Olorofim and the azoles are antagonistic in A. fumigatus and functional genomic screens reveal mechanisms of cross resistance.

Aspergillosis, in its various manifestations, is a major cause of morbidity and mortality. Very few classes of antifungal have been approved for clinical use to treat these diseases and resistance to the first line therapeutics is increasing. A new class of antifungals, the orotomides, are currently in development with the first compound in this class olorofim in late-stage clinical trials. In this study, we characterise a network of genes that govern olorofim response in A. fumigatus. We reveal that the number of transcription factors that regulate olorofim susceptibility are far fewer than we have previously observed for the azoles and the change in sensitivity observed in these isolates is less extreme. Intriguingly, loss of function in two higher order transcriptional regulators, HapB a member of the heterotrimeric HapB/C/E (CBC) complex or the regulator of nitrogen metabolic genes AreA, leads to cross resistance to both the azoles and olorofim. However, a clinical azole resistant isolate with a point mutation in HapE (hapEP88L) retains sensitivity to olorofim. Our transcriptomic analysis suggests that altered sensitivity to olorofim may emerge via modification of genes involved in the production of pyrimidine biosynthetic precursors. Finally, we also show that the action of the azoles are antagonistic to olorofim in vitro.

Olorofim and the azoles are antagonistic in Aspergillus fumigatus and functional genomic screens reveal mechanisms of cross resistance.

Aspergillosis, in its various manifestations, is a major cause of morbidity and mortality. Very few classes of antifungal have been approved for clinical use to treat these diseases and resistance to the first line therapeutics is increasing. A new class of antifungals, the orotomides, are currently in development with the first compound in this class olorofim in late-stage clinical trials. In this study, we characterise a network of genes that govern olorofim response in A. fumigatus. We reveal that the number of transcription factors that regulate olorofim susceptibility are far fewer than we have previously observed for the azoles and the change in sensitivity observed in these isolates is less extreme. Intriguingly, loss of function in two higher order transcriptional regulators, HapB a member of the heterotrimeric HapB/C/E (CBC) complex or the regulator of nitrogen metabolic genes AreA, leads to cross resistance to both the azoles and olorofim. However, a clinical azole resistant isolate with a point mutation in HapE (hapEP88L) retains sensitivity to olorofim. Our transcriptomic analysis suggests that altered sensitivity to olorofim may emerge via modification of genes involved in the production of pyrimidine biosynthetic precursors. Finally, we also show that the action of the azoles are antagonistic to olorofim in vitro.

Humans reconfigure target and distractor processing to address distinct task demands

When faced with distraction, we can focus more on goal-relevant information (targets) or focus less goal-conflicting information (distractors). How people decide to distribute cognitive control across targets and distractors remains unclear. To help address this question, we developed a parametric attentional control task with a graded manipulation to both target discriminability and distractor interference. We find that participants exert independent control over target and distractor processing. We measured control adjustments through the influence of incentives and previous conflict on target and distractor sensitivity, finding that these have dissociable influences on control. Whereas incentives preferentially led to target enhancement, conflict on the previous trial preferentially led to distractor suppression. These distinct drivers of control altered sensitivity to targets and distractors early in the trial, and were promptly followed by reactive reconfiguration towards task-appropriate feature sensitivity. Finally, we provide a process-level account of these findings by show that these control adjustments are well-captured by an evidence accumulation model with attractor dynamics over feature weights. These results help establish a process-level account of control configuration that provides new insights into how multivariate attentional signals are optimized to achieve task goals.

Overexpression of SgGH3.1 from Fine-Stem Stylo (Stylosanthes guianensis var. intermedia) Enhances Chilling and Cold Tolerance in Arabidopsis thaliana

Stylosanthes (stylo) species are commercially significant tropical and subtropical forage and pasture legumes that are vulnerable to chilling and frost. However, little is known about the molecular mechanisms behind stylos’ responses to low temperature stress. Gretchen-Hagen 3 (GH3) proteins have been extensively investigated in many plant species for their roles in auxin homeostasis and abiotic stress responses, but none have been reported in stylos. SgGH3.1, a cold-responsive gene identified in a whole transcriptome profiling study of fine-stem stylo (S. guianensis var. intermedia) was further investigated for its involvement in cold stress tolerance. SgGH3.1 shared a high percentage of identity with 14 leguminous GH3 proteins, ranging from 79% to 93%. Phylogenetic analysis classified SgGH3.1 into Group Ⅱ of GH3 family, which have been proven to involve with auxins conjugation. Expression profiling revealed that SgGH3.1 responded rapidly to cold stress in stylo leaves. Overexpression of SgGH3.1 in Arabidopsis thaliana altered sensitivity to exogenous IAA, up-regulated transcription of AtCBF1-3 genes, activated physiological responses against cold stress, and enhanced chilling and cold tolerances. This is the first report of a GH3 gene in stylos, which not only validated its function in IAA homeostasis and cold responses, but also gave insight into breeding of cold-tolerant stylos.

Crucial Mutations of Spike Protein on SARS-CoV-2 Evolved to Variant Strains Escaping Neutralization of Convalescent Plasmas and RBD-Specific Monoclonal Antibodies

Small number of SARS-CoV-2 epidemic lineages did not efficiently exhibit a neutralization profile, while single amino acid mutation in the spike protein has not been confirmed in altering viral antigenicity resulting in immune escape. To identify crucial mutations in spike protein that escape humoral immune response, we evaluated the cross-neutralization of convalescent plasmas and RBD-specific monoclonal antibodies (mAbs) against various spike protein-based pseudoviruses. Three of 24 SARS-CoV-2 pseudoviruses containing different mutations in spike protein, including D614G, A475V, and E484Q, consistently showed an altered sensitivity to neutralization by convalescent plasmas. A475V and E484Q mutants are highly resistant to neutralization by mAb B38 and 2-4, suggesting that some crucial mutations in spike protein might evolve SARS-CoV-2 variants capable of escaping humoral immune response.

Semmes-Weinstein monofilament: A tool to quantify skin sensation in macular lesions for leprosy diagnosis

Introduction: Hypochromatic macules with altered sensitivity are the first manifestations of skin leprosy. Validation of this sensory loss assists in the confirmation of the clinical diagnosis. Aims: The aim of the study was to quantify the loss of sensation in leprosy lesions using the Semmes-Weinstein monofilament to strengthen the clinical diagnosis mainly of macular forms. Methods: Seventy-four hypochromatic macules in the macular leprosy subgroup, 27 typical borderline leprosy subgroup lesions and 49 macules of other macular dermatoses (non-leprosy group) were evaluated using the 0.05 g force Semmes-Weinstein monofilament to quantify the alteration of sensitivity within and outside of the lesions. The esthesiometric change index was established as the total number of points with altered sensation divided by the total number of tested points within the lesions to calculate the internal esthesiometric change index and outside the lesions to calculate the peripheral esthesiometric change index; these indexes were calculated for all groups. The difference (Δ) between the esthesiometric change indices of the lesional area and the adjacent skin was calculated for the leprosy and nonleprosy groups. Results: The percentage of points with touch sensitivity alterations within the macular and typical borderline leprosy lesions was higher in leprosy than in the non-leprosy group. The borderline and macular leprosy presented higher esthesiometric change index within injured areas than outside injured areas or in the nonleprosy group (P < 0.005). When internal esthesiometric change index values in the macular and borderline leprosy groups were higher than 0.53 and 0.5, respectively, the receiver operating characteristic curve showed 98% sensitivity and approximately 99% specificity for both groups (P < 0.0001). Regarding the difference between indices, borderline and macular leprosy had values that were higher and closer to one than in the nonleprosy group (P < 0.0001), with 100% sensitivity and 96.5% specificity for leprosy diagnosis when ΔLG was higher than 0.34. A limitation was the inability to perform a double-blind study. Conclusion: Semmes-Weinstein esthesiometry is a simple, useful and low-cost tool to quantify the focal alteration of cutaneous sensitivity to improve clinical leprosy diagnosis, especially for macular lesions.

How Can Someone Do This to Themselves?

It is not uncommon to encounter patients who appear to exaggerate their pain complaints for one reason or another. However, these are to be differentiated form those diagnosed with malingering or factitious disorders (FD). Both can be difficult to identify. Malingerers engage in a willfully and deliberately attempt to misrepresent their situation for some type of gain. FD represents a group of patients with significant psychiatric problems. Their behavior often includes self-inflicted wounds, which need to be differentiated from actions that may reflect a suicide attempt, depression, or the self-injurious behavior related to dissociative disorder. The FD patient may well have an altered sensitivity to pain. Their treatment is complex and requires an experienced professional.

Dichlorvos Resistance in the House Fly Populations, Musca domestica, of Iranian Cattle Farms

Background: Insecticide resistance is one of the most important problems associated with the control of Musca domestica, due to the potential of the rapid development of resistance to different chemical insecticides. The present study was carried out to evaluate dichlorvos resistance in the house fly populations collected from central regions of Iran, Isfahan Province and Chaharmahal and Bakhtiari Province, during 2017 to 2019. Methods: Bioassays were carried out using a standard topical application method as well as a fumigation method. The Koohrang population (susceptible) with the lowest LD50 values to dichlorvos was chosen to calculate the resistance ratios (RR). Altered sensitivity of acetylcholinesterase (AChE), a target enzyme for dichlorvos, was investigated. Results: According to the results, very high levels of dichlorvos resistance were observed in the Mobarake population (RR= 80.25-fold by topical application and 33-fold by fumigation bioassay), and Isfahan population (RR= 107.30-fold by topical application and 43-fold by fumigation bioassay) compared to the Koohrang population. Acetylcholinesterase of the Koohrang population was the most sensitive to inhibition by dichlorvos based on the determination of median inhibitory concentration (IC50), but AChE of Mobarake and Isfahan populations were 741.93- and 343.94- fold less sensitive to inhibition. Conclusion: The insensitivity of AChE was possibly involved in dichlorvos resistance in the house fly populations.

Does disrupting the Orbitofrontal Cortex alter sensitivity to punishment? A potential mechanism of compulsivity

Abnormal orbitofrontal cortex (OFC) activity is one of the most common findings from neuroimaging studies of individuals with compulsive disorders such as substance use disorder and obsessive-compulsive disorder. The nature of this abnormality is complex however, with some studies reporting the OFC to be over-active in compulsive individuals relative to controls, whereas other studies report it being under-active, and a further set of studies reporting OFC abnormality in both directions within the same individuals. The OFC has been implicated in a broad range of cognitive processes such as decision-making and goal-directed action. OFC dysfunction could impair these processes leading to the kinds of cognitive/behavioural deficits observed in individuals with compulsive disorders. One such deficit that could arise as a result of OFC dysfunction is an altered sensitivity to punishment, which is one of the core characteristics displayed by individuals across multiple types of compulsive disorders. It is, therefore, the aim of the current review to assess the evidence implicating the OFC in adaptation to punishment and to attempt to identify the critical factors determining this relationship. We distil from this analysis some guidelines for future studies attempting to determine the precise role of the OFC in punishment.