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A bstract We bound EFT coefficients appearing in 2 → 2 photon scattering amplitudes in four dimensions. After reviewing unitarity and positivity conditions in this context, we use dispersion relations and crossing symmetry to compute sum rules and null constraints. This allows us to derive new rigorous bounds on operators with four, six, and eight derivatives, including two-sided bounds on their ratios. Comparing with a number of partial UV completions, we find that some of our bounds are saturated by the amplitudes that arise from integrating out a massive scalar or axion, while others suggest the existence of unknown amplitudes.

A bstract The black hole weak gravity conjecture (WGC) is a set of linear inequalities on the four-derivative corrections to Einstein-Maxwell theory. Remarkably, in four dimensions, these combinations appear in the 2 → 2 photon amplitudes, leading to the hope that the conjecture might be supported using dispersion relations. However, the presence of a pole arising in the forward limit due to graviton exchange greatly complicates the use of such arguments. In this paper, we apply recently developed numerical techniques to handle the graviton pole, and we find that standard dispersive arguments are not strong enough to imply the black hole WGC. Specifically, under a fairly typical set of assumptions, including weak coupling of the EFT and Regge boundedness, a small violation of the black hole WGC is consistent with unitarity and causality. We quantify the size of this violation, which vanishes in the limit where gravity decouples and also depends logarithmically on an infrared cutoff. We discuss the meaning of these bounds in various scenarios. We also implement a method for bounding amplitudes without manifestly positive spectral densities, which could be applied to any system of non-identical states, and we use it to improve bounds on the EFT of pure photons in absence of gravity.

The neuropeptides calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP) have emerged as mediators of migraine pathogenesis. Both are vasodilatory peptides that can cause migraine-like attacks when infused into people and migraine-like symptoms when injected into rodents. In this narrative review, we compare the similarities and differences between the peptides in both their clinical and preclinical migraine actions. A notable clinical difference is that PACAP, but not CGRP, causes premonitory-like symptoms in patients. Both peptides are found in distinct, but overlapping areas relevant to migraine, most notably with the prevalence of CGRP in trigeminal ganglia and PACAP in sphenopalatine ganglia. In rodents, the two peptides share activities, including vasodilation, neurogenic inflammation, and nociception. Most strikingly, CGRP and PACAP cause similar migraine-like symptoms in rodents that are manifested as light aversion and tactile allodynia. Yet, the peptides appear to act by independent mechanisms possibly by distinct intracellular signaling pathways. The complexity of these signaling pathways is magnified by the existence of multiple CGRP and PACAP receptors that may contribute to migraine pathogenesis. Based on these differences, we suggest PACAP and its receptors provide a rich set of targets to complement and augment the current CGRP-based migraine therapeutics.

Migraine is one of the most prevalent and disabling neurovascular disorders worldwide. However, despite the increase in awareness and research, the understanding of migraine pathophysiology and treatment options remain limited. For centuries, migraine was considered to be a vascular disorder. In fact, the throbbing, pulsating quality of the headache is thought to be caused by mechanical changes in vessels. Moreover, the most successful migraine treatments act on the vasculature and induction of migraine can be accomplished with vasoactive agents. However, over the past 20 years, the emphasis has shifted to the neural imbalances associated with migraine, and vascular changes have generally been viewed as an epiphenomenon that is neither sufficient nor necessary to induce migraine. With the clinical success of peripherally-acting antibodies that target calcitonin gene-related peptide (CGRP) and its receptor for preventing migraine, this neurocentric view warrants a critical re-evaluation. This review will highlight the likely importance of the vasculature in migraine.

Animal models have provided a growing body of information about the pathophysiology of headaches and novel therapeutic targets. In recent years, experiments in awake animals have gained attention as more relevant headache models. Pain can be assessed in animals using behavioral alterations, which includes sensory-discriminative, affective-emotional and cognitive aspects. Spontaneous behavioral alterations such as increased grooming, freezing, eye blinking, wet dog shake and head shake and decreased locomotion, rearing, food or water consumption observed during pain episodes are oftentimes easy to translate into clinical outcomes, but are giving little information about the localization and modality of the pain. Evoked pain response such as tactile and thermal hypersensitivity measures are less translatable but gives more insight into mechanisms of action. Mechanical allodynia is usually assessed with von Frey monofilaments and dynamic aesthesiometer, and thermal allodynia can be evaluated with acetone evaporation test and Hargreaves’ test in animal models. Anxiety and depression are the most frequent comorbid diseases in headache disorders. Anxiety-like behaviors are evaluated with the open-field, elevated plus-maze or light/dark box tests. Interpretation of the latter test is challenging in migraine models, as presence of photophobia or photosensitivity can also be measured in light/dark boxes. Depressive behavior is assessed with the forced-swim or tail suspension tests. The majority of headache patients complain of cognitive symptoms and migraine is associated with poor cognitive performance in clinic-based studies. Cluster headache and tension type headache patients also exhibit a reversible cognitive dysfunction during the headache attacks. However, only a limited number of animal studies have investigated cognitive aspects of headache disorders, which remains a relatively unexplored aspect of these pathologies. Thus, the headache field has an excellent and growing selection of model systems that are likely to yield exciting advances in the future.

The biotic and abiotic assets of the marine environment form the “marine natural capital” embedded in the global ocean. Marine natural capital provides the flow of “marine ecosystem services” that are directly used or enjoyed by people providing benefits to human well-being. They include provisioning services (e.g., food), regulation and maintenance services (e.g., carbon sequestration and storage, and coastal protection), and cultural services (e.g., tourism and recreational benefits). In recent decades, human activities have increased the pressures on marine ecosystems, often leading to ecosystem degradation and biodiversity loss and, in turn, affecting their ability to provide benefits to humans. Therefore, effective management strategies are crucial to the conservation of healthy and diverse marine ecosystems and to ensuring their long-term generation of goods and services. Biophysical, economic, and sociocultural assessments of marine ecosystem services are much needed to convey the importance of natural resources to managers and policy makers supporting the development and implementation of policies oriented for the sustainable management of marine resources. In addition, the accounting of marine ecosystem service values can be usefully complemented by their mapping to enable the identification of priority areas and management strategies and to facilitate science–policy dialogue. Given this premise, this study aims to review trends and evolution in the concept of marine ecosystem services. In particular, the global scientific literature on marine ecosystem services is explored by focusing on the following main aspects: the definition and classification of marine ecosystem services; their loss due to anthropogenic pressures, alternative assessment, and mapping approaches; and the inclusion of marine ecosystem services into policy and decision-making processes.

[...]looking towards the future, Lou et al., describe four migraine-associated loci, examining the link between gene expression, protein levels, and migraine pathophysiology [10]. While CGRP/CGRP receptor monoclonal antibodies and gepants target CGRP or CGRP receptors directly, endogenous descending pathways can also reduce migraine pain, possibly through modulation of CGRP signaling as well [11, 12–13]. [...]studying the sites of CGRP actions and roles is crucial, as Rees et al. show that amylin and CGRP interact with receptors in the upper cervical dorsal root ganglia [14]. [...]migraine is a complex condition influenced by many endogenous molecular mechanisms and comorbidities. The headache research priorities: research goals from the American headache society and an international multistakeholder expert group.

Migraine is a common and complex neurological disorder that has a high impact on quality of life. Recent advances with drugs that target the neuropeptide calcitonin gene-related peptide (CGRP) have helped, but treatment options remain insufficient. CGRP is released from trigeminal sensory fibers and contributes to peripheral sensitization, perhaps in part due to actions on immune cells in the trigeminovascular system. In this review, we will discuss the potential of cannabinoid targeting of immune cells as an innovative therapeutic target for migraine treatment. We will cover endogenous endocannabinoids, plant-derived phytocannabinoids and synthetically derived cannabinoids. The focus will be on six types of immune cells known to express multiple cannabinoid receptors: macrophages, monocytes, mast cells, dendritic cells, B cells, and T cells. These cells also contain receptors for CGRP and as such, cannabinoids might potentially modulate the efficacy of current CGRP-targeting drugs. Unfortunately, to date most studies on cannabinoids and immune cells have relied on cell cultures and only a single preclinical study has tested cannabinoid actions on immune cells in a migraine model. Encouragingly, in that study a synthetically created stable chiral analog of an endocannabinoid reduced meningeal mast cell degranulation. Likewise, clinical trials evaluating the safety and efficacy of cannabinoid-based therapies for migraine patients have been limited but are encouraging. Thus, the field is at its infancy and there are significant gaps in our understanding of the impact of cannabinoids on immune cells in migraine. Future research exploring the interactions between cannabinoids and immune cells could lead to more targeted and effective migraine treatments.

In this trial involving fetuses with severe left congenital diaphragmatic hernia, fetoscopic endoluminal tracheal occlusion at 27 to 29 weeks of gestation significantly increased survival to discharge, but it resulted in an increased incidence of preterm, prelabor rupture of membranes and preterm birth.

In the present study, we investigated neural correlates associated with gender differences in a simple response task (SRT) and in a discriminative response task (DRT) by means of event-related potential (ERP) technique. 120 adults participated in the study, and, based on their sex, were divided into two groups matched for age and education level. Behavioral performance was assessed with computing response speed, accuracy rates and response consistency. Pre- and post-stimulus ERPs were analyzed and compared between groups. Results indicated that males were faster than females in all tasks, while females were more accurate and consistent than males in the more complex tasks. This different behavioral performance was associated with distinctive ERP features. In the preparation phase, males showed smaller prefrontal negativity (pN) and visual negativity (vN), interpreted as reduced cognitive preparation to stimulus occurrence and reduced reliance on sensory proactive readiness, respectively. In the post-stimulus phase, gender differences were present over occipital (P1, N1, P2 components) and prefrontal (pN1, pP1, pP2 components) areas, suggesting allocation of attentional resources at distinct stages of information processing in the two groups. Overall, the present data provide evidence in favor of a more proactive and cautious cognitive processing in females and a more reactive and fast cognitive processing in males. In addition, we confirm that (1) gender is an important variable to be considered in ERP studies on perceptual processing and decision making, and (2) the pre-stimulus component analysis can provide useful information concerning neural correlates of upcoming performance.