Additive Effects Research Articles

Macromolecular crowding and bicarbonate enhance the hydrogen peroxide-induced inactivation of glyceraldehyde-3-phosphate dehydrogenase

The active site Cys residue in glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is sensitive to oxidation by hydrogen peroxide (H2O2), with this resulting in enzyme inactivation. This re-routes the carbon flux from glycolysis to the pentose phosphate pathway favoring the formation of NADPH and synthetic intermediates required for antioxidant defense and repair systems. Consequently, GAPDH inactivation serves as a redox switch for metabolic adaptation under conditions of oxidative stress. However, there is a major knowledge gap as to how GAPDH is efficiently oxidized and inactivated, when the increase in intracellular H2O2 is modest, and there is a high concentration of alternative (non-signaling) thiols and efficient peroxide removing systems. We have therefore explored whether GAPDH inactivation is enhanced by two factors of in vivo relevance: macromolecular crowding, an inherent property of biological environments, and the presence of bicarbonate, an abundant biological buffer. Bicarbonate is already known to modulate H2O2 metabolism via formation of peroxymonocarbonate. GAPDH activity was assessed in experiments with low doses of H2O2 under both dilute and crowded conditions (induced by inert high molecular mass polymers and small molecules), in both the absence and presence of 25 mM sodium bicarbonate. H2O2-induced inactivation of GAPDH was observed to be significantly enhanced under macromolecular crowding conditions, with bicarbonate having an additional effect. These data strongly suggest that these two factors are of major importance in redox switch mechanisms involving GAPDH (and possibly other thiol-dependent systems) within the cellular environment.

Antibacterial Activity of Clindamycin/BPO in Combination With Adapalene

Introduction: Acne guidelines recommend the addition of benzoyl peroxide (BPO) to antibiotics to reduce resistance in Cutibacterium acnes (C. acnes). Pairing the antibiotic/BPO combination with a retinoid, such as adapalene, may further increase treatment efficacy, although research on adapalene’s antibacterial activity is limited. To determine if adapalene improves antimicrobial activity, this in vitro study evaluated minimum inhibitory concentration (MIC) of clindamycin, adapalene, and BPO alone or in combination against both susceptible and resistant C. acnes isolates. Methods: Part 1a: C. acnes sensitivity to clindamycin, adapalene, or BPO was assessed via MIC values obtained by the broth microdilution method, with lower MIC indicating higher susceptibility. Part 1b: The effect (synergistic, additive, antagonistic, or indifferent [no interaction]) of combining adapalene with clindamycin or BPO on C. acnes inhibition was evaluated using a checkerboard assay, wherein two test compounds are combined in varying concentrations. Part 2: Susceptibility to single formulations of clindamycin, adapalene, and BPO, and fixed-dose combination formulations of an antibiotic (clindamycin or erythromycin) with BPO was determined by measuring antibacterial zone of inhibition using agar diffusion method, with larger diameter indicating increased bacterial inhibition. Results: Part 1a: Clindamycin demonstrated strain-dependent activity (MIC range: <0.125-64 μg/ml), while BPO and adapalene had no/low activity as indicated by high MIC (>512 and >64, respectively) against the 6 acne-associated strains tested. Part 1b: The combination of adapalene with clindamycin resulted in an additive effect for 3 and no interaction for 1 strain, whereas adapalene with BPO did not result in any interaction against the 4 acne-associated strains tested. Part 2: Activity of single formulations varied, with adapalene 0.1% having no activity (zone of inhibition: 0 cm) against any of the 8 acne-associated C. acnes strains tested. The fixed-dose combination formulations had generally similar activity against all strains tested (range: 0.9-5 cm). Conclusions: In these in vitro analyses, adapalene and BPO had no/low activity against C. acnes, whereas clindamycin alone or in combination formulations demonstrated strain-dependent activity. The relatively high MIC of BPO is not unexpected and aligns with previous studies in which the in vitro activity of BPO was low compared to its high in vivo antimicrobial activity. Further, addition of the retinoid adapalene had an additive effect on the antimicrobial activity of clindamycin against 3 out of 4 C. acnes strains tested, but no effect on the activity of BPO in vitro. Taken together, these data suggest that when combined with clindamycin/BPO, adapalene may enhance antimicrobial activity, while also bringing its own, unique retinoid mechanism of action to the triple combination, adding to clindamycin's bacteriostatic and anti-inflammatory properties. Funding: Ortho Dermatologics

Additive effect of Bisphenol A and Pefluoro-sulphoctanoic acid exposure at subacute toxic levels, on a murine model of sertoli cell

Additive effect of Bisphenol A and Pefluoro-sulphoctanoic acid exposure at subacute toxic levels, on a murine model of sertoli cell

Effectiveness of Game-Based Training of Selective Voluntary Motor Control in Children With Upper Motor Neuron Lesions: Randomized Multiple Baseline Design Study

Background Selective voluntary motor control (SVMC) is the ability to control joint movements independently. Impairments in SVMC can affect functional activities, but only a few interventions directly target SVMC. Therefore, we developed a game-based intervention for children with upper motor neuron lesions to improve SVMC. The intervention trained selective activation of a muscle or joint movement while providing immediate feedback about involuntarily occurring muscle activations or movements in another joint. The intervention was provided in a playful manner with a custom-made game environment and a technology-based interface to capture muscle activation or joint movements. Objective This study aimed to investigate the effectiveness of this game-based intervention and explore treatment response–related factors in children with impaired SVMC undergoing inpatient neurorehabilitation. Methods We conducted a single-case research study with a randomized, nonconcurrent, multiple baseline design. The study consisted of a random-length baseline phase where no SVMC-specific intervention was provided and an intervention phase with additional SVMC training. Concurrently in both phases, children attended their individual multimodal rehabilitation program at our clinic, Swiss Children’s Rehab. During the intervention phase, participants completed ten 45-minute sessions with our game-based SVMC training. SVMC was measured repeatedly throughout both phases and at the 3-month follow-up with a short custom-made assessment. Results Eighteen children with reduced SVMC from upper motor neuron lesions participated in the study. The mean age of the children was 12.7 (SD 2.9) years, and they mostly had spastic cerebral palsy. A linear mixed-effects model revealed a significant trend (P<.001) for improved SVMC already in the baseline phase. This trend did not change significantly (P=.15) when the game-based SVMC training was introduced in the intervention phase, suggesting no additional improvements due to the SVMC training. Although we could not find an overall treatment effect, we could explain 89.4% of the total random variation of the treatment effect by patient and therapy characteristics. Children with spasticity in the trained movement (20.1%), and those who trained the more affected side (23.5%) benefited most from the intervention. At the 3-month follow-up, SVMC had deteriorated compared to the end of the intervention but was still better than at the beginning of the study. Conclusions The regular concomitant rehabilitation program already yielded improvements in SVMC, while the game-based SVMC training showed no additional effects. Although the intervention did not show a group effect, we could identify patient and therapy characteristics that determine who is likely to profit from the intervention. Trial Registration German Clinical Trials Register DRKS00025184; https://tinyurl.com/msnkek9b

Generation Mean Analysis in Physio-morphic Traits of Aerobic Rice in Assam, India

An experiment was carried out to study the genetic architecture of few physio-morphic quantitative traits of rice under aerobic condition. Generation mean analysis was carried out in three selected crosses viz.Banglami/Luit, Koimurali/Luit and Guni/Gopinath, involving six generations (P­1, P2, F1, F2, BC1 and BC2) at the experimental farm of SCS college of Agriculture, Assam Agricultural University, Dhubri, Assam, India during 2017 and 2018. The individual scaling tests were used to test the adequacy of additive dominance model. The gene effects were estimated using three parameter models (joint scaling test) suggested by Cavalli (1952) and six parameter model suggested by Haymen (1958). The analysis of variance among different generations of different crosses revealed significant variation for most of the characters indicating considerable variability in the material studied. All the characters except height growth rate in cross II, recorded significance for at least one of the four individual scaling tests in all the 3 crosses. Estimation of different gene effects and their interactions were done in OPSTAT software. Significant positive additive effects were recorded for plant height and height growth rate for in all the three crosses. Preponderance of dominance effect in the expression of height growth rate, spikelet fertility, grain yield, harvest index, root weight and root shoot ratio was evident from the significant positive dominance (h) effect in all the three crosses. With respect to interaction effects, all the characters except height growth rate in cross II, exhibited significant interaction effect for one or more epistatic interactions i.e.[i], [j] or [l] in all the three crosses studied. It is evident that for all the yield and other adaptive traits, additive, dominance and interaction effects were present indicating the complex inheritance of the traits under aerobic condition. Hence, focus should be on improving individual characters separately based on the nature of gene action.

Acute Behavioral and Neurochemical Effects of Sulpiride in Adult Zebrafish.

Affective and psychotic disorders are highly prevalent and severely debilitating mental illnesses that often remain untreated or treatment-resistant. Sulpiride is a common antipsychotic (neuroleptic) drug whose well-established additional (e.g., antidepressant) therapeutic effects call for further studies of a wider spectrum of its CNS effects. Here, we examined effects of acute 20-min exposure to sulpiride (50-200mg/L) on anxiety- and depression-like behaviors, as well as on brain monoamines, in adult zebrafish (Danio rerio). Overall, sulpiride exerted overt anxiolytic-like effects in the novel tank test and showed tranquilizing-like effects in the zebrafish tail immobilization test, accompanied by lowered whole-brain dopamine and its elevated turnover, without affecting serotonin or norepinephrine levels and their turnover. Taken together, these findings support complex behavioral pharmacology of sulpiride in vivo and reconfirm high sensitivity of zebrafish-based screens to this and, likely, other related clinically active neuroleptics.

The antimicrobial and antibiofilm effects of gentamicin, imipenem, and fucoidan combinations against dual-species biofilms of Staphylococcus aureus and Acinetobacter baumannii isolated from diabetic foot ulcers.

Diabetes mellitus is a chronic metabolic disorder characterized by persistent hyperglycemia due to impaired insulin production or utilization, leading to severe health complications. Diabetic foot ulcers (DFUs) represent a major complication, often exacerbated by polymicrobial infections involving Staphylococcus aureus and Acinetobacter baumannii. These pathogens, notorious for their resistance to antibiotics, complicate treatment efforts, especially due to biofilm formation, which enhances bacterial survival and resistance. This study explores the synergistic effects of combining gentamicin, imipenem, and fucoidan, a sulfated polysaccharide with antimicrobial properties, against both planktonic and biofilm forms of S. aureus and A. baumannii. Isolates of S. aureus and A. baumannii were collected from DFUs and genetically confirmed. Methicillin resistance in S. aureus was identified through disk diffusion and PCR. Biofilm formation, including dual-species biofilms, was analyzed using the microtiter plate method. The antimicrobial efficacy of gentamicin, imipenem, and fucoidan was assessed by determining the minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), minimum biofilm inhibitory concentration (MBIC), and minimum biofilm eradication concentration (MBEC). Synergistic interactions were evaluated using the fractional inhibitory concentration index (FICi) and fractional bactericidal concentration index (FBCi). The expression of biofilm-associated genes (icaA in S. aureus and bap in A. baumannii) was analyzed, and the cytotoxicity of fucoidan was assessed. The study revealed that 77.4% of S. aureus and all A. baumannii isolates showed multidrug resistance. Among 837 tested conditions for dual-species biofilm formation, 72 resulted in strong biofilm formation and 67 in moderate biofilm formation. The geometric mean MIC values for gentamicin were 12.2µg/mL for S. aureus, 22.62µg/mL for A. baumannii, and 5.87µg/mL for their co-culture; for imipenem, they were 19.84, 9.18, and 3.70µg/mL, respectively, and for fucoidan, 48.50, 31.20, and 19.65µg/mL, respectively. The MBC values for gentamicin were 119.42, 128, and 11.75µg/mL; for imipenem, they were 48.50, 14.92, and 8µg/mL; and for fucoidan, they were 88.37, 62.62, and 42.48µg/mL. The MBIC values were 55.71, 119.42, and 18.66µg/mL for gentamicin; 68.59, 48.50, and 25.39µg/mL for imipenem; and 153.89, 101.49, and 53.53µg/mL for fucoidan. The MBEC values were 315.17, 362.03, and 59.25µg/mL for gentamicin; 207.93, 157.58, and 74.65µg/mL for imipenem; and 353.55, 189.46, and 99.19µg/mL for fucoidan. When cultured in planktonic form, the geometric mean FICi and FBCi values indicated additive effects, while co-culture showed FICi values of ≤ 0.5, suggesting a synergistic interaction. Treatment with gentamicin and fucoidan led to significant downregulation of the icaA and bap genes in both single-species and dual-species biofilms of S. aureus and A. baumannii. The reductions in gene expression were more pronounced in dual-species biofilms compared to single-species biofilms. Additionally, treatment with imipenem and fucoidan also resulted in significant downregulation of these genes in both biofilm types. Cytotoxicity assessments indicated that higher concentrations of fucoidan were toxic, yet no harmful effects were noted at the optimal synergistic concentrations used with antibiotics. In our investigation, we found that combining gentamicin, imipenem, and fucoidan had a synergistic effect on dual-species biofilms of S. aureus and A. baumannii, suggesting potential benefits for treating such infections effectively. This underscores the importance of understanding microbial interactions, antibiotic susceptibility, and biofilm formation in DFUs.

Co-Occurrence of Mycotoxins in the Diet and in the Milk of Dairy Cows from the Southeast Region of Brazil

Mycotoxins are toxic fungi secondary metabolites that develop on feedstuffs and can be transferred into milk, thus representing a public health risk. The objective of this study was to assess the co-occurrence of mycotoxins in the diet and in the milk of dairy cows from the southeast region of Brazil. Samples of total mixed ration (TMR, n = 70) and milk (n = 70) were collected in dairy farms and subjected to multi-mycotoxin analysis using liquid chromatography coupled to tandem mass spectrometry. The aflatoxins (AFs), ochratoxin A (OTA), and T-2 and HT-2 toxins were not detected in TMR samples. In contrast, fumonisins (FBs), zearalenone (ZEN), and deoxynivalenol (DON) were detected in 100, 93, and 24% of TMR samples at mean levels of 336.7 ± 36.98, 80.32 ± 16.06 µg/kg and 292.1 ± 85.68 µg/kg, respectively. Ninety-two percent of TMR samples exhibited co-occurring mycotoxins. In milk, 54% of samples (n = 38) had detectable levels of mycotoxin, while 43% (n = 30) contained two or more types of mycotoxins. DON, FB, and ZEN metabolites (α-zearalenol and β-zearalenol) were the most frequent mycotoxins detected in the milk samples analyzed, at mean concentrations of 0.562 ± 0.112, 2.135 ± 0.296 µg/kg, 2.472 ± 0.436 µg/kg, and 0.343 ± 0.062 µg/kg, respectively. However, none of the analyzed milk samples had levels higher than the maximum permitted limit for AFM1 in Brazil (0.5 µg/L). The results of this trial highlight the concern about the co-occurrence of multiple mycotoxins in TMR and in milk, due to the possible additive or synergistic effects of these compounds. The presence of co-occurring mycotoxins in milk underscores the need for stringent preventive practices to avoid mycotoxin contamination in the diet of dairy cows in Brazil.

Additive effect of clove essential oil combined with hydrogen inhalation improves psychological harm caused by lipopolysaccharide in mice.

Psychological anxiety and depression, as well as memory impairment, are frequently linked to inflammation. Clove essential oil (CEO) administration and hydrogen (H2) inhalation have been proven to have anti-inflammatory and alleviating effects on related psychological disorders in the past. The current study investigated the potential to improve anxiety-like behaviors and cognitive function by a combination of CEO and H2 treatment. The mice were administered lipopolysaccharide (LPS) to induce inflammation and oxidative stress response and cause psychological disorders. Using this animal model, we conducted experiments to test whether essential oil and H2 inhalation could improve the psychological damage in behavior caused by LPS. Subsequently, elevated plus maze (EPM), forced swimming test (FST), and passive avoidance (PA) test were performed for evaluation of mice anxiety, depression, and response to electric shock, respectively. Furthermore, the biochemical analysis was used to examine the expression levels of inflammatory and oxidative stress markers. Our results showed that CEO administration and H2 inhalation alone or in combination positively improved inflammation-induced anxiety, depression, and cognitive memory deficits in the mice. In the single treatment groups, CEO demonstrated better results than H2 inhalation in the elevated plus maze, forced swimming, and passive avoidance tests, while combined treatment with both provided a further improved enhancement effect. Biochemical analysis of the cerebral cortex revealed that CEO and H2 therapy reversed the LPS-induced inflammation and oxidative stress response. Our results suggest that a combination of CEO and H2 has the potential to treat psychological disorders or neuropsychiatric disorders.

Sirtuin inhibitors reduce intracellular growth of M. tuberculosis in human macrophages via modulation of host cell immunity.

Host-directed therapies aiming to strengthen the body's immune system, represent an underexplored opportunity to improve treatment of tuberculosis (TB). We have previously shown in Mycobacterium tuberculosis (Mtb)-infection models and clinical trials that treatment with the histone deacetylase (HDAC) inhibitor, phenylbutyrate (PBA), can restore Mtb-induced impairment of antimicrobial responses and improve clinical outcomes in pulmonary TB. In this study, we evaluated the efficacy of different groups of HDAC inhibitors to reduce Mtb growth in human immune cells. A panel of 21 selected HDAC inhibitors with different specificities that are known to modulate infection or inflammation was tested using high-content live-cell imaging and analysis. Monocyte-derived macrophages or bulk peripheral blood cells (PBMCs) were infected with the green fluorescent protein (GFP)-expressing Mtb strains H37Ra or H37Rv and treated with HDAC inhibitors in the micromolar range in parallel with a combination of the first-line antibiotics, rifampicin, and isoniazid. Host cell viability in HDAC inhibitor treated cell cultures was monitored with Cytotox-red. Seven HDAC inhibitors were identified that reduced Mtb growth in macrophages > 45-75% compared to average 40% for PBA. The most effective compounds were inhibitors of the class III HDAC proteins, the sirtuins. While these compounds may exhibit their effects by improving macrophage function, one of the sirtuin inhibitors, tenovin, was also highly effective in extracellular killing of Mtb bacilli. Antimicrobial synergy testing using checkerboard assays revealed additive effects between selected sirtuin inhibitors and subinhibitory concentrations of rifampicin or isoniazid. A customized macrophage RNA array including 23 genes associated with cytokines, chemokines and inflammation, suggested that Mtb-infected macrophages are differentially modulated by the sirtuin inhibitors as compared to PBA. Altogether, these results demonstrated that sirtuin inhibitors may be further explored as promising host-directed compounds to support immune functions and reduce intracellular growth of Mtb in human cells.

Improved management of Italian ryegrass (Lolium perenne spp. multiflorum) with mixtures of tiafenacil and ACCase or glutamine synthetase inhibitors

Abstract Herbicide-resistant Italian ryegrass [Lolium perenne L. spp. multiflorum (Lam.) Husnot] is a significant problem in multiple cropping systems because of its rapid growth, open pollination, prolific seed production, and multiple cases of resistance worldwide, except to protoporphyrinogen oxidase (PPO) inhibitors. This research evaluated tiafenacil, a new PPO inhibitor, in mixtures with glutamine synthetase or acetyl-CoA carboxylase (ACCase)-inhibiting herbicides to manage resistant L. multiflorum populations. Tiafenacil efficacy against L. multiflorum was growth stage-dependent, with increased efficacy at earlier stages in greenhouse studies. The LD90 was 41.06 g ai ha-1 at BBCH23, and increased to 9.0-fold at BBCH33. Field studies indicated that changes in carrier volume did not affect tiafenacil’s efficacy; the highest tested rate of tiafenacil (75 g ai ha-1) reduced L. multiflorum inflorescence weight by 50-90%. Mixtures of tiafenacil and glufosinate (1,150 g ai ha-1) improved L. multiflorum control (+24-43%) and reduced inflorescence weight (+15-34%), particularly at the highest tested rates (50 and 75 g ai ha-1), suggesting synergistic effects based on Colby’s test. Tiafenacil with ACCase inhibitors improved L. multiflorum control (+19-49%) and inflorescence weight reduction (+8-13%). These mixtures exhibited an additive effect when combined with fluazifop and a synergistic effect with clethodim. Herbicide mixtures and application strategies are critical to effective L. multiflorum management. Tiafenacil, especially when used with glufosinate or ACCase inhibitors, offers an effective solution to L. multiflorum management and is a strategic tool against herbicide resistance, as resistance to PPO inhibitors has not evolved. Further research should assess practices to ensure the long-term viability of these mixtures for resistance management.

Exploring the Relationship Between Refractive Errors and Common Chronic Diseases Via Blood Biochemistry Tests: A Large Prospective Cohort Study.

The purpose of this study was to examine the association between refractive errors and common chronic diseases using blood biochemistry tests, and to investigate the associated modifiable risk factors, with the goal of informing and developing effective preventive strategies. A total of 116,245 participants with refractometry at baseline enrolled in the UK Biobank were included in this prospective cohort study. Restricted cubic spline and Cox proportional hazards models were used to detect associations between refractive error, blood biochemistry tests, and common chronic diseases. Interaction effects on the additive scale and effect modification analysis were used to explore excess modifiable risk factors for disease prevention. Spherical equivalent significantly associated with vitamin D, sex hormone binding globulin, apolipoprotein A, blood glucose, and aspartate aminotransferase levels. Subjects with myopia demonstrated a 13% higher risk of type 2 diabetes mellitus (T2DM) incidence compared to those without myopia (hazard ratio [HR] = 1.13, 95% confidence interval [CI] = 1.08-1.19) throughout a median follow-up of 9.12years. Interaction analysis revealed 15% (95% CI = 9%-21%) of this risk was due to myopia-obesity interaction. However, active engagement in physical activity could potentially mitigate this risk (HR = 1.06, 95% CI = 0.93-1.20). Refractive errors were associated with specific blood indicators, particularly noting the association between myopia and higher T2DM incidence in middle-aged and elderly populations. This effect interacts with obesity, and promoting physical activity among myopia individuals provides greater benefits in the prevention of T2DM compared to non-myopic individuals.

Identification and validation of two quantitative trait loci showing pleiotropic effect on multiple grain-related traits in bread wheat (Triticum aestivum L.).

QKl/Tgw/Gns.yaas-2D associates with KL, TGW, and GNS, and QKl/Tgw.yaas-5A associates with KL and TGW. Significantly pleiotropic and additive effects of these two QTL were validated. The YM5 allele both at QKl/Tgw/Gns.yaas-2D and QKl/Tgw.yaas-5A was proved to be the best allelic combination for improving yield potential. Kernel length (KL), kernel width (KW), thousand grain weight (TGW), and grain number per spike (GNS) play important roles in the yield improvement of wheat. In this study, one recombinant inbred line (RIL) derived from a cross between Yangmai 5 (YM5) and Yanzhan 1 (YZ1) was used to identify quantitative trait loci (QTL) associated with KL, KW, TGW, and GNS across three years. Two pleiotropic QTL namely QKl/Tgw/Gns.yaas-2D and QKl/Tgw.yaas-5A were located in two genomic regions on chromosomes 2D and 5A, respectively. Breeder-friendly Kompetitive Allele-Specific PCR (KASP) markers for QKl/Tgw/Gns.yaas-2D and QKl/Tgw.yaas-5A were developed and validated in a set of 246 wheat cultivars/lines. Analysis of allelic combinations indicated that the YM5 allele both at QKl/Tgw/Gns.yaas-2D and QKl/Tgw.yaas-5A is probably the best one to promote TGW, GNS, and grain weight per spike. Based on the analysis of gene annotation, sequence variations, expression patterns, and GO enrichment, twenty-five and twenty-four candidate genes of QKl/Tgw/Gns.yaas-2D and QKl/Tgw.yaas-5A, respectively, were identified. These results provide the basis of fine-mapping the target QTL and marker-assisted selection in wheat yield-breeding programs.

Possible Potentiating Effects of Combined Administration of Alcohol, Caffeine, and Nicotine on In Vivo Dopamine Release in Addiction-Related Circuits Within the CNS of Rats

Background: Studies that assess the effects of the interaction of psychoactive substances on dopamine release, the key neurotransmitter in the neurochemical and behavioral effects related to drug consumption, are crucial to understand both their roles and the dysfunctions they produce in the central nervous system. Objective: We evaluated the effects of individual and combined administration of the three most widely consumed psychoactive substances in the world, ethanol, caffeine, and nicotine, on dopaminergic neurotransmission in three brain regions of rats related to addiction: the prefrontal cortex (PFC), the nucleus accumbens (NAcc), and the dorsal striatum. Methods: The dopamine levels were measured in vivo by cerebral microdialysis associated with HPLC-ED. Results: We observed that local administration of a single concentration of caffeine (5 mM) or nicotine (5 mM) significantly increased the dopamine levels in all three areas studied, while ethanol (300 mM) increased them in the NAcc and striatum. Perfusion of nicotine + caffeine produced a synergistic effect in both the NAcc and striatum, with increases in the in vivo dopamine release greater than the sum of the effects of both substances. When administering the combination of nicotine + caffeine + ethanol, we observed an additive effect in the NAcc, while in the PFC we observed a synergistic effect. Conclusions: Our results support the stimulating effects of caffeine, nicotine, and ethanol on the brain reward system. In addition, we also observed that the administration of different mixtures of these substances produces synergistic and additive effects on the release of dopamine in the mesocortical and nigrostriatal systems.

Trials factor for semi-supervised NN classifiers in searches for narrow resonances at the LHC

To mitigate the model dependencies of searches for new narrow resonances at the Large Hadron Collider (LHC), semi-supervised Neural Networks (NNs) can be used. Unlike fully supervised classifiers these models introduce an additional look-elsewhere effect in the process of optimising thresholds on the response distribution. We perform a frequentist study to quantify this effect, in the form of a trials factor. As an example, we consider simulated Z\gammaZγ data to perform narrow resonance searches using semi-supervised NN classifiers. The results from this analysis provide substantiation that the look-elsewhere effect induced by the semi-supervised NN is under control.

Newly Established Bermudagrass Response to Topramezone and Photosystem II-Inhibitor Herbicides

Abstract Bermudagrass is the most troublesome and difficult-to-control perennial grass weed in Florida sugarcane. Once established, it is only controlled effectively during the sugarcane fallow period using nonselective herbicides and tillage combinations. It is important to evaluate options for selective management of bermudagrass that escape sugarcane fallow period management programs to mitigate its progressive increase as the crop cycle increases from plant cane to ratoon crops. Greenhouse and field studies were conducted in Belle Glade, Florida, from 2017 to 2018 to determine the response of newly established bermudagrass from sprigs with stolons to two or three sequential applications of topramezone (25 and 50 g ha-1) every 14 d and the combinations of topramezone (25 and 50 g ha-1 ) with photosystem II (PS II)-inhibitor herbicides atrazine (2,240 g ha-1), ametryn (440 g ha-1), and metribuzin (2,240 g ha-1). Two or three sequential applications of topramezone with a cumulative total of 75 to 100 g ha-1 provided >93% bermudagrass control 42 d after the first sequential application under greenhouse and field conditions. These treatments had 12% chance of survival 70 d after the first sequential application. There was an additive effect of PS-II inhibitor herbicides on bermudagrass control in mixtures with topramezone. The mixture of topramezone (50 g ha-1) with metribuzin and atrazine provided more than 87% and 92% bermudagrass control under greenhouse and field conditions, respectively, 42 d after treatment. Bermudagrass treated with topramezone (50 g ha-1) mixture with metribuzin had 23% chance of survival 70 d after treatment. The results show good efficacy of sequential topramezone applications every 14 d or mixtures with PS-II inhibitor herbicides atrazine and metribuzin for control of newly established bermudagrass which typically escape control measures during the sugarcane fallow management period.

Enhancing Antibacterial Efficacy: Combining Novel Bacterial Topoisomerase Inhibitors with Efflux Pump Inhibitors and Other Agents Against Gram-Negative Bacteria

Background: The novel bacterial topoisomerase inhibitors (NBTIs) developed in our laboratory show potent on-target enzyme inhibition but suffer from low activity against Gram-negative bacteria. Methods: With the aim of improving the antibacterial activity of our compounds against Gram-negative bacteria, we tested them in combination with different efflux pump inhibitors (EPIs), a strategy that showed promise in several other classes of antimicrobials. We also investigated the combined effect of NBTIs with ATP-competitive inhibitors of bacterial type II topoisomerases (ACIs), as well as the antibiofilm properties of our compounds and the combination with EPIs against early and mature Acietobacter baumannii biofilm. Results: Our results demonstrate that combinations of NBTIs with EPI Phenylalanine-arginyl-β-naphthylamide significantly reduce the corresponding NBTIs’ minimal inhibitory concentration values and show potentiation of A. baumannii biofilm inhibition as compared to NBTIs alone. Although combinations of NBITs and ACIs did not show synergistic effects, the FIC index value calculations revealed additive effects for all the combinations of a selected NBTI in combination with three ACIs in all the assayed Gram-negative bacteria from the ESKAPE group. Conclusions: These results show for the first time that combinations of NBTIs with either EPIs or a different class of the topoisomerase inhibitors may be a beneficial strategy to combat difficult-to-treat bacterial infections.

Additive effects of cerebrovascular disease functional connectome phenotype and plasma p-tau181 on longitudinal neurodegeneration and cognitive outcomes.

We investigated the effects of multiple cerebrovascular disease (CeVD) neuroimaging markers on brain functional connectivity (FC), and how such CeVD-related FC changes interact with plasma phosphorylated tau (p-tau)181 (an Alzheimer's disease [AD] marker) to influence downstream neurodegeneration and cognitive changes. Multivariate associations among four CeVD markers and whole-brain FC in 529 participants across the dementia spectrum were examined using partial least squares correlation. Interactive effects of CeVD-related FC patterns and p-tau181 on longitudinal gray matter volume (GMV) and cognitive changes were investigated using linear mixed-effects models. We identified a brain FC phenotype associated with high CeVD burden across all markers. Further, expression of this general CeVD-related FC phenotype and p-tau181 contributed additively, but not synergistically, to baseline and longitudinal GMV and cognitive changes. Our findings suggest that CeVD exerts global effects on the brain connectome and highlight the additive nature of AD and CeVD on neurodegeneration and cognition. Effects of multiple cerebrovascular disease (CeVD) markers on functional connectivity were studied. A global network phenotype linked to high burden across CeVD markers was identified. CeVD phenotype and plasma phosphorylated tau 181 contributed additively to downstream outcomes.

Cerebrovascular markers of WMH and infarcts in ADNI: A historical perspective and future directions.

White matter hyperintensities (WMH) and infarcts found on magnetic resonance imaging (MR infarcts) are common biomarkers of cerebrovascular disease. In this review, we summarize the methods, publications, and conclusions stemming from the Alzheimer's Disease Neuroimaging Initiative (ADNI) related to these measures. We combine analysis of WMH and MR infarct data from across the three main ADNI cohorts with a review of existing literature discussing new methodologies and scientific findings derived from these data. Although ADNI inclusion criteria were designed to minimize vascular risk factors and disease, data across all the ADNI cohorts found consistent trends of increasing WMH volumes associated with advancing age, female sex, and cognitive impairment. ADNI, initially proposed as a study to investigate biomarkers of AD pathology, has also helped elucidate the impact of asymptomatic cerebrovascular brain injury on cognition within a cohort relatively free of vascular disease. Future ADNI work will emphasize additional vascular biomarkers. HIGHLIGHTS: White matter hyperintensities (WMHs) are common to advancing age and likely reflect brain vascular injury among older individuals. WMH and to a lesser extent, magnetic resonance (MR) infarcts, affect risk for transition to cognitive impairment. WMHs and MR infarcts are present, even among Alzheimer's Disease Neuroimaging Initiative (ADNI) participants highly selected to have Alzheimer's disease (AD) as the primary pathology. WMH burden in ADNI is greater among individuals with cognitive impairment and has been associated with AD neurodegenerative markers and cerebral amyloidosis. The negative additive effects of cerebrovascular disease appear present, even in select populations, and future biomarker work needs to further explore this relationship.

Application of Compensation Algorithms to Control the Speed and Course of a Four-Wheeled Mobile Robot

This article presents a tuned control algorithm for the speed and course of a four-wheeled automobile-type robot as a single nonlinear object, developed by the analytical approach of compensation for the object’s dynamics and additive effects. The method is based on assessment of external effects and as a result new, advanced feedback features may appear in the control system. This approach ensures automatic movement of the object with accuracy up to a given reference filter, which is important for stable and accurate control under various conditions. In the process of the synthesis control algorithm, an inverse mathematical model of the robot was built, and reference filters were developed for a closed-loop control system through external effect channels, providing the possibility of physical implementation of the control algorithm and compensation of external effects through feedback. This combined approach allows us to take into account various effects on the robot and ensure its stable control. The developed algorithm provides control of the robot both when moving forward and backward, which expands the capabilities of maneuvering and planning motion trajectories and is especially important for robots working in confined spaces or requiring precise movement into various directions. The efficiency of the algorithm is demonstrated using a computer simulation of a closed-loop control system under various external effects. It is planned to further develop a digital algorithm for implementation on an onboard microcontroller, in order to use the new algorithm in the overall motion control system of a four-wheeled mobile robot.