BRD4354 Is a Potent Covalent Inhibitor against the SARS-CoV-2 Main Protease.

Numerous organic molecules are known to inhibit the main protease (MPro) of SARS-CoV-2, the pathogen of Coronavirus Disease 2019 (COVID-19). Guided by previous research on zinc-ligand inhibitors of MPro and zinc-dependent histone deacetylases (HDACs), we identified BRD4354 as a potent inhibitor of MPro. The in vitro protease activity assays show that BRD4354 displays time-dependent inhibition against MPro with an IC50 (concentration that inhibits activity by 50%) of 0.72 ± 0.04 µM after 60 min of incubation. Inactivation follows a two-step process with an initial rapid binding step with a KI of 1.9 ± 0.5 µM followed by a second slow inactivation step, kinact,max of 0.040 ± 0.002 min-1. Native mass spectrometry studies indicate that a covalent intermediate is formed where the ortho-quinone methide fragment of BRD4354 forms a covalent bond with the catalytic cysteine C145 of MPro. Based on these data, a Michael-addition reaction mechanism between MPro C145 and BRD4354 was proposed. These results suggest that both preclinical testing of BRD4354 and structure-activity relationship studies based on BRD4354 are warranted to develop more effective anti-COVID therapeutics.

Slow myosin heavy chain 1 is required for slow myofibril and muscle fibre growth but not for myofibril initiation.

Slow myosin heavy chain 1 (Smyhc1) is the major sarcomeric myosin driving early contraction by slow skeletal muscle fibres in zebrafish. New mutant alleles lacking a functional smyhc1 gene move poorly, but recover motility as the later-formed fast muscle fibres of the segmental myotomes mature, and are adult viable. By motility analysis and inhibiting fast muscle contraction pharmacologically, we show that a slow muscle motility defect persists in mutants until about 1 month of age. Breeding onto a genetic background marking slow muscle fibres with EGFP revealed that mutant slow fibres undergo terminal differentiation, migration and fibre formation indistinguishable from wild type but fail to generate large myofibrils and maintain cellular orientation and attachments. In mutants, initial myofibrillar structures with 1.67 â€‹µm periodic actin bands fail to mature into the 1.96 â€‹µm sarcomeres observed in wild type, despite the presence of alternative myosin heavy chain molecules. The poorly-contractile mutant slow muscle cells generate numerous cytoplasmic organelles, but fail to grow and bundle myofibrils or to increase in cytoplasmic volume despite passive movements imposed by fast muscle. The data show that both slow myofibril maturation and cellular volume increase depend on the function of a specific myosin isoform and suggest that appropriate force production regulates muscle fibre growth.

Maternal Larp6 controls oocyte development, chorion formation and elevation.

La-related protein 6 (Larp6) is a conserved RNA-binding protein found across eukaryotes that has been suggested to regulate collagen biogenesis, muscle development, ciliogenesis, and various aspects of cell proliferation and migration. Zebrafish have two Larp6 family genes: larp6a and larp6b Viable and fertile single and double homozygous larp6a and larp6b zygotic mutants revealed no defects in muscle structure, and were indistinguishable from heterozygous or wild-type siblings. However, larp6a mutant females produced eggs with chorions that failed to elevate fully and were fragile. Eggs from larp6b single mutant females showed minor chorion defects, but chorions from eggs laid by larp6a;larp6b double mutant females were more defective than those from larp6a single mutants. Electron microscopy revealed defective chorionogenesis during oocyte development. Despite this, maternal zygotic single and double mutants were viable and fertile. Mass spectrometry analysis provided a description of chorion protein composition and revealed significant reductions in a subset of zona pellucida and lectin-type proteins between wild-type and mutant chorions that paralleled the severity of the phenotype. We conclude that Larp6 proteins are required for normal oocyte development, chorion formation and egg activation.

Prevalence of musculoskeletal complaints and health-related quality of life in a Maroon and Kalinya Indigenous rural village in Suriname.

PURPOSE: Musculoskeletal complaints (MSCs), a leading contributor to disability worldwide, have a major impact on health-related quality of life (HRQoL). Poor general health related to lifestyle factors such as smoking, alcohol consumption and physical inactivity can lead to a higher risk to suffer MSCs. For minority groups in Suriname such as the Maroons and the Indigenous peoples no research has been conducted regarding prevalence of MSCs, HRQoL and various lifestyle factors. The aims were to determine the prevalence of MSCs and HRQoL in two rural tribal villages in the forested interior of Suriname and to identify various lifestyle factors associated with HRQoL in these communities. METHOD: This was a cross-sectional community-based study using the Community Oriented Program for the Control of Rheumatic Diseases stage 1, phase 1 & 2 methodology in Goejaba, a Maroon village and Galibi, an Indigenous rural village. Sociodemographic data, self-reported comorbidities, past MSCs (for longer than seven days), lifestyle factors including smoking, alcohol use, body mass index (BMI) and physical activity (PA), and HRQoL (using the 36-item Short Form Survey (SF-36)) data were gathered among 153 Indigenous individuals in Galibi, and 516 Maroons in Goejaba. Regression models were constructed to explore associations between presence of MSCs, lifestyle factors and HRQoL. RESULTS: High prevalence rates for past MSCs were reported in Galibi (72.4%) and Goejaba (58.3%). In both communities, respondents with MSCs reported significantly worse HRQoL than persons without MSCs. MSCs and the presence of comorbidities had a strong negative association with HRQoL, whereas PA positively influenced the physical and mental health domains of the SF-36. Smoking, alcohol use and BMI showed no association with HRQoL. CONCLUSIONS: In this first study, a high prevalence for MSCs was reported in an Indigenous and Maroon rural community in Suriname. MSCs and comorbidities had a significant negative impact on HRQoL. PA was associated with higher self-reported HRQoL.

Risk of Streptococcus pneumoniae-associated haemolytic uraemic syndrome in industrialised nations: a systematic review of the literature.

BACKGROUND AND AIM: Haemolytic uraemic syndrome (HUS) is a triad of haemolytic anaemia, thrombocytopaenia, and acute kidney injury. It is a leading cause of acute kidney injury in children and has a high rate of long-term sequelae. Streptococcus pneumoniae-associated HUS (SpHUS) is a rare complication from pneumococcal disease. This article aims to systematically review SpHUS following the global introduction of pneumococcal conjugate vaccines (PCVs). MATERIAL AND METHODS: A comprehensive literature search was conducted in MEDLINE, EMBASE, and the Cochrane library from 1st January 2000 to 13th April 2022. RESULTS: Thirteen studies were included in this review, involving a total of 7,177 children with HUS, of which 336 cases were associated with Streptococcus pneumoniae. SpHUS accounted for 4.8% of all HUS cases, in which most patients were younger than 24 months old. Nine studies (80.4%, 281) were during the country's PCV era, whereas 4 studies (19.6%, 66) were before the introduction of PCV into the national vaccination programme. Pneumonia was the commonest clinical presentation (77.3%; 75/97), followed by septicaemia (33.0%; 32/97), and meningitis (29.9%; 29/97). Most cases presenting with pneumonia were complicated by empyema or pleural effusion (54.4%, n=49/90). Only 5 studies reported the isolated serotypes, with the most prevalent serotype being 19A (44.4%, n=20/45), followed by serotype 3 (17.8%, n = 8/45) and 7F (6.7%, n = 3/45). Of those reporting fatality, there were 12 deaths with a fatality rate of 9.8% (n = 12/122). CONCLUSION: SpHUS is rare, but commonly presents in children younger than 2 years old. There remains a high risk of long-term complications and relatively high mortality rate even in the era of conjugate vaccines.

Administration of BDNF in the ventral tegmental area produces a switch from a nicotine-non-dependent D1R-mediated motivational state to a nicotine-dependent-like D2R-mediated motivational state.

Brain-derived neurotrophic factor (BDNF) has been implicated in the transition from a non-dependent motivational state to a drug-dependent and drug-withdrawn motivational state. Chronic nicotine can increase BDNF in the rodent brain and is associated with smoking severity in humans; however, it is unknown whether this increased BDNF is linked functionally to the switch from a nicotine-non-dependent to a nicotine-dependent state. We used a place conditioning paradigm to measure the conditioned responses to nicotine, showing that a dose of acute nicotine that non-dependent male mice find aversive is found rewarding in chronic nicotine-treated mice experiencing withdrawal. A single BDNF injection in the ventral tegmental area (in the absence of chronic nicotine treatment) caused mice to behave as if they were nicotine dependent and in withdrawal, switching the neurobiological substrate mediating the conditioned motivational effects from dopamine D1 receptors to D2 receptors. Quantification of gene expression of BDNF and its receptor, tropomyosin-receptor-kinase B (TrkB), revealed an increase in TrkB mRNA but not BDNF mRNA in the VTA in nicotine-dependent and nicotine-withdrawn mice. These results suggest that BDNF signalling in the VTA is a critical neurobiological substrate for the transition to nicotine dependence. The modulation of BDNF signalling may be a promising new pharmacological avenue for the treatment of addictive behaviour.

Segregation of caffeine reward and aversion in the rat nucleus accumbens shell versus core.

Caffeine, the most commonly consumed psychoactive drug in the world, is readily available in dietary sources, including soft drinks, chocolate, tea and coffee. However, little is known about the neural substrates that underlie caffeine's rewarding and aversive properties and what ultimately leads us to seek or avoid caffeine consumption. Using male Wistar rats in a place conditioning procedure, we show that systemic caffeine at a low intraperitoneal dose of 2 mg/kg (or 100 µM injected directly into the rostral, but not caudal, portion of the ventral tegmental area) produced conditioned place preferences. By contrast, high doses of systemic caffeine at 10 and 30 mg/kg produced conditioned place aversions. These aversions were not recapitulated by a caffeine analog restricted to the periphery. Both caffeine reward and aversion were blocked by systemic D1-like receptor antagonism using SCH23390, while systemic D2-like receptor antagonism with eticlopride had smaller effects on caffeine motivation. Most important, we demonstrated that pharmacological blockade of dopamine receptors using α-flupenthixol injected into the nucleus accumbens shell, but not core, blocked caffeine-conditioned place preferences. Conversely, α-flupenthixol injected into the nucleus accumbens core, but not shell, blocked caffeine-conditioned place aversions. Thus, our findings reveal two dopamine-dependent and functionally dissociable mechanisms for processing caffeine motivation, which are segregated between nucleus accumbens subregions. These data provide novel evidence for the roles of the nucleus accumbens subregions in mediating approach and avoidance behaviours for caffeine.

Our first review: an evaluation of effectiveness of root cause analysis recommendations in Hong Kong public hospitals.

BACKGROUND: To evaluate the effectiveness of root cause analysis (RCA) recommendations and propose possible ways to enhance its quality in Hong Kong public hospitals. METHODS: A retrospective cross-sectional study was performed across 43 public hospitals and institutes in Hong Kong, reviewing RCA reports of all Sentinel Events and Serious Untoward Events within a two-year period. The incident nature, types of root causes and strengths of recommendations were analysed. The RCA recommendations were categorised as 'strong', 'medium' or 'weak' strengths utilizing the US's Veteran Affairs National Center for Patient Safety action hierarchy. RESULTS: A total of 214 reports from October 2016 to September 2018 were reviewed. These reports generated 504 root causes, averaging 2.4 per RCA report, and comprising 249 (49%) system, 233 (46%) staff behavioural and 22 (4%) patient factors. There were 760 recommendations identified in the RCA reports with an average of 3.6 per RCA. Of these, 18 (2%) recommendations were rated strong, 116 (15%) medium and 626 (82%) weak. Most recommendations were related to 'training and education' (466, 61%), 'additional study/review' (104, 14%) and 'review/enhancement of policy/guideline' (39, 5%). CONCLUSIONS: This study provided insights about the effectiveness of RCA recommendations across all public hospitals in Hong Kong. The results showed a high proportion of root causes were attributed to staff behavioural factors and most of the recommendations were weak. The reasons include the lack of training, tools and expertise, appropriateness of panel composition, and complicated processes in carrying out large scale improvements. The Review Team suggested conducting regular RCA training, adopting easy-to-use tools, enhancing panel composition with human factors expertise, promoting an organization-wide safety culture to staff and aggregating analysis of incidents as possible improvement actions.

A single administration of the hallucinogen, 4-acetoxy-dimethyltryptamine, prevents the shift to a drug-dependent state and the expression of withdrawal aversions in rodents.

Despite several studies suggesting the therapeutic use of 5-hydroxytryptamine receptors type 2A (5-HT2A ) agonists in the treatment of substance use disorders, the neurobiological basis accounting for such effects are still unknown. It has been observed that chronic exposure to drugs of abuse produces molecular and cellular adaptations in ventral tegmental area (VTA) neurons, mediated by brain-derived neurotrophic factor (BDNF). These BDNF-induced adaptations in the VTA are associated with the establishment of aversive withdrawal motivation that leads to a drug-dependent state. Growing evidence suggests that 5-HT2A receptor signaling can regulate the expression of BDNF in the brain. In this study, we observed that a single systemic or intra-VTA administration of a 5-HT2A agonist in rats and mice blocks both the aversive conditioned response to drug withdrawal and the mechanism responsible for switching from a drug-naive to a drug-dependent motivational system. Our results suggest that 5-HT2A agonists could be used as therapeutic agents to reverse a drug dependent state, as well as inhibiting the aversive effects produced by drug withdrawal.

Direct actions of androgen, estrogen and anti-Müllerian hormone on primate secondary follicle development in the absence of FSH in vitro.

STUDY QUESTION: What are effects of androgen, estrogen and anti-Müllerian hormone (AMH), independent of FSH action, on the development and function of primate follicles from the preantral to small antral stage in vitro? SUMMARY ANSWER: Androgen and estrogen, but not AMH, promote follicle survival and growth in vitro, in the absence of FSH. However, their growth-promoting effects are limited to the preantral to early antral stage. WHAT IS KNOWN ALREADY: FSH supports primate preantral follicle development in vitro. Androgen and estrogen augment follicle survival and growth in the presence of FSH during culture. STUDY DESIGN SIZE, DURATION: Nonhuman primate model; randomized, control versus treatment groups. Rhesus macaque (n = 6) secondary follicles (n = 24 per animal per treatment group) were cultured for 5 weeks. PARTICIPANTS/MATERIALS, SETTING, METHODS: Follicles were encapsulated in 0.25% (w/v) alginate and cultured individually in modified alpha minimum essential media with (i) FSH (1 ng/ml; control), (ii) no FSH, (iii) no FSH + estradiol (E2; 100 pg/ml)/dihydrotestosterone (DHT; 50 ng/ml) and (iv) no FSH + AMH (50 ng/ml). In a second experiment, follicles were cultured with (i) FSH (1 ng/ml), (ii) no FSH, (iii) no FSH + E2 (1 ng/ml), (iv) no FSH + DHT (50 ng/ml) and (v) no FSH + E2/DHT. Follicle survival, antrum formation and growth pattern were evaluated. Progesterone (P4), E2 and AMH concentrations in culture media were measured. MAIN RESULTS AND THE ROLE OF CHANCE: In the first experiment, FSH deprivation significantly decreased (P < 0.05) follicle survival rates in the no FSH group (16 ± 5%), compared to CTRL (66 ± 9%). E2/DHT (49 ± 5%), but not AMH (27 ± 8%), restored follicle survival rate to the CTRL level. Similarly, antrum formation rates were higher (P < 0.05) in CTRL (56 ± 6%) and E2/DHT groups (54 ± 14%), compared to no FSH (0 ± 0%) and AMH (11 ± 11%) groups. However, follicle growth rate after antrum formation and follicle diameter at week 5 was reduced (P < 0.05) in the E2/DHT group (405 ± 25 µm), compared to CTRL (522 ± 29 µm). Indeed, the proportion of fast-grow follicles at week 5 was higher in CTRL (29% ± 5), compared to E2/DHT group (10 ± 3%). No fast-grow follicles were observed in no FSH and AMH groups. AMH levels at week 3 remained similar in all groups. However, media concentrations of P4 and E2 at week 5 were lower (P < 0.05, undetectable) in no FSH, E2/DHT and AMH groups, compared to CTRL (P4 = 93 ± 10 ng/ml; E2 = 4 ± 1 ng/ml). In the second experiment, FSH depletion diminished follicle survival rate (66 ± 8% in control versus 45 ± 9% in no FSH, P = 0.034). E2 plus DHT (31.5 ± 11%) or DHT alone (69 ± 9%) restored follicle survival rate to the control (FSH) level as expected. Also, E2 plus DHT or DHT alone improved antrum formation rate. However, in the absence of FSH, E2 plus DHT or DHT alone did not support growth, in terms of follicle diameter, or steroid (P4 or E2) production after the antral stage. LIMITATIONS REASONS FOR CAUTION: This study is limited to in vitro effects of E2, DHT and AMH during the interval from the secondary to small antral stage of macaque follicular development. In addition, the primate follicle pool is heterogeneous and differs between animals; therefore, even though only secondary follicles were selected, follicle growth and developmental outcomes might differ from one animal to another. WIDER IMPLICATIONS OF THE FINDINGS: This study provides novel information on the possible actions of estrogen and androgen during early follicular development in primates. Our results suggest that sequential exposure of preantral follicles to local factors, e.g. E2 and DHT, followed by gonadotropin once the follicle reaches the antral stage, may better mimic primate folliculogenesis in vivo. STUDY FUNDING/COMPETING INTEREST(S): Research reported in this publication was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Center for Translational Research on Reproduction and Infertility 5P50HD071836, and the NIH Primate Centers Program 8P510D011092. There are no conflicts of interest.

High-power lasers for directed-energy applications: reply.

The comment by Vorontsov and Weyrauch [Appl. Opt.55, 9950 (2016)APOPAI0003-693510.1364/AO.55.009950] is aimed at rebutting the critiques in Sprangle et al. [Appl. Opt.54, F201 (2015)APOPAI0003-693510.1364/AO.54.00F201] and Nelson et al. [Appl. Opt.55, 1757 (2016)APOPAI0003-693510.1364/AO.55.001757]. In the comment, Vorontsov and colleagues describe their experiments aimed at demonstrating the feasibility of coherent combining of lasers on a distant target, using relatively low-power lasers and a cooperative retro-reflective target. The Naval Research Laboratory has demonstrated the capability to project high power on a distant target by making use of an incoherent combining architecture. The proof-of-concept experiments were performed in a realistic environment without employing cooperative targets and without sophisticated adaptive optics instrumentation.

Laser-Accelerated Ions from a Shock-Compressed Gas Foil.

We present results of energetic laser-ion acceleration from a tailored, near solid density gas target. Colliding hydrodynamic shocks compress a pure hydrogen gas jet into a 70 µm thick target prior to the arrival of the ultraintense laser pulse. A density scan reveals the transition from a regime characterized by a wide angle, low-energy beam (target normal sheath acceleration) to one of a more focused beam with a high-energy halo (magnetic vortex acceleration). In the latter case, three-dimensional simulations show the formation of a Z pinch driven by the axial current resulting from laser wakefield accelerated electrons. Ions at the rear of the target are then accelerated by a combination of space charge fields from accelerated electrons and Coulombic repulsion as the pinch dissipates.

Persistent Intraluminal Pressure After Endovascular Stent Grafting for Type B Aortic Dissection.

OBJECTIVES: Despite technically successful thoracic endovascular stent graft repair (TEVAR) in patients with Stanford Type B aortic dissection (TBAD), long-term follow up studies have shown that the false lumen may continue to dilate. The aim of this study was to analyze the possible mechanisms leading to such changes from a hemodynamic perspective. METHODS: Twenty-eight ex vivo fresh porcine TBAD models (Mo A: 10; Model B: 12; Model C: 6) were established to simulate three clinical situations: Model A with patent false lumen (pre-TEVAR); Model B with distal re-entry only (post-TEVAR), and Model C with thrombus filling in the false lumen and a distal re-entry (chronic stage of post-TEVAR). Synchronous pressure waveforms were taken from both the true and the false lumen. True lumen and false lumen pressure differences were calculated for each model as four indices: systolic index (SI), diastolic index (DI), mean pressure index (MPI) and area under curve index (AUCI). These indices were compared between the three models. RESULTS: False lumen pressure and corresponding pressure-accumulating effects were significantly higher in Model A than in Model C: SI (99.9% vs. 189.4%; p < .001); MPI and AUCI (99.5% vs. 128.2%; 99.5% vs. 128%; p < .001). The SI, MPI, and AUCI were significantly higher in Model B compared with Model C. The differences between the four indices were not significant between Model A and B. The false lumen area under curve (AUC) in Model C was merely lowered by 20% compared with its true lumen (67.5 mmHg vs. 85.2 mmHg). CONCLUSION: The false lumen pressure remained unchanged in the non-thrombosed segment with patent blood flow after the primary entry tear sealed. Intraluminal pressure reduction in the thrombosed false lumen was significant. However, nearly 80% of the pressure remained in the thrombosed false lumen. If this high intra-thrombus pressure persists, it may contribute to delayed aneurysmal formation after endovascular treatment.

Simulation of free-space optical guiding structure based on colliding gas flows: erratum.

A typographical error in Kaganovich et al. [Appl. Opt.54, F144 (2015)10.1364/AO.54.00F144APOPAI0003-6935] is corrected here.

BDNF signaling in the VTA links the drug-dependent state to drug withdrawal aversions.

Drug administration to avoid unpleasant drug withdrawal symptoms has been hypothesized to be a crucial factor that leads to compulsive drug-taking behavior. However, the neural relationship between the aversive motivational state produced by drug withdrawal and the development of the drug-dependent state still remains elusive. It has been observed that chronic exposure to drugs of abuse increases brain-derived neurotrophic factor (BDNF) levels in ventral tegmental area (VTA) neurons. In particular, BDNF expression is dramatically increased during drug withdrawal, which would suggest a direct connection between the aversive state of withdrawal and BDNF-induced neuronal plasticity. Using lentivirus-mediated gene transfer to locally knock down the expression of the BDNF receptor tropomyosin-receptor-kinase type B in rats and mice, we observed that chronic opiate administration activates BDNF-related neuronal plasticity in the VTA that is necessary for both the establishment of an opiate-dependent state and aversive withdrawal motivation. Our findings highlight the importance of a bivalent, plastic mechanism that drives the negative reinforcement underlying addiction.

Differential effects of estrogen and progesterone on development of primate secondary follicles in a steroid-depleted milieu in vitro.

STUDY QUESTION: What are the direct effects of progesterone (P4) and estradiol (E2) on the development and function of primate follicles in vitro from the pre-antral to early antral stage? SUMMARY ANSWER: In a steroid-depleted milieu, E2 improved follicle survival, growth, antrum formation and oocyte health, whereas P4 exerted minimal beneficial effects on follicle survival and reduced oocyte health. WHAT IS KNOWN ALREADY: Effects of P4 and E2 on follicle development have been studied primarily in large antral and pre-ovulatory follicles. Chronic P4 exposure suppresses antral follicle growth, but acute P4 exposure promotes oocyte maturation in pre-ovulatory follicles. Effects of E2 can be stimulatory or inhibitory depending upon species, dose and duration of exposure. STUDY DESIGN, SIZE, DURATION: Non-human primate model, randomized, control versus treatment. Macaque (n = 6) secondary follicles (n = 24 per animal per treatment group) were cultured for 5 weeks. PARTICIPANTS/MATERIALS, SETTING, METHODS: Adult rhesus macaque secondary follicles were encapsulated in 0.25% alginate and cultured individually in media containing follicle stimulating hormone plus (i) vehicle, (ii) a steroid-synthesis inhibitor, trilostane (TRL, 250 ng/ml), (iii) TRL + low E2 (100 pg/ml) or progestin (P, 10 ng/ml R5020) and (iv) TRL + high E2 (1 ng/ml E2) or P (100 ng/ml R5020). Follicles reaching the antral stage (≥750 µm) were treated with human chorionic gonadotrophin for 34 h. End-points included follicle survival, antrum formation, growth pattern, plus oocyte health and maturation status, as well as media concentrations of P4, E2 and anti-Müllerian hormone (AMH). MAIN RESULTS AND THE ROLE OF CHANCE: In a steroid-depleted milieu, low dose, but not high dose, P improved (P < 0.05) follicle survival, but had no effect (P > 0.05) on antrum formation and AMH production. Low-dose P increased (P < 0.05) P4 production in fast-grow follicles, and both doses of P elevated (P < 0.05) E2 production in slow-grow follicles. Additionally, low-dose P increased (P < 0.05) the percentage of no-grow follicles, and high-dose P promoted oocyte degeneration. In contrast, E2, in a steroid-depleted milieu, improved (P < 0.05) follicle survival, growth, antrum formation and oocyte health. E2 had no effect on P4 or E2 production. Follicles exposed to E2 yielded mature oocytes capable of fertilization and early cleavage, at a rate similar to untreated control follicles. LIMITATIONS, REASONS FOR CAUTION: This study is limited to in vitro effects of P and E2 during the interval from the secondary to small antral stage of macaque follicles. WIDER IMPLICATIONS OF THE FINDINGS: This study provides novel information on the direct actions of P4 and E2 on primate pre-antral follicle development. Combined with our previous report on the actions of androgens, our findings suggest that androgens appear to be a survival factor but hinder antral follicle differentiation, E2 appears to be a survival and growth factor at the pre-antral and early antral stage, whereas P4 may not be essential during early folliculogenesis in primates. STUDY FUNDING/COMPETING INTERESTS: NIH P50 HD071836 (NCTRI), NIH ORWH/NICHD 2K12HD043488 (BIRCWH), ONPRC 8P51OD011092. There are no conflicts of interest.

Simulation of free-space optical guiding structure based on colliding gas flows.

Preformed plasma channels with parabolic radial density profiles enable the extended and stable optical guiding of high-intensity laser pulses. High-voltage discharge capillaries, commonly used for channel formation, have limited guiding length and opaque walls, complicating the diagnosis of the plasma within. This paper proposes a free-space gas channel produced by the collision of several gas flows. The collision of the gas flows forms an on-axis density depression surrounded by higher density walls. By offsetting the flows, we demonstrated the creation of what we believe is a novel vortex structure that exhibits a long-lived parabolic density profile. Once ionized, the resulting plasma density profile has a near-parabolic dependence appropriate for guiding. We then performed detailed two-dimensional (2D) fluid dynamics simulations to examine the properties and stability of the guiding structure.

Determination of absorption coefficient based on laser beam thermal blooming in gas-filled tube.

Thermal blooming of a laser beam propagating in a gas-filled tube is investigated both analytically and experimentally. A self-consistent formulation taking into account heating of the gas and the resultant laser beam spreading (including diffraction) is presented. The heat equation is used to determine the temperature variation while the paraxial wave equation is solved in the eikonal approximation to determine the temporal and spatial variation of the Gaussian laser spot radius, Gouy phase (longitudinal phase delay), and wavefront curvature. The analysis is benchmarked against a thermal blooming experiment in the literature using a CO2 laser beam propagating in a tube filled with air and propane. New experimental results are presented in which a CW fiber laser (1 µm) propagates in a tube filled with nitrogen and water vapor. By matching laboratory and theoretical results, the absorption coefficient of water vapor is found to agree with calculations using MODTRAN (the MODerate-resolution atmospheric TRANsmission molecular absorption database) and HITRAN (the HIgh-resolution atmospheric TRANsmission molecular absorption database).

Rewarding Effects of the Hallucinogen 4-AcO-DMT Administration and Withdrawal in Rats: A Challenge to the Opponent-Process Theory.

According to the opponent-process theory of drug addiction, the intake of an addictive substance initiates two processes: a rapid primary process that results in the drug's rewarding effects, and a slower opponent process that leads to the aversive motivational state of drug aftereffects. This aversive state is integral in the desire, pursuit, and maintenance of drug use, potentially leading to dependence and addiction. However, current observational and experimental evidence suggests that the administration of a 5-hydroxytryptamine receptors-type 2A (5-HT2A) agonist, while capable of inducing a positive mental state in humans, may not generate the behavioral patterns typically associated with drugs of abuse. In this study, we found that administering the 5-HT2A agonist 4-Acetoxy-N,N-dimethyltryptamine fumarate (4-AcO-DMT) did not result in place preference in male rats compared to control saline administration 24 h later, after the drug has been cleared from the organism. However, in a modified place preference test where only the acute motivational effects of the drug were evaluated (excluding withdrawal), 4-AcO-DMT was found to be rewarding. Furthermore, in another modified place preference test where only the motivational effects of drug withdrawal were evaluated (excluding the acute effects of drug administration), the 24-hour aftereffect of 5-HT2A agonist administration also resulted in a robust place preference. Therefore, while 4-AcO-DMT administration was able to induce place preference, its 24-hour aftereffect also produced a strong reward. In the counterbalanced test, this reward from the aftereffect effectively overshadowed its acute rewarding properties, which could potentially create a false impression that 4-AcO-DMT lacks motivational properties. This suggests that 5-HT2A agonist administration follows a different dynamic than that proposed by the opponent-process theory of motivation and implies that the administration of 5-HT2A agonists may lead to behavioral patterns less typical of drugs associated with addiction.