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Alzheimer’s disease is the most common age-related neurodegenerative disorder. Familial forms of Alzheimer’s disease associated with the accumulation of a toxic form of amyloid-β (Aβ) peptides are linked to mitochondrial impairment. The coenzyme nicotinamide adenine dinucleotide (NAD + ) is essential for both mitochondrial bioenergetics and nuclear DNA repair through NAD + -consuming poly (ADP-ribose) polymerases (PARPs). Here we analysed the metabolomic changes in flies overexpressing Aβ and showed a decrease of metabolites associated with nicotinate and nicotinamide metabolism, which is critical for mitochondrial function in neurons. We show that increasing the bioavailability of NAD + protects against Aβ toxicity. Pharmacological supplementation using NAM, a form of vitamin B that acts as a precursor for NAD + or a genetic mutation of PARP rescues mitochondrial defects, protects neurons against degeneration and reduces behavioural impairments in a fly model of Alzheimer’s disease. Next, we looked at links between PARP polymorphisms and vitamin B intake in patients with Alzheimer’s disease. We show that polymorphisms in the human PARP1 gene or the intake of vitamin B are associated with a decrease in the risk and severity of Alzheimer’s disease. We suggest that enhancing the availability of NAD + by either vitamin B supplements or the inhibition of NAD + -dependent enzymes such as PARPs are potential therapies for Alzheimer’s disease.

Many animals use Earth’s magnetic field (also known as the geomagnetic field) for navigation 1 . The favoured mechanism for magnetosensitivity involves a blue-light-activated electron-transfer reaction between flavin adenine dinucleotide (FAD) and a chain of tryptophan residues within the photoreceptor protein CRYPTOCHROME (CRY). The spin-state of the resultant radical pair, and therefore the concentration of CRY in its active state, is influenced by the geomagnetic field 2 . However, the canonical CRY-centric radical-pair mechanism does not explain many physiological and behavioural observations 2 – 8 . Here, using electrophysiology and behavioural analyses, we assay magnetic-field responses at the single-neuron and organismal levels. We show that the 52 C-terminal amino acid residues of Drosophila melanogaster CRY, lacking the canonical FAD-binding domain and tryptophan chain, are sufficient to facilitate magnetoreception. We also show that increasing intracellular FAD potentiates both blue-light-induced and magnetic-field-dependent effects on the activity mediated by the C terminus. High levels of FAD alone are sufficient to cause blue-light neuronal sensitivity and, notably, the potentiation of this response in the co-presence of a magnetic field. These results reveal the essential components of a primary magnetoreceptor in flies, providing strong evidence that non-canonical (that is, non-CRY-dependent) radical pairs can elicit magnetic-field responses in cells. Non-CRYPTOCHROME-dependent radical pairs can elicit responses to magnetic fields in neurons in Drosophila melanogaster .

Many higher animals have evolved the ability to use the Earth’s magnetic field, particularly for orientation. Drosophila melanogaster also respond to electromagnetic fields (EMFs), although the reported effects are quite modest. Here we report that negative geotaxis in flies, scored as climbing, is disrupted by a static EMF, and this is mediated by cryptochrome (CRY), the blue-light circadian photoreceptor. CRYs may sense EMFs via formation of radical pairs of electrons requiring photoactivation of flavin adenine dinucleotide (FAD) bound near a triad of Trp residues, but mutation of the terminal Trp in the triad maintains EMF responsiveness in climbing. In contrast, deletion of the CRY C terminus disrupts EMF responses, indicating that it plays an important signalling role. CRY expression in a subset of clock neurons, or the photoreceptors, or the antennae, is sufficient to mediate negative geotaxis and EMF sensitivity. Climbing therefore provides a robust and reliable phenotype for studying EMF responses in Drosophila . The earth’s electromagnetic field has a modest effect on the behaviour of Drosophila melanogaster . Here, Fedele et al . use an assessment of climbing behaviour to describe how the blue-light circadian photoreceptor cryptochrome mediates a negative movement response to gravity in flies.

Pertussis is an acute respiratory disease caused by . Due to its frequency and severity, prevention of pertussis has been considered an important public health issue for many years. The development of the whole-cell pertussis vaccine (wPV) and its introduction into the pediatric immunization schedule was associated with a marked reduction in pertussis cases in the vaccinated cohort. However, due to the frequency of local and systemic adverse events after immunization with wPV, work on a less reactive vaccine was undertaken based on isolated components that induced protective immune responses with fewer local and systemic reactions. These component vaccines were termed acellular vaccines and contained one or more pertussis antigens, including pertussis toxin (PT), filamentous haemagglutinin (FHA), pertactin (PRN), and fimbrial proteins 2 (FIM2) and 3 (FIM3). Preparations containing up to five components were developed, and several efficacy trials clearly demonstrated that the aPVs were able to confer comparable short-term protection than the most effective wPVs with fewer local and systemic reactions. There has been a resurgence of pertussis observed in recent years. This paper reports the results of a Consensus Conference organized by the World Association for Infectious Disease and Immunological Disorders (WAidid) on June 22, 2018, in Perugia, Italy, with the goal of evaluating the most important reasons for the pertussis resurgence and the role of different aPVs in this resurgence.

Adenylate cyclase toxin (CyaA) is released in the course of B. pertussis infection in the host’s respiratory tract in order to suppress its early innate and subsequent adaptive immune defense. CD11b-expressing dendritic cells (DC), macrophages and neutrophils are professional phagocytes and key players of the innate immune system that provide a first line of defense against invading pathogens. Recent findings revealed the capacity of B. pertussis CyaA to intoxicate DC with high concentrations of 3′,5′-cyclic adenosine monophosphate (cAMP), which ultimately skews the host immune response towards the expansion of Th17 cells and regulatory T cells. CyaA-induced cAMP signaling swiftly incapacitates opsonophagocytosis, oxidative burst and NO-mediated killing of bacteria by neutrophils and macrophages. The subversion of host immune responses by CyaA after delivery into DC, macrophages and neutrophils is the subject of this review.

The blue-light sensitive photoreceptor cryptochrome (CRY) may act as a magneto-receptor through formation of radical pairs involving a triad of tryptophans. Previous genetic analyses of behavioral responses of Drosophila to electromagnetic fields using conditioning, circadian and geotaxis assays have lent some support to the radical pair model (RPM). Here, we describe a new method that generates consistent and reliable circadian responses to electromagnetic fields that differ substantially from those already reported. We used the Schuderer apparatus to isolate Drosophila from local environmental variables, and observe extremely low frequency (3 to 50 Hz) field-induced changes in two locomotor phenotypes, circadian period and activity levels. These field-induced phenotypes are CRY- and blue-light dependent, and are correlated with enhanced CRY stability. Mutational analysis of the terminal tryptophan of the triad hypothesised to be indispensable to the electron transfer required by the RPM reveals that this residue is not necessary for field responses. We observe that deletion of the CRY C-terminus dramatically attenuates the EMF-induced period changes, whereas the N-terminus underlies the hyperactivity. Most strikingly, an isolated CRY C-terminus that does not encode the Tryptophan triad nor the FAD binding domain is nevertheless able to mediate a modest EMF-induced period change. Finally, we observe that hCRY2, but not hCRY1, transformants can detect EMFs, suggesting that hCRY2 is blue light-responsive. In contrast, when we examined circadian molecular cycles in wild-type mouse suprachiasmatic nuclei slices under blue light, there was no field effect. Our results are therefore not consistent with the classical Trp triad-mediated RPM and suggest that CRYs act as blue-light/EMF sensors depending on trans-acting factors that are present in particular cellular environments.

Coronavirus disease 2019 (COVID-19) severity is closely associated with dysregulated inflammatory responses, with cytokines and chemokines emerging as key mediators and potential early biomarkers of adverse clinical outcomes. A retrospective study on 103 RT-PCR-confirmed COVID-19 patients during the first pandemic wave (January-May 2020) was performed to evaluate the prognostic value of a panel of cytokines and chemokines measured at hospital admission. Samples and clinical data were collected at the Department of Public Health and Infectious Diseases, Sapienza University of Rome, and sent to Istituto Superiore di Sanità for further characterization. Serum concentrations of IL-1β, IL-6, IL-8, IL-10, TNF-α, CCL3, and CXCL10 (IP-10) were quantified using multiplex ELISA. Associations with in-hospital mortality, intensive care unit (ICU) admission, and a composite outcome (death or ICU admission) were assessed using multivariable logistic regression. ICU admission occurred in 6.8% of patients and mortality in 11.7%. Among inflammatory mediators, CXCL10 emerged as the strongest predictor of adverse outcomes. In adjusted models, each 1,000 pg/mL increase in CXCL10 was associated with increased odds of death (OR 1.26; 95% CI 1.17-1.35), ICU admission (OR 1.13; 95% CI 1.06-1.21), and the composite outcome (OR 1.21; 95% CI 1.12-1.31). Elevated respiratory frequency and blood urea nitrogen were also independently associated with worse outcomes, while TNF-α tended to be associated with ICU admission. Conversely, IL-6 and other cytokines were not significant predictors in the multivariable models. These findings identify CXCL10 as a key early immunological predictor of COVID-19 severity, suggesting that its integration with clinical parameters may improve risk stratification and guide targeted management. CXCL10 may also represent a potential therapeutic target, warranting validation in larger prospective studies.

Exaggerated immune responses to respiratory viruses may contribute to increased morbidity in older adults. To investigate virus-specific immune activation in this population, we developed an ex vivo whole blood stimulation model using samples from 30 healthy individuals aged ≥65 years. Whole blood was stimulated with UV-inactivated influenza A virus (IAV), respiratory syncytial virus (RSV), and SARS-CoV-2, and the expression of 22 immune-related genes was assessed by quantitative RT-PCR array. All three viruses elicited responses with marked variability across individuals, as well as differences in the magnitude and distribution of cytokine expression across stimuli. RSV stimulation was associated with relatively higher expression of inflammatory mediators, while IAV and SARS-CoV-2 induced greater expression of Type I interferon. SARS-CoV-2 also led to an increased expression of regulatory cytokines. Although individual responses varied, correlation analysis indicated coordinated gene expression within functional categories, and Uniform Manifold Approximation and Projection (UMAP) showed distinct grouping of cytokine responses by virus and function. These findings describe differential immune mRNA expression profiles in response to viral stimuli in older adults and may support future studies aimed at understanding age-related differences in host–virus interactions.

To date there has been limited head-to-head evaluation of immune responses to different types of COVID-19 vaccines. A real-world population-based longitudinal study was designed with the aim to define the magnitude and duration of immunity induced by each of four different COVID-19 vaccines available in Italy at the time of this study. Overall, 2497 individuals were enrolled at time of their first vaccination (T0). Vaccine-specific antibody responses induced over time by Comirnaty, Spikevax, Vaxzevria, Janssen Ad26.COV2.S and heterologous vaccination were compared up to six months after immunization. On a subset of Comirnaty vaccinees, serology data were correlated with the ability to neutralize a reference SARS-CoV-2 B strain, as well as Delta AY.4 and Omicron BA.1. The frequency of SARS-CoV-2-specific CD4+ T cells, CD8+ T cells, and memory B cells induced by the four different vaccines was assessed six months after the immunization. We found that mRNA vaccines are stronger inducer of anti-Spike IgG and B-memory cell responses. Humoral immune responses are lower in frail elderly subjects. Neutralization of the Delta AY.4 and Omicron BA.1 variants is severely impaired, especially in older individuals. Most vaccinees display a vaccine-specific T-cell memory six months after the vaccination. By describing the immunological response during the first phase of COVID-19 vaccination campaign in different cohorts and considering several aspects of the immunological response, this study allowed to collect key information that could facilitate the implementation of effective prevention and control measures against SARS-CoV-2.