An Atomically Dispersed Mn-Photocatalyst for Generating Hydrogen Peroxide from Seawater via the Water Oxidation Reaction (WOR).

In this work, we have fabricated an aryl amino-substituted graphitic carbon nitride (g-C3N4) catalyst with atomically dispersed Mn capable of generating hydrogen peroxide (H2O2) directly from seawater. This new catalyst exhibited excellent reactivity, obtaining up to 2230 µM H2O2 in 7 h from alkaline water and up to 1800 µM from seawater under identical conditions. More importantly, the catalyst was quickly recovered for subsequent reuse without appreciable loss in performance. Interestingly, unlike the usual two-electron oxygen reduction reaction pathway, the generation of H2O2 was through a less common two-electron water oxidation reaction (WOR) process in which both the direct and indirect WOR processes occurred; namely, photoinduced h+ directly oxidized H2O to H2O2 via a one-step 2e- WOR, and photoinduced h+ first oxidized a hydroxide (OH-) ion to generate a hydroxy radical (•OH), and H2O2 was formed indirectly by the combination of two •OH. We have characterized the material, at the catalytic sites, at the atomic level using electron paramagnetic resonance, X-ray absorption near edge structure, extended X-ray absorption fine structure, high-resolution transmission electron microscopy, X-ray photoelectron spectroscopy, magic-angle spinning solid-state NMR spectroscopy, and multiscale molecular modeling, combining classical reactive molecular dynamics simulations and quantum chemistry calculations.

GLB-3: A resilient, cysteine-rich, membrane-tethered globin expressed in the reproductive and nervous system of Caenorhabditis elegans.

The popular genetic model organism Caenorhabditis elegans (C. elegans) encodes 34 globins, whereby the few that are well-characterized show divergent properties besides the typical oxygen carrier function. Here, we present a biophysical characterization and expression analysis of C. elegans globin-3 (GLB-3). GLB-3 is predicted to exist in two isoforms and is expressed in the reproductive and nervous system. Knockout of this globin causes a 99% reduction in fertility and reduced motility. Spectroscopic analysis reveals that GLB-3 exists as a bis-histidyl-ligated low-spin form in both the ferrous and ferric heme form. A function in binding of diatomic gases is excluded on the basis of the slow CO-binding kinetics. Unlike other globins, GLB-3 is also not capable of reacting with H2O2, H2S, and nitrite. Intriguingly, not only does GLB-3 contain a high number of cysteine residues, it is also highly stable under harsh conditions (pH = 2 and high concentrations of H2O2). The resilience diminishes when the N- and C-terminal extensions are removed. Redox potentiometric measurements reveal a slightly positive redox potential (+8 ± 19 mV vs. SHE), suggesting that the heme iron may be able to oxidize cysteines. Electron paramagnetic resonance shows that formation of an intramolecular disulphide bridge, involving Cys70, affects the heme-pocket region. The results suggest an involvement of the globin in (cysteine) redox chemistry.

Correlation between the Fluorination Degree of Perfluorinated Zinc Phthalocyanines, Their Singlet Oxygen Generation Ability, and Their Photoelectrochemical Response for Phenol Sensing.

Electron-withdrawing perfluoroalkyl peripheral groups grafted on phthalocyanine (Pc) macrocycles improve their single-site isolation, solubility, and resistance to self-oxidation, all beneficial features for catalytic applications. A high degree of fluorination also enhances the reducibility of Pcs and could alter their singlet oxygen (1O2) photoproduction. The ethanol/toluene 20:80 vol % solvent mixture was found to dissolve perfluorinated FnPcZn complexes, n = 16, 52, and 64, and minimize the aggregation of the sterically unencumbered F16PcZn. The 1O2 production ability of FnPcZn complexes was examined using 9,10-dimethylanthracene (DMA) and 2,2,6,6-tetramethylpiperidine (TEMP) in combination with UV-vis and electron paramagnetic resonance (EPR) spectroscopy, respectively. While the photoreduction of F52PcZn and F64PcZn in the presence of redox-active TEMP lowered 1O2 production, DMA was a suitable 1O2 trap for ranking the complexes. The solution reactivity was complemented by solid-state studies via the construction of photoelectrochemical sensors based on TiO2-supported FnPcZn, FnPcZn|TiO2. Phenol photo-oxidation by 1O2, followed by its electrochemical reduction, defines a redox cycle, the 1O2 production having been found to depend on the value of n and structural features of the supported complexes. Consistent with solution studies, F52PcZn was found to be the most efficient 1O2 generator. The insights on reactivity testing and structural-activity relationships obtained may be useful for designing efficient and robust sensors and for other 1O2-related applications of FnPcZn.

Lignin-Supported Heterogeneous Photocatalyst for the Direct Generation of H2O2 from Seawater.

The development of smart and sustainable photocatalysts is in high priority for the synthesis of H2O2 because the global demand for H2O2 is sharply rising. Currently, the global market share for H2O2 is around 4 billion US$ and is expected to grow by about 5.2 billion US$ by 2026. Traditional synthesis of H2O2 via the anthraquinone method is associated with the generation of substantial chemical waste as well as the requirement of a high energy input. In this respect, the oxidative transformation of pure water is a sustainable solution to meet the global demand. In fact, several photocatalysts have been developed to achieve this chemistry. However, 97% of the water on our planet is seawater, and it contains 3.0-5.0% of salts. The presence of salts in water deactivates the existing photocatalysts, and therefore, the existing photocatalysts have rarely shown reactivity toward seawater. Considering this, a sustainable heterogeneous photocatalyst, derived from hydrolysis lignin, has been developed, showing an excellent reactivity toward generating H2O2 directly from seawater under air. In fact, in the presence of this catalyst, we have been able to achieve 4085 µM of H2O2. Expediently, the catalyst has shown longer durability and can be recycled more than five times to generate H2O2 from seawater. Finally, full characterizations of this smart photocatalyst and a detailed mechanism have been proposed on the basis of the experimental evidence and multiscale/level calculations.

Radical Formation in Sugar-Derived Acetals under Solvent-Free Conditions.

The degradation of acetal derivatives of the diethylester of galactarate (GalX) was investigated by electron paramagnetic resonance (EPR) spectroscopy in the context of solvent-free, high-temperature reactions like polycondensations. It was demonstrated that less substituted cyclic acetals are prone to undergo radical degradation at higher temperatures as a result of hydrogen abstraction. The EPR observations were supported by the synthesis of GalX based polyamides via ester-amide exchange-type polycondensations in solvent-free conditions at high temperatures in the presence and in the absence of radical inhibitors. The radical degradation can be offset by the addition of a radical inhibitor. The radical is probably formed on the methylene unit between the oxygen atoms and subsequently undergoes a rearrangement.

Copper(II) Complexes of Sulfonated Salan Ligands: Thermodynamic and Spectroscopic Features and Applications for Catalysis of the Henry Reaction.

Copper(II) complexes formed with sulfonated salan ligands (HSS) have been synthesized, and their coordination chemistry has been characterized using pH-potentiometry and spectroscopic methods [UV-vis, electron paramagnetic resonance (EPR), and electron-electron double resonance (ELDOR)-detected NMR (EDNMR)] in aqueous solution. Several bridging moieties between the two salicylamine functions were introduced, e.g., ethyl (HSS), propyl (PrHSS), butyl (BuHSS), cyclohexyl (cis-CyHSS, trans-CyHSS), and diphenyl (dPhHSS). All of the investigated ligands feature excellent copper(II) binding ability via the formation of a (O-,N,N,O-) chelate system. The results indicated that the cyclohexyl moiety significantly enhances the stability of the copper(II) complexes. EPR studies revealed that the arrangement of the coordinated donor atoms is more symmetrical around the copper(II) center and similar for HSS, BuHSS, CyHSS, and dPhHSS, respectively, and a higher rhombicity of the g tensor was detected for PrHSS. The copper(II) complexes of the sulfosalan ligands were isolated in solid form also and showed moderate catalytic activity in the Henry (nitroaldol) reaction of aldehydes and nitromethane. The best yield for nitroaldol production was obtained for copper(II) complexes of PrHSS and BuHSS, although their metal binding ability is moderate compared to that of the cyclohexyl counterparts. However, these complexes possess larger spin density on the nitrogen nuclei than that for the other cases, which alters their catalytic activity.

Effects of solvation shell relaxation on chain association mechanisms in poly(3-hexylthiophene) solutions.

Using poly(3-hexylthiophene) (P3HT) as a model conjugated polymer and atomistic molecular dynamics simulations with carefully verified force fields, we performed in-depth investigations of solvation shell properties of P3HT chains (15 repeating units per chain) in two representative groups of non-polar (or aprotic) organic solvents (better solvents: ortho-dichlorobenzene, bromobenzene, and chlorobenzene; poorer solvents: chloroform, para-xylene, and toluene). We demonstrated that solvation shell relaxation properties in P3HT solutions dictate the formation of regular π-π associations and, hence, crystallinity through the initial chain association and subsequent chain sliding. In contrast, the mean features of polymer-solvent interactions, including solvation free energy and radial distribution function, present little or no difference for all solvent media investigated. Better-solvent media were revealed to bear relatively large values of the first solvation shell relaxation time (τ1 ≫ 100 ps) as well as larger ratios of relaxation times for the first two solvation shells (τ1/τ2 > 2), and vice versa for poorer-solvent media (τ1 ≪ 100 ps and τ1/τ2 < 2). The linear hexyl side-chain unit was noted to substantially enlarge both quantities while notably reducing the solvation free energy as well. As discussed herein, these findings shed new light on the mechanistic features by which solvent quality impacts the degree of π-π association crucial for modern applications with crystalline conjugated polymers.

Crystal structures of zinc(II) complexes with ß-hydroxypyridinecarboxylate ligands: examples of structure-directing effects used in inorganic crystal engineering.

The coordination properties of four hydroxypyridinecarboxylates, designed for the treatment of iron-overloading conditions as bidentate O,O'-donor ligands, have been studied with ZnII in the solid state. The coordination compounds [Zn(A1)2(H2O)2] (1), [Zn(A2)2(H2O)] (2), [Zn(A3)2(H2O)]·2H2O (3) and [Zn2(B1)4(H2O)2]·4H2O (4), where the ligands are 1-methyl-4-oxidopyridinium-3-carboxylate (A1, C7H6NO3), 1,6-dimethyl-4-oxidopyridinium-3-carboxylate (A2, C8H8NO3), 1,5-dimethyl-4-oxido-pyridinium-3-carboxylate (A3, C8H8NO3) and 1-methyl-3-oxidopyridinium-4-carboxylate (B1, C7H6NO3), have been synthesized and analysed by single-crystal X-ray diffraction. The ligands were chosen to probe (i) the electronic effects of inverting the positions of the O-atom donor groups (i.e. A1 versus B1) and (ii) the electronic and steric effects of the addition of a second methyl group in different positions on the pyridine ring. Two axially coordinated water molecules resulting in a six-coordinated symmetrical octahedron complement the bis-ligand complex of A1. Ligands A2 and A3 form five-coordinated trigonal bipyramidal complexes with one additional water molecule in the coordination sphere, which is a rarely reported geometry for ZnII complexes. Ligand B1 shows a dimeric structure, where the two Zn2+ dications have slightly distorted octahedral geometry and the pyridinolate O atom of the neighbouring complex bridges them. The coordination spheres of the Zn2+ dications and the supramolecular structures are discussed in detail. The packing arrangements of 1-3 are similar, having alternating hydrophilic and hydrophobic layers, however the similarity is broken in 4. The obtained coordination geometries are compared with their previously determined CuII analogues. The study of the individual complexes is complemented with a comprehensive analysis of ZnII complexes with oxygen donor ligands with data from the Cambridge Structural Database.

PRSS50 is a testis protease responsible for proper sperm tail formation and function.

Multiple morphological abnormalities of the sperm flagella (MMAF) are a major cause of asthenoteratozoospermia. We have identified protease serine 50 (PRSS50) as having a crucial role in sperm development, because Prss50-null mice presented with impaired fertility and sperm tail abnormalities. PRSS50 could also be involved in centrosome function because these mice showed a threefold increase in acephalic sperm (head-tail junction defect), sperm with multiple heads (spermatid division defect) and sperm with multiple tails, including novel two conjoined sperm (complete or partial parts of several flagellum on the same plasma membrane). Our data support that, in the testis, as in tumorigenesis, PRSS50 activates NFκB target genes, such as the centromere protein leucine-rich repeats and WD repeat domain-containing protein 1 (LRWD1), which is required for heterochromatin maintenance. Prss50-null testes have increased IκκB, and reduced LRWD1 and histone expression. Low levels of de-repressed histone markers, such as H3K9me3, in the Prss50-null mouse testis may cause increases in post-meiosis proteins, such as AKAP4, affecting sperm formation. We provide important insights into the complex mechanisms of sperm development, the importance of testis proteases in fertility and a novel mechanism for MMAF.

E2F1 regulates testicular descent and controls spermatogenesis by influencing WNT4 signaling.

Cryptorchidism is the most common urologic birth defect in men and is a predisposing factor of male infertility and testicular cancer, yet the etiology remains largely unknown. E2F1 microdeletions and microduplications contribute to cryptorchidism, infertility and testicular tumors. Although E2f1 deletion or overexpression in mice causes spermatogenic failure, the mechanism by which E2f1 influences testicular function is unknown. This investigation revealed that E2f1-null mice develop cryptorchidism with severe gubernacular defects and progressive loss of germ cells resulting in infertility and, in rare cases, testicular tumors. It was hypothesized that germ cell depletion resulted from an increase in WNT4 levels. To test this hypothesis, the phenotype of a double-null mouse model lacking both Wnt4 and E2f1 in germ cells was analyzed. Double-null mice are fertile. This finding indicates that germ cell maintenance is dependent on E2f1 repression of Wnt4, supporting a role for Wnt4 in germ cell survival. In the future, modulation of WNT4 expression in men with cryptorchidism and spermatogenic failure due to E2F1 copy number variations may provide a novel approach to improve their spermatogenesis and perhaps their fertility potential after orchidopexy.

A Cross-Sectional Study of Nemaline Myopathy.

OBJECTIVE: Nemaline myopathy (NM) is a rare neuromuscular condition with clinical and genetic heterogeneity. To establish disease natural history, we performed a cross-sectional study of NM, complemented by longitudinal assessment and exploration of pilot outcome measures. METHODS: Fifty-seven individuals with NM were recruited at 2 family workshops, including 16 examined at both time points. Participants were evaluated by clinical history and physical examination. Functional outcome measures included the Motor Function Measure (MFM), pulmonary function tests (PFTs), myometry, goniometry, and bulbar assessments. RESULTS: The most common clinical classification was typical congenital (54%), whereas 42% had more severe presentations. Fifty-eight percent of individuals needed mechanical support, with 26% requiring wheelchair, tracheostomy, and feeding tube. The MFM scale was performed in 44 of 57 participants and showed reduced scores in most with little floor/ceiling effect. Of the 27 individuals completing PFTs, abnormal values were observed in 65%. Last, bulbar function was abnormal in all patients examined, as determined with a novel outcome measure. Genotypes included mutations in ACTA1 (18), NEB (20), and TPM2 (2). Seventeen individuals were genetically unresolved. Patients with pathogenic ACTA1 and NEB variants were largely similar in clinical phenotype. Patients without genetic resolution had more severe disease. CONCLUSION: We present a comprehensive cross-sectional study of NM. Our data identify significant disabilities and support a relatively stable disease course. We identify a need for further diagnostic investigation for the genetically unresolved group. MFM, PFTs, and the slurp test were identified as promising outcome measures for future clinical trials.

Proliferative Vitreoretinopathy After Combat Ocular Trauma in Operation Iraqi Freedom and Operation Enduring Freedom: 2001-2011.

BACKGROUND AND OBJECTIVE: To determine the risk factors associated with developing proliferative vitreoretinopathy (PVR) from combat ocular injuries in U.S. service members. PATIENTS AND METHODS: Retrospective review of associated risk factors and outcomes of PVR within the Walter Reed Ocular Trauma Database. Ocular injuries in U.S. service members wounded during Operation Enduring Freedom and Operation Iraqi Freedom from 2001 to 2011 were assessed, and of these all cases of PVR were studied. Principal outcome measures were the risk factors associated with PVR development and rate of final visual acuity (VA) less than 20/200. RESULTS: Eight hundred ninety eyes of 651 U.S. service members were evaluated. A total of 76 eyes (8.5%) of 66 patients developed PVR. Five patients had bilateral PVR. Nineteen patients had bilateral eye injuries. Sixty-one eyes (80.2%) had a final VA less than 20/200. PVR was found to be a significant risk factor for a poor final VA (P < .001). Retinal detachment (RD) was found in 52 eyes (68.4%) of patients. In patients with a RD, intraocular foreign bodies (IOFBs) (P < .001), unsuccessful repair (P = .002), and macular hemorrhage (P = .04) were significant risk factors for the development of PVR. Time to initial retina surgery was not found to be a risk factor for PVR development (P = .5). Time to initial retina surgery was available in 41 patients and the time to surgery on average was 22.56 days (range: 3 to 87 days). CONCLUSIONS: PVR occurs frequently in combat trauma and is a significant cause of poor final VA. In patients with PVR and RD, injuries caused by an IOFB, macular hemorrhage, or unsuccessful repair were significant risk factors for the development of PVR. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:556-563.].

Understanding the g-tensors of perchlorotriphenylmethyl and Finland-type trityl radicals.

The 285 GHz EPR spectra of perchlorotriphenylmethyl and tetrathiatriarylmethyl radicals in frozen solution have been accurately measured. The relationship between their molecular structures and their g-tensors has been investigated with the aid of DFT calculations, revealing that the degree of spin density delocalization away from the central methylene carbon is an important determining factor of the g-anisotropy. In particular, the small amount of spin densities on the Cl or S heteroatoms at the 2 and 6 positions with respect to the central carbon have the strongest influence. Furthermore, the amount of spin densities on these heteroatoms and thus the anisotropy can be modulated by the protonation (esterification) state of the carboxylate groups at the 4 position. These results provide unique insights into the g-anisotropy of persistent trityl radicals and how it can be tuned.

Variants in ALX4 and their association with genitourinary defects.

BACKGROUND: Genitourinary anomalies occur in approximately 1% of humans, but in most cases, the cause is unknown. Aristaless-like homeobox 4 (ALX4) is an important homeodomain transcription factor. ALX4 mutations in humans and mouse have been associated with craniofacial defects and genitourinary anomalies such as cryptorchidism and epispadias. OBJECTIVES: To investigate the presence and the functional impact of ALX4 variants in patients with genitourinary defects. MATERIALS AND METHODS: Two separate patient cohorts were analyzed. One includes clinical exome-sequencing (ES) data from 7500 individuals. The other includes 52 ALX4 Sanger-sequenced individuals with bladder exstrophy-epispadias complex (BEEC). Dual luciferase assays were conducted to investigate the functional transcriptional impact of ALX4 variants in HeLa cells and HEK293 cells. RESULTS: A total of 41 distinct ALX4 heterozygous missense variants were identified in the ES cohort with 15 variants present as recurrent in multiple patients. p.G369E and p.L373F were the only two present in individuals with genitourinary defects. A p.L373F heterozygous variant was also identified in one of the 52 individuals in the BEEC cohort. p.L373F and p.G369E were tested in vitro as both are considered damaging by MutationTaster, although only p.G369E was considered damaging by PolyPhen-2. p.L373F did not alter transcriptional activity in HeLa and HEK293 cells. p.G369E caused a significant 3.4- and 1.8-fold decrease in transcriptional activities relative to wild-type ALX4 in HEK293 and HeLa cells, respectively. DISCUSSION AND CONCLUSIONS: Our study supports the idea that transcription factors like ALX4 could influence the normal development of the GU tract in humans as demonstrated in mouse models as ALX4 variant p.G369E (predicted pathogenic by multiple databases) affects ALX4 function in vitro. Variant p.L373F (predicted pathogenic by only MutationTaster) did not affect ALX4 function in vitro. Exon-sequence information and mouse genetics provide important insights into the complex mechanisms driving genitourinary defects allowing the association of transcriptional defects with congenital disorders.

Anti-inflammatory activity of superoxide dismutase mimics functionalized with cell-penetrating peptides.

A superoxide dismutase mimic (Mn1) was functionalized with three positively charged-peptides: RRRRRRRRR (Mn1-R9), RRWWWRRWRR (Mn1-RW9) or Fx-r-Fx-K (Mn1-MPP). Characterization of the physico-chemical properties of the complexes show that they share similar binding affinity for Mn2+, apparent reduction potential and intrinsic superoxide dismutase activity. However, their accumulation in cells is different (Mn1-R9 < Mn1-MPP < Mn1-RW9 < Mn1), as well as their subcellular distribution. In addition, the three functionalized-complexes display a better anti-inflammatory activity than Mn1 when assayed at 10 µM. This improvement is due to a combination of an anti-inflammatory effect of the peptidyl moiety itself, and of the SOD mimic for Mn1-RW9 and Mn1-MPP. In contrast, the enhanced anti-inflammatory activity of Mn1-R9 is solely due to the SOD mimic.

Degradation of Computer-aided Design/Computer-aided Manufacturing Composites by Dietary Solvents: An Optical Three-dimensional Surface Analysis.

CLINICAL RELEVANCE: Computer-aided design/computer-aided manufacturing (CAD/CAM) composite resins are susceptible to degradation by dietary solvents. Dietary counselling is prudent when placing such CAD/CAM restorations. SUMMARY: This study determined the effect of dietary solvents on the surface roughness (Ra) of direct, indirect, and computer-aided design/computer-aided manufacturing (CAD/CAM) dental composites. The materials evaluated were a direct composite (Filtek Z350 XT [FZ]), an indirect composite (Shofu Ceramage [CM]), and four CAD/CAM composites (Lava Ultimate [LU], Shofu Block HC [HC], Cerasmart [CS], and Vita Enamic [VE]). Specimens (12×14×1.5 mm) of each material were prepared, measured for baseline Ra, ranked, divided into six groups (n=12), and conditioned in the following media for 1 week at 37°C: air (control), distilled water, 0.02 N citric acid, 0.02 N lactic acid, heptane, and 50% ethanol-water solution. The composite specimens were then subjected to postconditioning Ra testing using an optical three-dimensional surface analyzer (G4e, Alicona Imaging GmbH, Raaba, Austria). Inter-medium and inter-material comparisons were performed with one-way analysis of variance and post hoc Bonferroni test at a significance level of α=0.05. Mean Ra values ranged from 0.086 ± 0.004 µm to 0.153 ± 0.005 µm for the various material/medium combinations. For all materials, conditioning in air (control) and distilled water generally resulted in significantly lower mean Ra than exposure to other dietary solvents. Conditioning in citric acid presented the roughest surfaces for FZ, CM, and CS. For LU, HC, and VE, exposure to lactic acid, heptane, and ethanol solution resulted in the highest mean Ra. Regardless of conditioning media, FZ had the highest and VE the lowest mean Ra compared with other composites. The CAD/CAM composites remained susceptible to surface degradation by dietary solvents despite their industrial polymerization.

A novel technique to identify the nerve of origin in head and neck schwannomas.

OBJECTIVE: Identifying the nerve of origin in head and neck schwannomas is a diagnostic challenge. Surgical management leads to a risk of permanent deficit. Accurate identification of the nerve would improve operative planning and patient counselling. METHODS: Three patients with head and neck schwannomas underwent a diagnostic procedure hypothesised to identify the nerve of origin. The masses were infiltrated with 1 per cent lidocaine solution, and the patients were observed for neurological deficits. RESULTS: All three patients experienced temporary loss of nerve function after lidocaine injection. Facial nerve palsy, voice changes with documented unilateral same-side vocal fold paralysis, and numbness in the distribution of the maxillary nerve (V2), respectively, led to a likely identification of the nerve of origin. CONCLUSION: Injection of lidocaine into a schwannoma is a safe, in-office procedure that produces a temporary nerve deficit, which may enable accurate identification of the nerve of origin of a schwannoma. Identifying the nerve of origin enhances operative planning and patient counselling.

Repurposing Zidovudine in combination with Tigecycline for treating carbapenem-resistant Enterobacteriaceae infections.

The global emergence of carbapenem-resistant Enterobacteriaceae (CRE) presents a significant clinical concern, prompting the WHO to prioritize CRE as a top priority pathogen in their 2017 global antibiotic-resistant bacteria priority list. Due to the fast-depleting antibiotic arsenal, clinicians are now resorting to using once-abandoned, highly toxic antibiotics such as the polymyxins and aminoglycosides, creating an urgent need for new antibiotics. Drug repurposing, the application of an approved drug for a new therapeutic indication, is deemed a plausible solution to this problem. A total of 1,163 FDA-approved drugs were screened for activity against a clinical carbapenem- and multidrug-resistant E. coli isolate using a single-point 10 µM assay. Hit compounds were then assessed for their suitability for repurposing. The lead candidate was then tested against a panel of clinical CREs, a bactericidal/static determination assay, a time-kill assay and a checkerboard assay to evaluate its suitability for use in combination with Tigecycline against CRE infections. Three drugs were identified. The lead candidate was determined to be Zidovudine (azidothymidine/AZT), an oral anti-viral drug used for HIV treatment. Zidovudine was shown to be the most promising candidate for use in combination with Tigecycline to treat systemic CRE infections. Further experiments should involve the use of animal infection models.

Paratubal Cyst Size Correlates With Obesity and Dysregulation of the Wnt Signaling Pathway.

STUDY OBJECTIVE: Paratubal cysts (PTCs) occur in 7%-10% of women, regardless of age. Although common, PTCs often are found incidentally because of the potential for these cysts to be asymptomatic. The specific aims of the study were to determine if PTC number and size correlated with signs of hyperandrogenism and obesity, as well as to investigate the molecular profiles of these PTCs in samples derived from female adolescents. DESIGN, SETTING, PARTICIPANTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: A prospective cohort study was performed in a single children's hospital. Girls 18 years of age or younger who underwent surgery for PTC suspected on the basis of the presence of a persistent adnexal cyst on imaging or a concern for adnexal torsion involving a cyst were consented to participate in the study. RESULTS: Nineteen patients met enrollment criteria with a mean age at menarche of 11.2 ± 1.3 years. Most of the patients (84%; n = 16/19) had adnexal torsion at the time of diagnosis of PTC. Irregular menses and hirsutism was found in 52.6% (n = 10/19) of the patients, among whom 36.8% (n = 7/19) were obese. The mean PTC size was 10.4 ± 4.3 cm with 57.9% (n = 11/19) of the cohort having more than 1 PTC. When patients were compared on the basis of their body mass index, the size of PTCs was significantly larger in the overweight/obese group. The wingless-type (WNT) signaling members catenin beta 1 (CTNBB1) and wingless-type MMTV integration site family, member 7A (WNT7A) were upregulated in 86% (n = 12/14) and 79% (n = 11/14) of the patients, respectively. WNT7A was significantly upregulated in girls with 1 cyst and low body mass index. CONCLUSION: A correlation exists between obesity, cyst size, and hyperandrogenism. Activation of the WNT/CTNBB1 pathway via WNT7A might play a role in PTC development.