDNA flap structures interfered with Rad27 (Fen1 in humans)-mediated Okazaki fragment maturation (OFM) in vitro. Here we demonstrate that elevated Msh2-Msh3 levels interfere with DNA replication and base excision repair in vivo. Elevated Msh2-Msh3 also induced a cell cycle arrest that was dependent on RAD9 and ELG1 and led to PCNA modification. These phenotypes also required Msh2-Msh3 ATPase activity and downstream MMR proteins, indicating an active mechanism that is not simply a result of Msh2-Msh3 DNA-binding activity. This study provides new mechanistic details regarding how excess Msh2-Msh3 can disrupt DNA replication and repair and highlights the role of Msh2-Msh3 protein abundance in Msh2-Msh3-mediated genomic instability., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

A new arthropod, Carimersa neptuni gen. et sp. nov., is described from the Silurian (Wenlock Series) Herefordshire Konservat-Lagerstätte, UK. The head bears pedunculate eyes and five pairs of appendages. Triflagellate antennae are followed by two pairs of uniramous limbs each with an endopod bearing a pronounced gnathobasic basipod. The posterior two pairs of head limbs and all trunk limbs bear an endopod, exopod and filamentous exite. The trunk consists of 10 appendage-bearing segments followed by an apodous abdomen of four segments. The arthropod resolves as sister taxon to Kodymirus and Eozetetes + Aglaspidida. It is the first representative of Vicissicaudata reported from the Herefordshire Lagerstätte and the first Silurian example with well-preserved appendages. The preservation of a cluster of radiolarians apparently captured by the trunk appendages is the first direct association of predator and prey discovered in the Herefordshire fauna, and suggests that Carimersa was a nektobenthic form that used its gnathobasic basipods in microdurophagy., Competing Interests: We declare we have no competing interests., (© 2023 The Authors.)

Translesion synthesis (TLS) by specialized DNA polymerases (Pols) is an evolutionarily conserved mechanism for tolerating replication-blocking DNA lesions. Using the Escherichia coli dinB -encoded Pol IV as a model to understand how TLS is coordinated with the actions of the high-fidelity Pol III replicase, we previously described a novel Pol IV mutant containing a threonine 120-to-proline mutation (Pol IV-T120P) that failed to exchange places with Pol III at the replication fork in vitro as part of a Pol III-Pol IV switch. This in vitro defect correlated with the inability of Pol IV-T120P to support TLS in vivo , suggesting Pol IV gains access to the DNA, at least in part, via a Pol III-Pol IV switch. Interaction of Pol IV with the β sliding clamp and the single-stranded DNA binding protein (SSB) significantly stimulates Pol IV replication and facilitates its access to the DNA. In this work, we demonstrate that Pol IV interacts physically with Pol III. We further show that Pol IV-T120P interacts normally with the β clamp, but is impaired in interactions with the α catalytic and εθ proofreading subunits of Pol III, as well as SSB. Taken together with published work, these results provide strong support for the model in which Pol IV-Pol III and Pol IV-SSB interactions help to regulate the access of Pol IV to the DNA. Finally, we describe several additional E. coli Pol-Pol interactions, suggesting Pol-Pol interactions play fundamental roles in coordinating bacterial DNA replication, DNA repair, and TLS. IMPORTANCE Specialized DNA polymerases (Pols) capable of catalyzing translesion synthesis (TLS) generate mutations that contribute to bacterial virulence, pathoadaptation, and antimicrobial resistance. One mechanism by which the bacterial TLS Pol IV gains access to the DNA to generate mutations is by exchanging places with the bacterial Pol III replicase via a Pol III-Pol IV switch. Here, we describe multiple Pol III-Pol IV interactions and discuss evidence that these interactions are required for the Pol III-Pol IV switch. Furthermore, we describe several additional E. coli Pol-Pol interactions that may play fundamental roles in managing the actions of the different bacterial Pols in DNA replication, DNA repair, and TLS.

Expression of the Escherichia coli dnaN -encoded β clamp at ≥10-fold higher than chromosomally expressed levels impedes growth by interfering with DNA replication. We hypothesized that the excess β clamp sequesters the replicative DNA polymerase III (Pol III) to inhibit replication. As a test of this hypothesis, we obtained eight mutant clamps with an inability to impede growth and measured their ability to stimulate Pol III replication in vitro . Compared with the wild-type clamp, seven of the mutants were defective, consistent with their elevated cellular levels failing to sequester Pol III. However, the β E202K mutant that bears a glutamic acid-to-lysine substitution at residue 202 displayed an increased affinity for Pol IIIα and Pol III core (Pol IIIαεθ), suggesting that it could still sequester Pol III effectively. Of interest, β E202K supported in vitro DNA replication by Pol II and Pol IV but was defective with Pol III. Genetic experiments indicated that the dnaN E202K strain remained proficient in DNA damage-induced mutagenesis but was induced modestly for SOS and displayed sensitivity to UV light and methyl methanesulfonate. These results correlate an impaired ability of the mutant β E202K clamp to support Pol III replication in vivo with its in vitro defect in DNA replication. Taken together, our results (i) support the model that sequestration of Pol III contributes to growth inhibition, (ii) argue for the existence of an additional mechanism that contributes to lethality, and (iii) suggest that physical and functional interactions of the β clamp with Pol III are more extensive than appreciated currently. IMPORTANCE The β clamp plays critically important roles in managing the actions of multiple proteins at the replication fork. However, we lack a molecular understanding of both how the clamp interacts with these different partners and the mechanisms by which it manages their respective actions. We previously exploited the finding that an elevated cellular level of the β clamp impedes Escherichia coli growth by interfering with DNA replication. Using a genetic selection method, we obtained novel mutant β clamps that fail to inhibit growth. Their analysis revealed that β E202K is unique among them. Our work offers new insights into how the β clamp interacts with and manages the actions of E. coli DNA polymerases II, III, and IV.

Expression of the Escherichia coli dnaN -encoded β clamp at ≥10-fold higher than chromosomally expressed levels impedes growth by interfering with DNA replication. A mutant clamp (β E202K bearing a glutamic acid-to-lysine substitution at residue 202) binds to DNA polymerase III (Pol III) with higher affinity than the wild-type clamp, suggesting that its failure to impede growth is independent of its ability to sequester Pol III away from the replication fork. Our results demonstrate that the dnaN E202K strain underinitiates DNA replication due to insufficient levels of DnaA-ATP and expresses several DnaA-regulated genes at altered levels, including nrdAB , that encode the class 1a ribonucleotide reductase (RNR). Elevated expression of nrdAB was dependent on hda function. As the β clamp-Hda complex regulates the activity of DnaA by stimulating its intrinsic ATPase activity, this finding suggests that the dnaN E202K allele supports an elevated level of Hda activity in vivo compared with the wild-type strain. In contrast, using an in vitro assay reconstituted with purified components the β E202K and wild-type clamp proteins supported comparable levels of Hda activity. Nevertheless, co-overexpression of the nrdAB -encoded RNR relieved the growth defect caused by elevated levels of the β clamp. These results support a model in which increased cellular levels of DNA precursors relieve the ability of elevated β clamp levels to impede growth and suggest either that multiple effects stemming from the dnaN E202K mutation contribute to elevated nrdAB levels or that Hda plays a noncatalytic role in regulating DnaA-ATP by sequestering it to reduce its availability. IMPORTANCE DnaA bound to ATP acts in initiation of DNA replication and regulates the expression of several genes whose products act in DNA metabolism. The state of the ATP bound to DnaA is regulated in part by the β clamp-Hda complex. The dnaN E202K allele was identified by virtue of its inability to impede growth when expressed ≥10-fold higher than chromosomally expressed levels. While the dnaN E202K strain exhibits several phenotypes consistent with heightened Hda activity, the wild-type and β E202K clamp proteins support equivalent levels of Hda activity in vitro . Taken together, these results suggest that β E202K -Hda plays a noncatalytic role in regulating DnaA-ATP. This, as well as alternative models, is discussed.

The SOS response to DNA damage is a conserved stress response in Gram-negative and Gram-positive bacteria. Although this pathway has been studied for years, its relevance is still not familiar to many working in the fields of clinical antibiotic resistance and stewardship. Under some conditions, the SOS response favors DNA repair and preserves the genetic integrity of the organism. On the other hand, the SOS response also includes induction of error-prone DNA polymerases, which can increase the rate of mutation, called the mutator phenotype or "hypermutation." As a result, mutations can occur in genes conferring antibiotic resistance, increasing the acquisition of resistance to antibiotics. Almost all of the work on the SOS response has been on bacteria exposed to stressors in vitro . In this study, we sought to quantitate the effects of SOS-inducing drugs in vivo , in comparison with the same drugs in vitro . We used a rabbit model of intestinal infection with enteropathogenic Escherichia coli strain E22. SOS-inducing drugs triggered the mutator phenotype response in vivo as well as in vitro . Exposure of E. coli strain E22 to ciprofloxacin or zidovudine, both of which induce the SOS response in vitro , resulted in increased antibiotic resistance to 3 antibiotics: rifampin, minocycline, and fosfomycin. Zinc was able to inhibit the SOS-induced emergence of antibiotic resistance in vivo , as previously observed in vitro . Our findings may have relevance in reducing the emergence of resistance to new antimicrobial drugs.

It has often been suggested that the productivity of an ecosystem affects the number of species that it can support. Despite decades of study, the nature, extent, and underlying mechanisms of this relationship are unclear. One suggested mechanism is the "more individuals" hypothesis (MIH). This proposes that productivity controls the number of individuals in the ecosystem, and that more individuals can be divided into a greater number of species before their population size is sufficiently small for each to be at substantial risk of extinction. Here, we test this hypothesis using REvoSim: an individual-based eco-evolutionary system that simulates the evolution and speciation of populations over geological time, allowing phenomena occurring over timescales that cannot be easily observed in the real world to be evaluated. The individual-based nature of this system allows us to remove assumptions about the nature of speciation and extinction that previous models have had to make. Many of the predictions of the MIH are supported in our simulations: Rare species are more likely to undergo extinction than common species, and species richness scales with productivity. However, we also find support for relationships that contradict the predictions of the strict MIH: species population size scales with productivity, and species extinction risk is better predicted by relative than absolute species population size, apparently due to increased competition when total community abundance is higher. Furthermore, we show that the scaling of species richness with productivity depends upon the ability of species to partition niche space. Consequently, we suggest that the MIH is applicable only to ecosystems in which niche partitioning has not been halted by species saturation. Some hypotheses regarding patterns of biodiversity implicitly or explicitly overlook niche theory in favor of neutral explanations, as has historically been the case with the MIH. Our simulations demonstrate that niche theory exerts a control on the applicability of the MIH and thus needs to be accounted for in macroecology., Competing Interests: The authors declare no conflict of interest., (© 2021 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

There is significant geographic variation in species richness. However, the nature of the underlying relationships, such as that between species richness and environmental stability, remains unclear. The stability-time hypothesis suggests that environmental instability reduces species richness by suppressing speciation and increasing extinction risk. By contrast, the patch-mosaic hypothesis suggests that small-scale environmental instability can increase species richness by providing a steady supply of non-equilibrium environments. Although these hypotheses are often applied to different time scales, their core mechanisms are in conflict. Reconciling these apparently competing hypotheses is key to understanding how environmental conditions shape the distribution of biodiversity. Here, we use REvoSim, an individual-based, eco-evolutionary system, to model the evolution of sessile organisms in environments with varying magnitudes and scales of environmental instability. We demonstrate that when environments have substantial permanent heterogeneity, a high level of localized environmental instability reduces biodiversity, whereas in environments lacking permanent heterogeneity, high levels of localized instability increase biodiversity. By contrast, broad-scale environmental instability, acting on the same time scale, invariably reduces biodiversity. Our results provide a new view of the biodiversity-disturbance relationship that reconciles contrasting hypotheses within a single model and implies constraints on the environmental conditions under which those hypotheses apply. These constraints can inform attempts to conserve adaptive potential in different environments during the current biodiversity crisis.

Evolutionary inferences require reliable phylogenies. Morphological data have traditionally been analyzed using maximum parsimony, but recent simulation studies have suggested that Bayesian analyses yield more accurate trees. This debate is ongoing, in part, because of ambiguity over modes of morphological evolution and a lack of appropriate models. Here, we investigate phylogenetic methods using two novel simulation models-one in which morphological characters evolve stochastically along lineages and another in which individuals undergo selection. Both models generate character data and lineage splitting simultaneously: the resulting trees are an emergent property, rather than a fixed parameter. Standard consensus methods for Bayesian searches (Mki) yield fewer incorrect nodes and quartets than the standard consensus trees recovered using equal weighting and implied weighting parsimony searches. Distances between the pool of derived trees (most parsimonious or posterior distribution) and the true trees-measured using Robinson-Foulds (RF), subtree prune and regraft (SPR), and tree bisection reconnection (TBR) metrics-demonstrate that this is related to the search strategy and consensus method of each technique. The amount and structure of homoplasy in character data differ between models. Morphological coherence, which has previously not been considered in this context, proves to be a more important factor for phylogenetic accuracy than homoplasy. Selection-based models exhibit relatively lower homoplasy, lower morphological coherence, and higher inaccuracy in inferred trees. Selection is a dominant driver of morphological evolution, but we demonstrate that it has a confounding effect on numerous character properties which are fundamental to phylogenetic inference. We suggest that the current debate should move beyond considerations of parsimony versus Bayesian, toward identifying modes of morphological evolution and using these to build models for probabilistic search methods. [Bayesian; evolution; morphology; parsimony; phylogenetics; selection; simulation.]., (© The Author(s) 2020. Published by Oxford University Press, on behalf of the Society of Systematic Biologists.)

How does past evolutionary performance impact future evolutionary performance? This is an important question not just for macroevolutionary biologists who wish to chart the phenomena that describe deep-time changes in biodiversity but also for conservation biologists, as evolutionarily distinct species-which may be deemed 'low-performing' in our current era-are increasingly the focus of conservation efforts. Contrasting hypotheses exist to account for the history and future of evolutionarily distinct species: on the one hand, they may be relicts of large radiations, potentially 'doomed' to extinction; or they may be slow-evolving, 'living fossils', likely neither to speciate nor go extinct; or they may be seeds of future radiations. Here, we attempt to test these hypotheses in Mammalia by combining a molecular phylogenetic supertree with fossil record occurrences and measuring change in evolutionary distinctness (ED) at different time slices. With these time slices, we modelled future ED as a function of past ED. We find that past evolutionary performance does indeed have an impact on future evolutionary performance: the most evolutionarily isolated clades tend to become more evolutionarily distinct with time, indicating that low-performing clades tend to remain low-performing throughout their evolutionary history. This article is part of a discussion meeting issue 'The past is a foreign country: how much can the fossil record actually inform conservation?'

Sponges (Porifera), as one of the earliest-branching animal phyla, are crucial for understanding early metazoan phylogeny. Recent studies of Lower Palaeozoic sponges have revealed a variety of character states and combinations unknown in extant taxa, challenging our views of early sponge morphology. The Herefordshire Konservat-Lagerstätte yields an abundant, diverse sponge fauna with three-dimensional preservation of spicules and soft tissue. Carduispongia pedicula gen. et sp. nov. possesses a single layer of hexactine spicules arranged in a regular orthogonal network. This spicule type and arrangement is characteristic of the reticulosans, which have traditionally been interpreted as early members of the extant siliceous Class Hexactinellida. However, the unusual preservation of the spicules of C . pedicula reveals an originally calcareous composition, which would be diagnostic of the living Class Calcarea. The soft tissue architecture closely resembles the complex sylleibid or leuconid structure seen in some modern calcareans and homoscleromorphs. This combination of features strongly supports a skeletal continuum between primitive calcareans and hexactinellid siliceans, indicating that the last common ancestor of Porifera was a spiculate, solitary, vasiform animal with a thin skeletal wall., Competing Interests: We have no competing interests.

The β-clamp is a protein hub central to DNA replication and fork management. Proteins interacting with the β-clamp harbor a conserved clamp-binding motif that is often found in extended regions. Therefore, clamp interactions have -almost exclusively- been studied using short peptides recapitulating the binding motif. This approach has revealed the molecular determinants that mediate the binding but cannot describe how proteins with clamp-binding motifs embedded in structured domains are recognized. The mismatch repair protein MutL has an internal clamp-binding motif, but its interaction with the β-clamp has different roles depending on the organism. In Bacillus subtilis, the interaction stimulates the endonuclease activity of MutL and it is critical for DNA mismatch repair. Conversely, disrupting the interaction between Escherichia coli MutL and the β-clamp only causes a mild mutator phenotype. Here, we determined the structures of the regulatory domains of E. coli and B. subtilis MutL bound to their respective β-clamps. The structures reveal different binding modes consistent with the binding to the β-clamp being a two-step process. Functional characterization indicates that, within the regulatory domain, only the clamp binding motif is required for the interaction between the two proteins. However, additional motifs beyond the regulatory domain may stabilize the interaction. We propose a model for the activation of the endonuclease activity of MutL in organisms lacking methyl-directed mismatch repair., (© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Reconstructing the evolutionary assembly of animal body plans is challenging when there are large morphological gaps between extant sister taxa, as in the case of echinozoans (echinoids and holothurians). However, the inclusion of extinct taxa can help bridge these gaps. Here we describe a new species of echinozoan, Sollasina cthulhu, from the Silurian Herefordshire Lagerstätte, UK. Sollasina cthulhu belongs to the ophiocistioids, an extinct group that shares characters with both echinoids and holothurians. Using physical-optical tomography and computer reconstruction, we visualize the internal anatomy of S. cthulhu in three dimensions, revealing inner soft tissues that we interpret as the ring canal, a key part of the water vascular system that was previously unknown in fossil echinozoans. Phylogenetic analyses strongly suggest that Sollasina and other ophiocistioids represent a paraphyletic group of stem holothurians, as previously hypothesized. This allows us to reconstruct the stepwise reduction of the skeleton during the assembly of the holothurian body plan, which may have been controlled by changes in the expression of biomineralization genes.

The SOS response is a conserved response to DNA damage that is found in Gram-negative and Gram-positive bacteria. When DNA damage is sustained and severe, activation of error-prone DNA polymerases can induce a higher mutation rate than is normally observed, which is called the SOS mutator phenotype or hypermutation. We previously showed that zinc blocked the hypermutation response induced by quinolone antibiotics and mitomycin C in Escherichia coli and Klebsiella pneumoniae . In this study, we demonstrate that zinc blocks the SOS-induced development of chloramphenicol resistance in Enterobacter cloacae . Zinc also blocked the transfer of an extended spectrum beta-lactamase (ESBL) gene from Enterobacter to a susceptible E. coli strain. A zinc ionophore, zinc pyrithione, was ~100-fold more potent than zinc salts in inhibition of ciprofloxacin-induced hypermutation in E. cloacae . Other divalent metals, such as iron and manganese, failed to inhibit these responses. Electrophoretic mobility shift assays (EMSAs) revealed that zinc, but not iron or manganese, blocked the ability of the E. coli RecA protein to bind to single-stranded DNA, an important early step in the recognition of DNA damage in enteric bacteria. This suggests a mechanism for zinc's inhibitory effects on bacterial SOS responses, including hypermutation.

Ostracod crustaceans are diverse and ubiquitous in aqueous environments today but relatively few known species have gills. Ostracods are the most abundant fossil arthropods but examples of soft-part preservation, especially of gills, are exceptionally rare. A new ostracod, Spiricopia aurita (Myodocopa), from the marine Silurian Herefordshire Lagerstätte (430 Mya), UK, preserves appendages, lateral eyes and gills. The respiratory system includes five pairs of gill lamellae with hypobranchial and epibranchial canals that conveyed haemolymph. A heart and associated vessels had likely evolved in ostracods by the Mid-Silurian., (© 2018 The Authors.)

The Herefordshire (Silurian) Lagerstätte (approx. 430 Myr BP) has yielded, among many exceptionally preserved invertebrates, a wide range of new genera belonging to crown-group Panarthropoda. Here, we increase this panarthropod diversity with the lobopodian Thanahita distos , a new total-group panarthropod genus and species. This new lobopodian preserves at least nine paired, long, slender appendages, the anterior two in the head region and the posterior seven representing trunk lobopods. The body ends in a short post-appendicular extension. Some of the trunk lobopods bear two claws, others a single claw. The body is covered by paired, tuft-like papillae. Thanahita distos joins only seven other known three-dimensionally preserved lobopodian or onychophoran (velvet worm) fossil specimens and is the first lobopodian to be formally described from the Silurian. Phylogenetic analysis recovered it, together with all described Hallucigenia species, in a sister-clade to crown-group panarthropods. Its placement in a redefined Hallucigeniidae, an iconic Cambrian clade, indicates the survival of this clade to Silurian times., Competing Interests: The authors have no financial or other competing interests concerning this study.

Echinoderms are unique in having a water vascular system with tube feet, which perform a variety of functions in living forms. Here, we report the first example of preserved tube feet in an extinct group of echinoderms. The material, from the Silurian Herefordshire Lagerstätte, UK, is assigned to a new genus and species of rhenopyrgid edrioasteroid, Heropyrgus disterminus The tube feet attach to the inner surface of compound interradial plates and form two sets, an upper and a lower, an arrangement never reported previously in an extant or extinct echinoderm. Cover plates are absent and floor plates are separated creating a large permanent entrance to the interior of the oral area. The tube feet may have captured food particles that entered the oral area and/or enhanced respiration. The pentameral symmetry of the oral surface transitions to eight columns in which the plates are vertically offset resulting in a spiral appearance. This change in symmetry may reflect flexibility in the evolutionary development of the axial and extraxial zones in early echinoderm evolution., (© 2017 The Author(s).)

Zinc inhibits the virulence of diarrheagenic E. coli by inducing the envelope stress response and inhibiting the SOS response. The SOS response is triggered by damage to bacterial DNA. In Shiga-toxigenic E. coli, the SOS response strongly induces the production of Shiga toxins (Stx) and of the bacteriophages that encode the Stx genes. In E. coli, induction of the SOS response is accompanied by a higher mutation rate, called the mutator response, caused by a shift to error-prone DNA polymerases when DNA damage is too severe to be repaired by canonical DNA polymerases. Since zinc inhibited the other aspects of the SOS response, we hypothesized that zinc would also inhibit the mutator response, also known as hypermutation. We explored various different experimental paradigms to induce hypermutation triggered by the SOS response, and found that hypermutation was induced not just by classical inducers such as mitomycin C and the quinolone antibiotics, but also by antiviral drugs such as zidovudine and anti-cancer drugs such as 5-fluorouracil, 6-mercaptopurine, and azacytidine. Zinc salts inhibited the SOS response and the hypermutator phenomenon in E. coli as well as in Klebsiella pneumoniae, and was more effective in inhibiting the SOS response than other metals. We then attempted to determine the mechanism by which zinc, applied externally in the medium, inhibits hypermutation. Our results show that zinc interferes with the actions of RecA, and protects LexA from RecA-mediated cleavage, an early step in initiation of the SOS response. The SOS response may play a role in the development of antibiotic resistance and the effect of zinc suggests ways to prevent it.