The Gas Phase Protonation Sites of Six Naturally Occurring Nicotinoids.

The gas phase protonation sites of six naturally occurring nicotinoids, namely nicotine (NIC), nornicotine (NOR), anabasine (ANB), anatabine (ANT), cotinine (COT), and myosmine (MYO), consisting of a common Pyridine and differing non-Pyridine rings, have been determined for the first time at the physiological temperature from cryogenic ion trap infrared spectroscopy and electronic structure calculations. The protonation site on either of these two rings is related to the nicotinoid's biological activity. At room temperature, NIC is a mixture of Pyridine and Pyrrolidine (non-Pyridine) protomers, whereas NOR, ANB, ANT, and COT are pure Pyridine protomers and finally MYO is mostly a Pyroline (non-Pyridine) protomer. The nearly planar structure of MYO-H+, induced by the presence of a conjugated π system and confirmed from calculations and the UV absorption spectra, breaks from the trends observed for NIC, NOR, and ANB, since its structure is drastically different from the structures of the other nicotinoids.

Virulence characteristics of Gram-positive bacteria isolated from diabetic foot ulcers.

Diabetic wound infections including diabetic foot ulcers (DFUs) are a major global health concern and a leading cause of non-traumatic amputations. Numerous bacterial species establish infection in DFUs, and treatment with antibiotics often fails due to widespread antibiotic resistance and biofilm formation. Determination of bacterial species that reside in DFU and their virulence potential is critical to inform treatment options. Here, we isolate bacteria from debridement tissues from patients with diabetes at the University of Colorado Anschutz Medical Center. The most frequent species were Gram-positive including Enterococcus faecalis, Staphylococcus aureus, and Streptococcus agalactiae, also known as Group B Streptococcus (GBS). Most tissues had more than one species isolated with E. faecalis and GBS frequently occurring in polymicrobial infection with S. aureus. S. aureus was the best biofilm producing species with E. faecalis and GBS isolates exhibiting little to no biofilm formation. Antibiotic susceptibility varied amongst strains with high levels of penicillin resistance amongst S. aureus, clindamycin resistance amongst GBS and intermediate vancomycin resistance amongst E. faecalis. Finally, we utilized a murine model of diabetic wound infection and found that the presence of S. aureus led to significantly higher recovery of GBS and E. faecalis compared to mice challenged in mono-infection.

Affinity of Nicotinoids to a Model Nicotinic Acetylcholine Receptor (nAChR) Binding Pocket in the Human Brain.

The binding affinity of nicotinoids to the binding residues of the α4ß2 variant of the nicotinic acetylcholine receptor (nAChR) was identified as a strong predictor of the nicotinoid's addictive character. Using ab initio calculations for model binding pockets of increasing size composed of 3, 6, and 14 amino acids (3AA, 6AA, and 14AA) that are derived from the crystal structure, the differences in binding affinity of 6 nicotinoids, namely, nicotine (NIC), nornicotine (NOR), anabasine (ANB), anatabine (ANT), myosmine (MYO), and cotinine (COT) were correlated to their previously reported doses required for increases in intracranial self-stimulation (ICSS) thresholds, a metric for their addictive function. By employing the many-body decomposition, the differences in the binding affinities of the various nicotinoids could be attributed mainly to the proton exchange energy between the pyridine and non-pyridine rings of the nicotinoids and the interactions between them and a handful of proximal amino acids, namely Trp156, Trpß57, Tyr100, and Tyr204. Interactions between the guest nicotinoid and the amino acids of the binding pocket were found to be mainly classical in nature, except for those between the nicotinoid and Trp156. The larger pockets were found to model binding structures more accurately and predicted the addictive character of all nicotinoids, while smaller models, which are more computationally feasible, would only predict the addictive character of nicotinoids that are similar to nicotine. The present study identifies the binding affinity of the guest nicotinoid to the host binding pocket as a strong descriptor of the nicotinoid's addiction potential, and as such it can be employed as a fast-screening technique for the potential addiction of nicotine analogs.

Preparation of von Hippel-Lindau (VHL) E3 ubiquitin ligase ligands exploiting constitutive hydroxyproline for benzylic amine protection.

The von Hippel-Lindau (VHL) protein serves as the substrate recognition subunit of the multi-subunit Cullin-2 RING E3 ubiquitin ligase (CRL2VHL), which regulates intracellular concentrations of hypoxia inducible factors (HIFs) through a ubiquitin proteasome system (UPS) cascade. Strategic recruitment of CRL2VHL by bi- or trifunctional targeted protein degraders (e.g., PROTACs®) offers the prospect of promoting aberrant polyubiquitination and ensuing proteasomal degradation of disease-related proteins. Non-peptidic, l-hydroxyproline-bearing VHL ligands such as VH032 (1) and its chiral benzylic amine analog Me-VH032 (2), are functional components of targeted protein degraders commonly employed for this purpose. Herein, we compare two approaches for the preparation of 1 and 2 primarily highlighting performance differences between Pd(OAc)2 and Pd-PEPPSI-IPr for the key C-H arylation of 4-methylthiazole. Results from this comparison prompted the development of a unified, five-step route for the preparation of either VH032 (1) or Me-VH032 (2) in multigram quantities, resulting in yields of 56% and 61% for 1 and 2, respectively. Application of N-Boc-l-4-hydroxyproline rather than N-tert-butoxycarbonyl to shield the benzylic amine during the coupling step enhances step economy. Additionally, we identified previously undisclosed minor byproducts generated during arylation steps along with observations from amine deprotection and amidation reaction steps that may prove helpful not only for the preparation of 1 and 2, but for other VHL recruiting ligands, as well.

Towards space-deployable laser stabilization systems based on vibration-insensitive cubic cavities with crystalline coatings.

We present the development of a transportable laser frequency stabilization system with application to both optical clocks and a next-generation gravity mission (NGGM) in space. This effort leverages a 5-cm long cubic cavity with crystalline coatings operating at room temperature and with a center wavelength of 1064 nm. The cavity is integrated in a custom vacuum chamber with dedicated low-noise locking electronics. Our vacuum-mounted cavity and control system are well suited for space applications, exhibiting state-of-the-art noise performance while being resilient to radiation exposure, vibration, shock, and temperature variations. Furthermore, we demonstrate a robust means of automatically (re)locking the laser to the cavity when resonance is lost. We show that the mounted cavity is capable of reaching technology readiness level (TRL) 6, paving the way for high-performance ultrastable laser systems and eventually optical atomic clocks amenable to future satellite platforms.

The Greater Celandine: Identification and Characterization of an Antimicrobial Peptide from Chelidonium majus.

Chelidonium majus, known as Greater Celandine, is a latex-bearing plant that has been leveraged for its anticancer and antimicrobial properties. Herein, C. majus aerial tissue is mined for the presence of antimicrobial peptides. A highly abundant cysteine-rich peptide with a length of 25 amino acids, deemed CM-AMP1, is characterized through multiple mass spectrometric approaches. Electron-activated dissociation is leveraged to differentiate between isoleucine and leucine residues and complement conventional collision-induced dissociation to gain full sequence coverage of the full-length peptide. CM-AMP1 shares little sequence similarity with any proteins in publicly available databases, highlighting the novelty of its cysteine landscape and core motif. The presence of three disulfide bonds in the native peptide confers proteolytic stability, and antimicrobial activity is greatly decreased upon the alkylation of the cysteine residues. Synthetic variants of CM-AMP1 are used to confirm the activity of the full-length sequence and the core motif. To assess the biological impact, E. coli was grown in a sublethal concentration of CM-AMP1 and quantitative proteomics was used to identify proteins produced by the bacteria under stress, ultimately suggesting a membrane lytic antimicrobial mechanism of action. This study integrates multiple analytical methods for molecular and biological characterization of a unique antimicrobial peptide identified from C. majus.

Descriptors of water aggregation.

We rely on a total of 23 (cluster size, 8 structural, and 14 connectivity) descriptors to investigate structural patterns and connectivity motifs associated with water cluster aggregation. In addition to the cluster size n (number of molecules), the 8 structural descriptors can be further categorized into (i) one-body (intramolecular): covalent OH bond length (rOH) and HOH bond angle (θHOH), (ii) two-body: OO distance (rOO), OHO angle (θOHO), and HOOX dihedral angle (ϕHOOX), where X lies on the bisector of the HOH angle, (iii) three-body: OOO angle (θOOO), and (iv) many-body: modified tetrahedral order parameter (q) to account for two-, three-, four-, five-coordinated molecules (qm, m = 2, 3, 4, 5) and radius of gyration (Rg). The 14 connectivity descriptors are all many-body in nature and consist of the AD, AAD, ADD, AADD, AAAD, AAADD adjacencies [number of hydrogen bonds accepted (A) and donated (D) by each water molecule], Wiener index, Average Shortest Path Length, hydrogen bond saturation (% HB), and number of non-short-circuited three-membered cycles, four-membered cycles, five-membered cycles, six-membered cycles, and seven-membered cycles. We mined a previously reported database of 4 948 959 water cluster minima for (H2O)n, n = 3-25 to analyze the evolution and correlation of these descriptors for the clusters within 5 kcal/mol of the putative minima. It was found that rOH and % HB correlated strongly with cluster size n, which was identified as the strongest predictor of energetic stability. Marked changes in the adjacencies and cycle count were observed, lending insight into changes in the hydrogen bond network upon aggregation. A Principal Component Analysis (PCA) was employed to identify descriptor dependencies and group clusters into specific structural patterns across different cluster sizes. The results of this study inform our understanding of how water clusters evolve in size and what appropriate descriptors of their structural and connectivity patterns are with respect to system size, stability, and similarity. The approach described in this study is general and can be easily extended to other hydrogen-bonded systems.

Identifying the function of the NMDA NR1 C2 subunit through its interaction with Magi-2 during inflammatory pain.

Much is understood about the structure and gating properties of NMDA receptors (NMDAR), but the function of the carboxy-terminal splice variant of the NR1 subunit, NR1 C2 has never been identified. By studying the scaffolding protein Magi-2 in animal models of inflammatory pain, we discovered how NR1 C2 protein is specifically regulated. We found that Magi-2 deficiency resulted in decreased pain behavior and a concomitant reduction in NR1 C2 protein. Magi-2 contains WW domains, domains typically found in ubiquitin ligases. We identified an atypical WW-binding domain within NR1 C2 which conferred susceptibility to Nedd4-1 ubiquitin-ligase dependent degradation. We used lipidated peptidomimetics derived from the NR1 C2 sequence and found that NR1 C2 protein levels and pain behavior can be pharmacologically targeted. The function of NR1 C2 is to give lability to a pool of NMDAR, important for pain signaling.

Switching of Protonation Sites in Hydrated Nicotine via a Grotthuss Mechanism.

The switching of the protonation sites in hydrated nicotine, probed by experimental infrared (IR) spectroscopy and theoretical ab initio calculations, is facilitated via a Grotthuss instead of a bimolecular proton transfer (vehicle) mechanism at the experimental temperature (T = 130 K) as unambiguously confirmed by experiments with deuterated water. In contrast, the bimolecular vehicle mechanism is preferred at higher temperatures (T = 300 K) as determined by theory. The Grotthuss mechanism for the concerted proton transfer results in the production of nicotine's bioactive and addictive pyrrolidine-protonated (Pyrro-H+) protomer with just 5 water molecules. Theoretical analysis suggests that the concerted proton transfer occurs via hydrogen-bonded bridges consisting of a 3 water molecule "core" that connects the pyridine protonated (Pyri-H+) with the pyrrolidine-protonated (Pyrro-H+) protomers. Additional water molecules attached as acceptors to the hydrogen-bonded "core" bridge result in lowering the reaction barrier of the concerted proton transfer down to less than 6 kcal/mol, which is consistent with the experimental observations.

Collaborative Recall and the Construction of Collective Memory Organization: The Impact of Group Structure.

Collaborative recall synchronizes downstream individual retrieval processes, giving rise to collective organization. However, little is known about whether particular stimulus features (e.g., semantic relatedness) are necessary for constructing collective organization and how group dynamics (e.g., reconfiguration) moderates it. We leveraged novel quantitative measures and a rich dataset reported in recent articles to address, (a) whether collective organization emerges even for semantically unrelated material and (b) how group reconfiguration-changing partners from one recall to the next-influences collective organization. Participants studied unrelated words and completed three consecutive recalls in one of three conditions: Always recalling individually (III), collaborating with the same partners twice before recalling alone (CCI), or collaborating with different group members during two initial recalls, before recalling alone (CRI). Collective organization increased significantly following any collaboration (CCI or CRI), relative to "groups" who never collaborated (III). Interestingly, collaborating repeatedly with the same partners (CCI) did not increase collective organization compared to reconfigured groups, irrespective of the reference group structure (from Recall 1 or 2). Individuals, however, did tend to base their final individual retrieval on the most recent group recall. We discuss how the fundamental processes that underlie dynamic social interactions align the cognitive processes of many, laying the foundation for other collective phenomena, including shared biases, attitudes, and beliefs.

Placenta accreta spectrum care infrastructure: an evidence-based review of needed resources supporting placenta accreta spectrum care.

The incidence of placenta accreta spectrum, the deeply adherent placenta with associated increased risk of maternal morbidity and mortality, has seen a significant rise in recent years. Therefore, there has been a rise in clinical and research focus on this complex diagnosis. There is international consensus that a multidisciplinary coordinated approach optimizes outcomes. The composition of the team will vary from center to center; however, central themes of complex surgical experts, specialists in prenatal diagnosis, critical care specialists, neonatology specialists, obstetrics anesthesiology specialists, blood bank specialists, and dedicated mental health experts are universal throughout. Regionalization of care is a growing trend for complex medical needs, but the location of care alone is just a starting point. The goal of this article is to provide an evidence-based framework for the crucial infrastructure needed to address the unique antepartum, delivery, and postpartum needs of the patient with placenta accreta spectrum. Rather than a clinical checklist, we describe the personnel, clinical unit characteristics, and breadth of contributing clinical roles that make up a team. Screening protocols, diagnostic imaging, surgical and potential need for critical care, and trauma-informed interaction are the basis for comprehensive care. The vision from the author group is that this publication provides a semblance of infrastructure standardization as a means to ensure proper preparation and readiness.

Association between body mass index and chronic hypertension in patients with hypertension disorders of pregnancy one-year postpartum.

OBJECTIVES: To determine the association between body mass index (BMI) and chronic hypertension (CHTN) one-year postpartum following pregnancies complicated by hypertensive disorders of pregnancy (HDP). STUDY DESIGN: A retrospective cohort study of patients with HDP (gestational hypertension or preeclampsia) in a single Midwestern academic center from 2014 to 2018. The primary outcome was CHTN at one-year postpartum, defined as systolic blood pressure ≥ 130 mmHg or diastolic blood pressure ≥ 80 mmHg or taking antihypertensive medication at one-year postpartum. The primary exposure variable was BMI at one-year postpartum, categorized as underweight (<18.5 kg/m2), normal (18.5-24.9 kg/m2), overweight (25-<30 kg/m2), and obese (≥30 kg/m2) and as continuous BMI variable. Descriptive statistics and adjusted logistic regression analysis were performed. RESULTS: Out of 596 patients with HDP included in this analysis, 275 (46.1 %) had CHTN one-year postpartum. Mean one-year postpartum BMI was 27.9 ± 5.2 kg/m2. Prevalence of CHTN at one-year postpartum was higher in obese (38.1 %) and overweight (30.0 %) groups compared to the normal weight group (29.9 %), p < 0.001. In multivariate logistic regression, obesity at one-year postpartum, compared to normal, was associated with 73 % higher likelihood of CHTN following HDP (adjusted OR 1.73, 95 % CI 1.06-2.84). With BMI as a continuous variable, each unit increase in BMI one-year postpartum was associated with 6 % higher likelihood of CHTN (adjusted OR 1.06, 95 % CI 1.02-1.15). CONCLUSIONS: Obesity at one-year postpartum following HDP was associated with a higher risk of CHTN compared with normal BMI. Weight is a modifiable risk factor that should be targeted in postpartum interventions to reduce cardiovascular disease following HDP.

Mid-infrared supermirrors with finesse exceeding 400 000.

For trace gas sensing and precision spectroscopy, optical cavities incorporating low-loss mirrors are indispensable for path length and optical intensity enhancement. Optical interference coatings in the visible and near-infrared (NIR) spectral regions have achieved total optical losses below 2 parts per million (ppm), enabling a cavity finesse in excess of 1 million. However, such advancements have been lacking in the mid-infrared (MIR), despite substantial scientific interest. Here, we demonstrate a significant breakthrough in high-performance MIR mirrors, reporting substrate-transferred single-crystal interference coatings capable of cavity finesse values from 200 000 to 400 000 near 4.5 µm, with excess optical losses (scatter and absorption) below 5 ppm. In a first proof-of-concept demonstration, we achieve the lowest noise-equivalent absorption in a linear cavity ring-down spectrometer normalized by cavity length. This substantial improvement in performance will unlock a rich variety of MIR applications for atmospheric transport and environmental sciences, detection of fugitive emissions, process gas monitoring, breath-gas analysis, and verification of biogenic fuels and plastics.

Medical Cannabis Legalization: No Contribution to Rising Stimulant Rates in the USA.

INTRODUCTION: There has been a pronounced increase in the use of Schedule II stimulants to treat attention-deficit hyperactivity disorder (ADHD) in the United States over the last two decades. Interestingly, chronic medical cannabis (MC) use can present with cognitive impairments that resemble ADHD symptoms. This study aimed to determine if MC legalization increased prescription stimulant distribution. METHODS: Information on the distribution of methylphenidate, amphetamine, and lisdexamfetamine for 2006 to 2021 was extracted from the Drug Enforcement Administration's comprehensive database and the three-year population-corrected slopes of stimulant distribution before and after MC program implementation were compared. RESULTS: We found a significant main effect of time (p<0.001); however, contrary to the hypothesis, the sales status of states' MC, did not influence slopes of distribution (p=0.391). There was a significantly large interaction effect of time and MC sales status on slopes of distribution (p<0.001). Slopes of distribution rates of stimulants were significantly lower in states that proceeded to legalize MC prior to MC program implementation than those states that did not (p=0.022). After MC program implementation, however, the distribution rates of the Schedule II stimulants were not significantly different when comparing states with MC sales to those without (p=0.355). DISCUSSION: These findings suggest that MC program legalization did not contribute to certain states having rapid increases in Schedule II stimulant distribution rates over time. Other factors, including the liberalization of the adult ADHD diagnostic criteria in the DSM-5 and the introduction of Binge Eating Disorder, also likely contributed to elevations in stimulant distribution.

Programmable Monodisperse Glyco-Multivalency Using Self-Assembled Coordination Cages as Scaffolds.

The multivalent presentation of glycans leads to enhanced binding avidity to lectins due to the cluster glycoside effect. Most materials used as scaffolds for multivalent glycan arrays, such as polymers or nanoparticles, have intrinsic dispersity: meaning that in any sample, a range of valencies are presented and it is not possible to determine which fraction(s) are responsible for binding. The intrinsic dispersity of many multivalent glycan scaffolds also limits their reproducibility and predictability. Here we make use of the structurally programmable nature of self-assembled metal coordination cages, with polyhedral metal-ion cores supporting ligand arrays of predictable sizes, to assemble a 16-membered library of perfectly monodisperse glycoclusters displaying valencies from 2 to 24 through a careful choice of ligand/metal combinations. Mono- and trisaccharides are introduced into these clusters, showing that the synthetic route is tolerant of biologically relevant glycans, including sialic acids. The cluster series demonstrates increased binding to a range of lectins as the number of glycans increases. This strategy offers an alternative to current glycomaterials for control of the valency of three-dimensional (3-D) glycan arrays, and may find application across sensing, imaging, and basic biology.

Recruitment of the SNX17-Retriever recycling pathway regulates synaptic function and plasticity.

Trafficking of cell-surface proteins from endosomes to the plasma membrane is a key mechanism to regulate synaptic function. In non-neuronal cells, proteins recycle to the plasma membrane either via the SNX27-Retromer-WASH pathway or via the recently discovered SNX17-Retriever-CCC-WASH pathway. While SNX27 is responsible for the recycling of key neuronal receptors, the roles of SNX17 in neurons are less understood. Here, using cultured hippocampal neurons, we demonstrate that the SNX17 pathway regulates synaptic function and plasticity. Disruption of this pathway results in a loss of excitatory synapses and prevents structural plasticity during chemical long-term potentiation (cLTP). cLTP drives SNX17 recruitment to synapses, where its roles are in part mediated by regulating the surface expression of ß1-integrin. SNX17 recruitment relies on NMDAR activation, CaMKII signaling, and requires binding to the Retriever and PI(3)P. Together, these findings provide molecular insights into the regulation of SNX17 at synapses and define key roles for SNX17 in synaptic maintenance and in regulating enduring forms of synaptic plasticity.

Patient Outcomes Based on the 2011 CDC Guidelines for Field Triage of Injured Patients.

BACKGROUND: The Centers for Disease Control and Prevention Guidelines for Field Triage of Injured Patients drive the destination decision for millions of emergency medical services (EMS)-transported trauma patients annually, yet limited information exists regarding performance and relationship with patient outcomes as a whole. OBJECTIVE: To evaluate the association of positive findings on Centers for Disease Control and Prevention Guidelines for Field Triage of Injured Patients with hospitalization and mortality. METHODS: This retrospective study included all 911 responses from the 2019 ESO Data Collaborative research dataset with complete Centers for Disease Control and Prevention Guidelines for Field Triage of Injured Patients and linked emergency department dispositions, excluding children and cardiac arrests prior to EMS arrival. Patients were categorized by Centers for Disease Control and Prevention Guidelines for Field Triage of Injured Patients step(s) met. Outcomes were hospitalization and emergency department or inhospital mortality. RESULTS: There were 86,462 records included: n = 65,967 (76.3%) met no criteria, n = 16,443 (19.0%) met one step (n = 1,571 [9.6%] vitals, n = 1,030 [6.3%] anatomy of injury, n = 993 [6.0%] mechanism of injury, and n = 12,849 [78.1%] special considerations), and n = 4,052 (4.7%) met multiple. Compared with meeting no criteria, hospitalization odds increased threefold for vitals (odds ratio [OR]: 3.07, 95% confidence interval [CI]: 2.77-3.40), fourfold for anatomy of injury (OR: 3.94, 95% CI: 3.48-4.46), twofold for mechanism of injury (OR: 2.00, 95% CI: 1.74-2.29), or special considerations (OR: 2.46, 95% CI: 2.36-2.56). Hospitalization odds increased ninefold when positive in multiple steps (OR: 8.97, 95% CI: 8.37-9.62). Overall, n = 84,473 (97.7%) had mortality data available, and n = 886 (1.0%) died. When compared with meeting no criteria, mortality odds increased 10-fold when positive in vitals (OR: 9.58, 95% CI: 7.30-12.56), twofold for anatomy of injury (OR: 2.34, 95% CI: 1.28-4.29), or special considerations (OR: 2.10, 95% CI: 1.71-2.60). There was no difference when only positive for mechanism of injury (OR: 0.22, 95% CI: 0.03-1.54). Mortality odds increased 23-fold when positive in multiple steps (OR: 22.7, 95% CI: 19.7-26.8). CONCLUSIONS: Patients meeting multiple Centers for Disease Control and Prevention Guidelines for Field Triage of Injured Patients steps were at greater risk of hospitalization and death. When meeting only one step, anatomy of injury was associated with greater risk of hospitalization; vital sign criteria were associated with greater risk of mortality.

Collective memory: Collaborative recall synchronizes what and how people remember.

Memory researchers and theorists have long advanced the idea that the manner in which information is retrieved is critical. The way retrieval unfolds provides critical insights into how memories are organized and accessed-an important aspect of memory missed by focusing only on quantity. Cognitive studies of memory in social contexts, deploying the collaborative memory paradigm, have also noted the importance of such retrieval organization. Such memory studies often focus on how relative to "groups" that never collaborated, former members of collaborating groups recall more of the same material (collective memory) and they do so in a more synchronized fashion (collective retrieval organization). In this review, we leverage the diverse methodological and quantitative toolkits that have traditionally targeted individual retrieval to highlight the ways in which this social memory research has examined collective memory and collective retrieval organization. To that end, we consider how the collaborative memory paradigm has integrated methods, such as free recall, that afford rich assessments of retrieval organization. Likewise, we consider the application of metrics that characterize organization patterns in different contexts. With this background in mind, we discuss the important theoretical and broader implications of research on collective memory and collective retrieval organization. This article is categorized under: Psychology > Memory.

Group B Streptococcus adaptation promotes survival in a hyperinflammatory diabetic wound environment.

Diabetic wounds have poor healing outcomes due to the presence of numerous pathogens and a dysregulated immune response. Group B Streptococcus (GBS) is commonly isolated from diabetic wound infections, but the mechanisms of GBS virulence during these infections have not been investigated. Here, we develop a murine model of GBS diabetic wound infection and, using dual RNA sequencing, demonstrate that GBS infection triggers an inflammatory response. GBS adapts to this hyperinflammatory environment by up-regulating virulence factors including those known to be regulated by the two-component system covRS, such as the surface protein pbsP, and the cyl operon, which is responsible for hemolysin/pigmentation production. We recover hyperpigmented/hemolytic GBS colonies from the murine diabetic wound, which we determined encode mutations in covR. We further demonstrate that GBS mutants in cylE and pbsP are attenuated in the diabetic wound. This foundational study provides insight into the pathogenesis of GBS diabetic wound infections.

Hybrid membrane-external-cavity surface-emitting laser.

We develop, analyze, and demonstrate an optically-pumped semiconductor disk laser using an active mirror architecture formed by sandwiching the semiconductor gain membrane between two heatspreaders, one of which is coated with a high-reflectivity multilayer. Thermal modeling indicates that this structure outperforms traditional VECSELs. Employing an InGaAs/GaAs MQW gain structure, we demonstrate output powers of approximately 30 W at a center wavelength of λ ≈ 1178 nm in a TEM00 mode using an in-well pumped geometry.