The SOD1 Inhibitor, LCS-1, Oxidizes H2S to Reactive Sulfur Species, Directly and Indirectly, through Conversion of SOD1 to an Oxidase.

LCS-1, a putative selective inhibitor of SOD1, is a substituted pyridazinone with rudimentary similarity to quinones and naphthoquinones. As quinones catalytically oxidize H2S to biologically active reactive sulfur species (RSS), we hypothesized LCS-1 might have similar attributes. Here, we examine LCS-1 reactions with H2S and SOD1 using thiol-specific fluorophores, liquid chromatography-mass spectrometry, electron paramagnetic resonance (EPR), UV-vis spectrometry, and oxygen consumption. We show that LCS-1 catalytically oxidizes H2S in buffer solutions to form RSS, namely per- and polyhydrosulfides (H2Sn, n = 2-6). These reactions consume oxygen and produce hydrogen peroxide, but they do not have an EPR signature, nor do they affect the UV-vis spectrum. Surprisingly, LCS-1 synergizes with SOD1, but not SOD2, to oxidize H2S to H2S3-6. LCS-1 forms monothiol adducts with H2S, glutathione (GSH), and cysteine (Cys), but not with oxidized glutathione or cystine; both thiol adducts inhibit LCS-1-SOD1 synergism. We propose that LCS-1 forms an adduct with SOD1 that disrupts the intramolecular Cys57-Cys146 disulfide bond and transforms SOD1 from a dismutase to an oxidase. This would increase cellular ROS and polysulfides, the latter potentially affecting cellular signaling and/or cytoprotection.

Spinal manipulation and mobilisation in paediatrics - an international evidence-based position statement for physiotherapists.

INTRODUCTION: An international taskforce of clinician-scientists was formed by specialty groups of World Physiotherapy - International Federation of Orthopaedic Manipulative Physical Therapists (IFOMPT) & International Organisation of Physiotherapists in Paediatrics (IOPTP) - to develop evidence-based practice position statements directing physiotherapists clinical reasoning for the safe and effective use of spinal manipulation and mobilisation for paediatric populations (<18 years) with varied musculoskeletal or non-musculoskeletal conditions. METHOD: A three-stage guideline process using validated methodology was completed: 1. Literature review stage (one scoping review, two reviews exploring psychometric properties); 2. Delphi stage (one 3-Round expert Delphi survey); and 3. Refinement stage (evidence-to-decision summative analysis, position statement development, evidence gap map analyses, and multilayer review processes). RESULTS: Evidence-based practice position statements were developed to guide the appropriate use of spinal manipulation and mobilisation for paediatric populations. All were predicated on clinicians using biopsychosocial clinical reasoning to determine when the intervention is appropriate.1. It is not recommended to perform:• Spinal manipulation and mobilisation on infants.• Cervical and lumbar spine manipulation on children.•Spinal manipulation and mobilisation on infants, children, and adolescents for non-musculoskeletal paediatric conditions including asthma, attention deficit hyperactivity disorder, autism spectrum disorder, breastfeeding difficulties, cerebral palsy, infantile colic, nocturnal enuresis, and otitis media.2. It may be appropriate to treat musculoskeletal conditions including spinal mobility impairments associated with neck-back pain and neck pain with headache utilising:• Spinal mobilisation and manipulation on adolescents;• Spinal mobilisation on children; or• Thoracic manipulation on children for neck-back pain only.3. No high certainty evidence to recommend these interventions was available.Reports of mild to severe harms exist; however, risk rates could not be determined. CONCLUSION: Specific directives to guide physiotherapists' clinical reasoning on the appropriate use of spinal manipulation or mobilisation were identified. Future research should focus on trials for priority conditions (neck-back pain) in children and adolescents, psychometric properties of key outcome measures, knowledge translation, and harms.

Perceived factors and barriers affecting physiotherapists' decision to use spinal manipulation and mobilisation among infants, children, and adolescents: an international survey.

OBJECTIVE: To identify factors and barriers, which affect the utilisation of spinal manipulation and mobilisation among infants, children, and adolescents. METHODS: Twenty-six international expert physiotherapists in manual therapy and paediatrics were invited to participate in a Delphi investigation using QualtricsⓇ. In Round-1 physiotherapists selected from a list of factors and barriers affecting their decision to use spinal manipulation and mobilisation in the paediatric population and had opportunity to add to the list. Round-2 asked respondents to select as many factors and barriers that they agreed with, resulting in a frequency count. The subset of responses to questions around barriers and facilitators are the focus of this study. RESULTS: Twelve physiotherapists completed both rounds of the survey. Medical diagnosis, mechanism of injury, patient presentation, tolerance to handling, and therapist's knowledge of techniques were the dominant deciding factors to use spinal manipulation and mobilisation among infants, children, and adolescents across spinal levels. More than 90% of the respondents selected manipulation as inappropriate among infants as their top barrier. Additional dominant barriers to using spinal manipulation among infants and children identified by ≥ 75% of the respondents included fear of injuring the patient, fear of litigation, lack of communication, lack of evidence, lack of guardian consent, and precision of the examination to inform clinical reasoning. CONCLUSION: This international survey provides much needed insight regarding the factors and barriers physiotherapists should consider when contemplating the utilisation of spinal mobilisation and manipulation in the paediatric population.

Reaction Mechanisms of H2S Oxidation by Naphthoquinones.

1,4-naphthoquinones (NQs) catalytically oxidize H2S to per- and polysufides and sulfoxides, reduce oxygen to superoxide and hydrogen peroxide, and can form NQ-SH adducts through Michael addition. Here, we measured oxygen consumption and used sulfur-specific fluorophores, liquid chromatography tandem mass spectrometry (LC-MS/MS), and UV-Vis spectrometry to examine H2S oxidation by NQs with various substituent groups. In general, the order of H2S oxidization was DCNQ ~ juglone > 1,4-NQ > plumbagin >DMNQ ~ 2-MNQ > menadione, although this order varied somewhat depending on the experimental conditions. DMNQ does not form adducts with GSH or cysteine (Cys), yet it readily oxidizes H2S to polysulfides and sulfoxides. This suggests that H2S oxidation occurs at the carbonyl moiety and not at the quinoid 2 or 3 carbons, although the latter cannot be ruled out. We found little evidence from oxygen consumption studies or LC-MS/MS that NQs directly oxidize H2S2-4, and we propose that apparent reactions of NQs with inorganic polysulfides are due to H2S impurities in the polysulfides or an equilibrium between H2S and H2Sn. Collectively, NQ oxidation of H2S forms a variety of products that include hydropersulfides, hydropolysulfides, sulfenylpolysulfides, sulfite, and thiosulfate, and some of these reactions may proceed until an insoluble S8 colloid is formed.

Spinal manipulation and mobilisation among infants, children, and adolescents: an international Delphi survey of expert physiotherapists.

OBJECTIVE: The aim of this study was to establish international consensus regarding the use of spinal manipulation and mobilisation among infants, children, and adolescents among expert international physiotherapists. METHODS: Twenty-six international expert physiotherapists in manual therapy and paediatrics voluntarily participated in a 3-Round Delphi survey to reach a consensus via direct electronic mail solicitation using Qualtrics®. Consensus was defined a-priori as ≥75% agreement on all items with the same ranking of agreement or disagreement. Round 1 identified impairments and conditions where spinal mobilisation and manipulation might be utilised. In Rounds 2 and 3, panelists agreed or disagreed using a 4-point Likert scale. RESULTS: Eleven physiotherapists from seven countries representing five continents completed all three Delphi rounds. Consensus regarding spinal mobilisation or manipulation included:Manipulation is not recommended: (1) for infants across all conditions, impairments, and spinal levels; and (2) for children and adolescents across most conditions and spinal levels.Manipulation may be recommended for adolescents to treat spinal region-specific joint hypomobility (thoracic, lumbar), and pain (thoracic).Mobilisation may be recommended for children and adolescents with hypomobility, joint pain, muscle/myofascial pain, or stiffness at all spinal levels. CONCLUSION: Consensus revealed spinal manipulation should not be performed on infants regardless of condition, impairment, or spinal level. Additionally, the panel agreed that manipulation may be recommended only for adolescents to treat joint pain and joint hypomobility (limited to thoracic and/or lumbar levels). Spinal mobilisation may be recommended for joint hypomobility, joint pain, muscle/myofascial pain, and muscle/myofascial stiffness at all spinal levels among children and adolescents.

Effects of Zilpaterol Hydrochloride Supplementation on Growth Performance, Carcass Characteristics and Meat Quality for Steers Differing in Breed Type.

To determine the effects of zilpaterol hydrochloride (ZH) on growth performance, carcass characteristics and meat quality for steers differing in breed type, steers with British (B; n = 76) or British × Continental (BC; n = 57) backgrounds were allocated to a randomized incomplete block design with a 2 × 2 treatment structure. Pens within each block × breed type were randomly assigned to either ZH (8.3 mg/kg of DM; fed for 20 d before slaughter, followed by a 3-day withdrawal) or control (CON; 0 mg/kg ZH). Steers were subjected to ultrasound immediately before ZH inclusion and following withdrawal to determine the influence of ZH on changes in longissimus muscle area (LMA), fat thickness and percent intramuscular fat (IMF). Carcass data were collected, and the longissimus lumborum was collected for analysis of tenderness, moisture percentage, crude fat content, collagen content, postmortem proteolysis and sensory attributes. The ZH × breed type interaction did not influence (p > 0.05) the feedlot performance, carcass or meat quality attribute traits evaluated, with the exception of moisture percentage. Responses among breed types were as expected for B vs. BC cattle types. Supplementation with ZH improved (p < 0.05) LMA and yield grade but increased Warner-Bratzler shear force.

Oxidation of Hydrogen Sulfide to Polysulfide and Thiosulfate by a Carbon Nanozyme: Therapeutic Implications with an Emphasis on Down Syndrome.

Hydrogen sulfide (H2 S) is a noxious, potentially poisonous, but necessary gas produced from sulfur metabolism in humans. In Down Syndrome (DS), the production of H2 S is elevated and associated with degraded mitochondrial function. Therefore, removing H2 S from the body as a stable oxide could be an approach to reducing the deleterious effects of H2 S in DS. In this report we describe the catalytic oxidation of hydrogen sulfide (H2 S) to polysulfides (HS2+n - ) and thiosulfate (S2 O3 2- ) by poly(ethylene glycol) hydrophilic carbon clusters (PEG-HCCs) and poly(ethylene glycol) oxidized activated charcoal (PEG-OACs), examples of oxidized carbon nanozymes (OCNs). We show that OCNs oxidize H2 S to polysulfides and S2 O3 2- in a dose-dependent manner. The reaction is dependent on O2 and the presence of quinone groups on the OCNs. In DS donor lymphocytes we found that OCNs increased polysulfide production, proliferation, and afforded protection against additional toxic levels of H2 S compared to untreated DS lymphocytes. Finally, in Dp16 and Ts65DN murine models of DS, we found that OCNs restored osteoclast differentiation. This new action suggests potential facile translation into the clinic for conditions involving excess H2 S exemplified by DS.

Beef color and tenderness response to production systems utilizing additive combinations of growth-promotant technologies.

The objective of this study was to compare the influence of beef production systems using additive combinations of growth-promotant technologies on meat quality. Steer calves (n = 120) were assigned to 1 of 4 treatments: 1) no technology (NT; control), 2) antibiotic treated (ANT; NT plus therapeutic antibiotics, monensin, and tylosin), 3) implant treated (IMP; ANT plus a series of three implants), and 4) beta-agonist treated (BA; IMP plus ractopamine-HCl). Muscle biopsy samples from the longissimus lumborum were extracted from a subset (n = 4 per treatment) of steers to evaluate expression of calpain-1, calpain-2, and calpastatin using real-time RT-PCR. Following carcass chilling, objective color (L*, a*, and b*) was evaluated. The right strip loin was removed from each carcass, portioned into 2.54-cm steaks, and designated to 7, 14, or 21 d postmortem aging periods for analysis of cook loss and Warner-Bratzler shear force (WBSF). The anterior face of each strip loin was used for analysis of crude fat and moisture. Treatment influenced (P < 0.001) L*, a*, and b*. The NT and IMP treatments had greater (P < 0.01) L* values, ANT was intermediate, and BA had the lowest (P < 0.01) L* values. The NT and IMP treatments had higher (P < 0.01) a* and b* values compared with ANT, which were higher (P < 0.01) than BA. Steaks from implanted steers (IMP and BA) tended (P ≤ 0.067) to exhibit higher a* and b* than steaks from nonimplanted steers. Cattle in the NT and ANT treatments produced steaks with increased (P < 0.01) crude fat percentage compared with the IMP and BA treatments, which were similar (P > 0.05). Percent moisture of NT steaks was lower (P < 0.01) than all other treatments, ANT was intermediate, and IMP and BA were similar (P > 0.05) and had the highest (P < 0.01) moisture content. Cook loss tended to be greater (P = 0.088) for implanted steers (IMP and BA) compared to nonimplanted steers (NT and ANT). Steaks from NT and ANT treatments were more tender (P < 0.05) than IMP and BA, which were similar (P > 0.05). Thus, WBSF was lower (P < 0.001) in nonimplanted than implanted steaks. Expression of calpastatin was increased (P ≤ 0.025) in ANT and BA treatments, and there was a tendency for expression of calpain-2 to be increased (P = 0.081) in ANT compared to NT. These results suggest that production systems with limited use of growth promoting technology produced strip loins with more crude fat, less moisture and cook loss, and improved tenderness.

Always enough but never too much: the how and why of downregulating tissue oxygenation.

Cardiovascular regulation of tissue oxygenation is generally viewed as an anti-drop process that prevents tissue oxygen concentration from falling below some minimum. I propose that cardiovascular regulation is predominately an anti-rise process designed to downregulate oxygen delivery. This maintains an evolutionarily conserved, reduced intracellular environment to prevent oxidation of redox-sensitive regulatory protein thiols. A number of points support this hypothesis. First, oxygen is the only nutrient with a positive, fourfold diffusion gradient from the environment to systemic tissues, minimizing the likelihood that oxygen delivery is limited. Second, hemoglobin (Hb) retains oxygen unless offloading is absolutely necessary. The allosteric properties of Hb keep oxygen tightly bound until absolutely needed, and the Bohr shift, which favors offloading, is only transient and lost when metabolism is restored. Third, a myoglobin-like Hb (xHb) would offload all of its oxygen and could easily have evolved, but it did not. Fourth, oxygen-sensitive vasoconstrictors and hyperoxic-rarefaction prevent acute and chronic over perfusion. Fifth, Fåhraeus and Fåhraeus-Lindqvist effects reduce capillary hematocrit to minimize microcirculatory oxygen content. Sixth, venous blood remains 75% saturated, wasting 75% of cardiac output were an oxygen reserve not needed. Finally, xHb-containing red blood cells could be considerably smaller and thereby decrease Fåhraeus and Fåhraeus-Lindqvist effects and cardiac load. In summary, the capacity of the cardiovascular system to deliver oxygen to the tissues generally exceeds demand, and although maintenance of an oxygen delivery reserve is important, it is more important to prevent excess oxygen delivery.

Redox and Nucleophilic Reactions of Naphthoquinones with Small Thiols and Their Effects on Oxidization of H2S to Inorganic and Organic Hydropolysulfides and Thiosulfate.

Naphthoquinone (1,4-NQ) and its derivatives (NQs, juglone, plumbagin, 2-methoxy-1,4-NQ, and menadione) have a variety of therapeutic applications, many of which are attributed to redox cycling and the production of reactive oxygen species (ROS). We previously demonstrated that NQs also oxidize hydrogen sulfide (H2S) to reactive sulfur species (RSS), potentially conveying identical benefits. Here we use RSS-specific fluorophores, mass spectroscopy, EPR and UV-Vis spectrometry, and oxygen-sensitive optodes to examine the effects of thiols and thiol-NQ adducts on H2S-NQ reactions. In the presence of glutathione (GSH) and cysteine (Cys), 1,4-NQ oxidizes H2S to both inorganic and organic hydroper-/hydropolysulfides (R2Sn, R=H, Cys, GSH; n = 2-4) and organic sulfoxides (GSnOH, n = 1, 2). These reactions reduce NQs and consume oxygen via a semiquinone intermediate. NQs are also reduced as they form adducts with GSH, Cys, protein thiols, and amines. Thiol, but not amine, adducts may increase or decrease H2S oxidation in reactions that are both NQ- and thiol-specific. Amine adducts also inhibit the formation of thiol adducts. These results suggest that NQs may react with endogenous thiols, including GSH, Cys, and protein Cys, and that these adducts may affect both thiol reactions as well as RSS production from H2S.

Case study: effects of low-stress weaning on calf growth performance and carcass characteristics.

The objective of this study was to compare the influence of two low-stress weaning methods with conventional weaning on post-weaning performance and carcass characteristics of beef steers. Single-sourced steer calves (n = 89) were stratified by body weight (BW) and dam age into three groups in a completely randomized design (n = 29 or 30 steers/treatment): ABRUPT (calves isolated from dams on the day of weaning), FENCE (calves separated from dams via a fence for 7 d prior to completely weaning), and NOSE (nose-flap inserted and calves remained with dams for 7 d prior to completely weaning). At day +7 post-weaning, calves were transported to a commercial feedlot where they received standard step-up and finishing rations typical for a Northern Plains feedlot. BWs were recorded in study day -7 (PreTreat), 0 (Weaning), 7 (PostWean), 26 (Receiving), 175 (Ultrasound), and 238 or 268 (Final), and average daily gains (ADG) were calculated for each time period. Blood samples were collected via coccygeal venipuncture at d -7 (PreTreat), 0 (Weaning), and +7 (PostWean) from a subsample of calves (n = 10 per treatment) and analyzed for haptoglobin (acute-phase stress protein) concentrations using a bovine haptoglobin ELISA kit. On day 175, ultrasound fat thickness and intramuscular fat were determined and utilized to project marketing dates when steers reached 1.27 cm of backfat (day 238 or 268). Carcass measurements were recorded at the time of harvest. The weaning method interacted (P < 0.01) with a time period for ADG and BW. Calf ADG was greater (P < 0.01) in the NOSE treatment during PreTreat to Weaning than ABRUPT or FENCE. In the Weaning to PostWean period, the FENCE calves had greater (P < 0.01) ADG than ABRUPT and NOSE. During the Postwean to Receiving period ADG was greater (P < 0.04) for ABRUPT compared to FENCE and NOSE. Calf ADG was similar (P > 0.05) among treatments for the remainder of the feeding period. Calf BW did not differ among treatments (P > 0.05) at all times of weighing. Haptoglobin was undetectable in all samples except two samples collected on day -7. The weaning method did not influence (P > 0.05) carcass measurements. Collectively these data suggest low-stress weaning methods do not significantly improve post-weaning growth performance or carcass characteristics compared to using conventional methods despite minor, short-term alterations in ADG during the weaning period.

The Effects of Antioxidant Nutraceuticals on Cellular Sulfur Metabolism and Signaling.

Significance: Nutraceuticals are ingested for health benefits, in addition to their general nutritional value. These dietary supplements have become increasingly popular since the late 20th century and they are a rapidly expanding global industry approaching a half-trillion U.S. dollars annually. Many nutraceuticals are promulgated as potent antioxidants. Recent Advances: Experimental support for the efficacy of nutraceuticals has lagged behind anecdotal exuberance. However, accumulating epidemiological evidence and recent, well-controlled clinical trials are beginning to support earlier animal and in vitro studies. Although still somewhat limited, encouraging results have been suggested in essentially all organ systems and against a wide range of pathophysiological conditions. Critical Issues: Health benefits of "antioxidant" nutraceuticals are largely attributed to their ability to scavenge oxidants. This has been criticized based on several factors, including limited bioavailability, short tissue retention time, and the preponderance of endogenous antioxidants. Recent attention has turned to nutraceutical activation of downstream antioxidant systems, especially the Keap1/Nrf2 (Kelch like ECH associated protein 1/nuclear factor erythroid 2-related factor 2) axis. The question now becomes, how do nutraceuticals activate this axis? Future Directions: Reactive sulfur species (RSS), including hydrogen sulfide (H2S) and its metabolites, are potent activators of the Keap1/Nrf2 axis and avid scavengers of reactive oxygen species. Evidence is beginning to accumulate that a variety of nutraceuticals increase cellular RSS by directly providing RSS in the diet, or through a number of catalytic mechanisms that increase endogenous RSS production. We propose that nutraceutical-specific targeting of RSS metabolism will lead to the design and development of even more efficacious antioxidant therapeutic strategies. Antioxid. Redox Signal. 38, 68-94.

Spinal manipulation and mobilisation in the treatment of infants, children, and adolescents: a systematic scoping review.

PURPOSE: To i) identify and map the available evidence regarding effectiveness and harms of spinal manipulation and mobilisation for infants, children and adolescents with a broad range of conditions; ii) identify and synthesise policies, regulations, position statements and practice guidelines informing their clinical use. DESIGN: Systematic scoping review, utilising four electronic databases (PubMed, Embase, CINHAL and Cochrane) and grey literature from root to 4th February 2021. PARTICIPANTS: Infants, children and adolescents (birth to < 18 years) with any childhood disorder/condition. INTERVENTION: Spinal manipulation and mobilisation OUTCOME MEASURES: Outcomes relating to common childhood conditions were explored. METHOD: Two reviewers (A.P., L.L.) independently screened and selected studies, extracted key findings and assessed methodological quality of included papers using Joanna Briggs Institute Checklist for Systematic Reviews and Research Synthesis, Joanna Briggs Institute Critical Appraisal Checklist for Text and Opinion Papers, Mixed Methods Appraisal Tool and International Centre for Allied Health Evidence Guideline Quality Checklist. A descriptive synthesis of reported findings was undertaken using a levels of evidence approach. RESULTS: Eighty-seven articles were included. Methodological quality of articles varied. Spinal manipulation and mobilisation are being utilised clinically by a variety of health professionals to manage paediatric populations with adolescent idiopathic scoliosis (AIS), asthma, attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), back/neck pain, breastfeeding difficulties, cerebral palsy (CP), dysfunctional voiding, excessive crying, headaches, infantile colic, kinetic imbalances due to suboccipital strain (KISS), nocturnal enuresis, otitis media, torticollis and plagiocephaly. The descriptive synthesis revealed: no evidence to explicitly support the effectiveness of spinal manipulation or mobilisation for any condition in paediatric populations. Mild transient symptoms were commonly described in randomised controlled trials and on occasion, moderate-to-severe adverse events were reported in systematic reviews of randomised controlled trials and other lower quality studies. There was strong to very strong evidence for 'no significant effect' of spinal manipulation for managing asthma (pulmonary function), headache and nocturnal enuresis, and inconclusive or insufficient evidence for all other conditions explored. There is insufficient evidence to draw conclusions regarding spinal mobilisation to treat paediatric populations with any condition. CONCLUSION: Whilst some individual high-quality studies demonstrate positive results for some conditions, our descriptive synthesis of the collective findings does not provide support for spinal manipulation or mobilisation in paediatric populations for any condition. Increased reporting of adverse events is required to determine true risks. Randomised controlled trials examining effectiveness of spinal manipulation and mobilisation in paediatric populations are warranted.

Naphthoquinones Oxidize H2S to Polysulfides and Thiosulfate, Implications for Therapeutic Applications.

1,4-Napththoquinones (NQs) are clinically relevant therapeutics that affect cell function through production of reactive oxygen species (ROS) and formation of adducts with regulatory protein thiols. Reactive sulfur species (RSS) are chemically and biologically similar to ROS and here we examine RSS production by NQ oxidation of hydrogen sulfide (H2S) using RSS-specific fluorophores, liquid chromatography-mass spectrometry, UV-Vis absorption spectrometry, oxygen-sensitive optodes, thiosulfate-specific nanoparticles, HPLC-monobromobimane derivatization, and ion chromatographic assays. We show that NQs, catalytically oxidize H2S to per- and polysulfides (H2Sn, n = 2−6), thiosulfate, sulfite and sulfate in reactions that consume oxygen and are accelerated by superoxide dismutase (SOD) and inhibited by catalase. The approximate efficacy of NQs (in decreasing order) is, 1,4-NQ ≈ juglone ≈ plumbagin > 2-methoxy-1,4-NQ ≈ menadione >> phylloquinone ≈ anthraquinone ≈ menaquinone ≈ lawsone. We propose that the most probable reactions are an initial two-electron oxidation of H2S to S0 and reduction of NQ to NQH2. S0 may react with H2S or elongate H2Sn in variety of reactions. Reoxidation of NQH2 likely involves a semiquinone radical (NQ·−) intermediate via several mechanisms involving oxygen and comproportionation to produce NQ and superoxide. Dismutation of the latter forms hydrogen peroxide which then further oxidizes RSS to sulfoxides. These findings provide the chemical background for novel sulfur-based approaches to naphthoquinone-directed therapies.

Recent Development of the Molecular and Cellular Mechanisms of Hydrogen Sulfide Gasotransmitter.

Hydrogen sulfide has been recently identified as the third biological gasotransmitter, along with the more well studied nitric oxide (NO) and carbon monoxide (CO). Intensive studies on its potential as a therapeutic agent for cardiovascular, inflammatory, infectious and neuropathological diseases have been undertaken. Here we review the possible direct targets of H2S in mammals. H2S directly interacts with reactive oxygen/nitrogen species and is involved in redox signaling. H2S also reacts with hemeproteins and modulates metal-containing complexes. Once being oxidized, H2S can persulfidate proteins by adding -SSH to the amino acid cysteine. These direct modifications by H2S have significant impact on cell structure and many cellular functions, such as tight junctions, autophagy, apoptosis, vesicle trafficking, cell signaling, epigenetics and inflammasomes. Therefore, we conclude that H2S is involved in many important cellular and physiological processes. Compounds that donate H2S to biological systems can be developed as therapeutics for different diseases.

Influence of Maternal Protein Restriction in Primiparous Beef Heifers during Mid- and/or Late-Gestation on Progeny Feedlot Performance and Carcass Characteristics.

This study investigated the impacts of metabolizable protein (MP) restriction in primiparous heifers during mid- and/or late-gestation on progeny performance and carcass characteristics. Heifers were allocated to 12 pens in a randomized complete block design. The factorial treatment structure included two stages of gestation (mid- and late-) and two levels of dietary protein (control (CON); ~101% of MP requirements and restricted (RES); ~80% of MP requirements). Half of the pens on each treatment were randomly reassigned to the other treatment at the end of mid-gestation. Progeny were finished in a GrowSafe feeding system and carcass measurements were collected. Gestation treatment x time interactions indicated that MP restriction negatively influenced heifer body weight (BW), body condition score, and longissimus muscle (LM) area (p < 0.05), but not fat thickness (p > 0.05). Treatment did not affect the feeding period, initial or final BW, dry matter intake, or average daily gain of progeny (p > 0.05). The progeny of dams on the RES treatment in late gestation had a greater LM area (p = 0.04), but not when adjusted on a hot carcass weight basis (p > 0.10). Minimal differences in the animal performance and carcass characteristics suggest that the level of MP restriction imposed during mid- and late-gestation in this study did not have a significant developmental programming effect.

Identification of salivary gland escape barriers to western equine encephalitis virus in the natural vector, Culex tarsalis.

Herein we describe a previously uninvestigated salivary gland escape barrier (SEB) in Culex tarsalis mosquitoes infected with two different strains of Western equine encephalitis virus (WEEV). The WEEV strains were originally isolated either from mosquitoes (IMP181) or a human patient (McMillan). Both IMP181 and McMillan viruses were fully able to infect the salivary glands of Culex tarsalis after intrathoracic injection as determined by expression of mCherry fluorescent protein. IMP181, however, was better adapted to transmission as measured by virus titer in saliva as well as transmission rates in infected mosquitoes. We used chimeric recombinant WEEV strains to show that inclusion of IMP181-derived structural genes partially circumvents the SEB.