Microscale Chiral Rectennas for Energy Harvesting.

Wireless radiofrequency rectifiers have the potential to power the billions of "Internet of Things" (IoT) devices currently in use by effectively harnessing ambient electromagnetic radiation. However, the current technology relies on the implementation of rectifiers based on Schottky diodes, which exhibit limited capabilities for high-frequency and low-power applications. Consequently, they require an antenna to capture the incoming signal and amplify the input power, thereby limiting the possibility of miniaturizing devices to the millimeter scale. Here, the authors report wireless rectification at the GHz range in a microscale device built on single chiral tellurium with extremely low input powers. By studying the crystal symmetry and the temperature dependence of the rectification, the authors demonstrate that its origin is the intrinsic nonlinear conductivity of the material. Additionally, the unprecedented ability to modulate the rectification output by an electrostatic gate is shown. These results open the path to developing tuneable microscale wireless rectifiers with a single material.

Nonvolatile Electric Control of Antiferromagnet CrSBr.

van der Waals magnets are emerging as a promising material platform for electric field control of magnetism, offering a pathway toward the elimination of external magnetic fields from spintronic devices. A further step is the integration of such magnets with electrical gating components that would enable nonvolatile control of magnetic states. However, this approach remains unexplored for antiferromagnets, despite their growing significance in spintronics. Here, we demonstrate nonvolatile electric field control of magnetoelectric characteristics in van der Waals antiferromagnet CrSBr. We integrate a CrSBr channel in a flash-memory architecture featuring charge trapping graphene multilayers. The electrical gate operation triggers a nonvolatile 200% change in the antiferromagnetic state of CrSBr resistance by manipulating electron accumulation/depletion. Moreover, the nonvolatile gate modulates the metamagnetic transition field of CrSBr and the magnitude of magnetoresistance. Our findings highlight the potential of manipulating magnetic properties of antiferromagnetic semiconductors in a nonvolatile way.

Odd Nonlinear Conductivity under Spatial Inversion in Chiral Tellurium.

Electrical transport in noncentrosymmetric materials departs from the well-established phenomenological Ohm's law. Instead of a linear relation between current and electric field, a nonlinear conductivity emerges along specific crystallographic directions. This nonlinear transport is fundamentally related to the lack of spatial inversion symmetry. However, the experimental implications of an inversion symmetry operation on the nonlinear conductivity remain to be explored. Here, we report on a large, nonlinear conductivity in chiral tellurium. By measuring samples with opposite handedness, we demonstrate that the nonlinear transport is odd under spatial inversion. Furthermore, by applying an electrostatic gate, we modulate the nonlinear output by a factor of 300, reaching the highest reported value excluding engineered heterostructures. Our results establish chiral tellurium as an ideal compound not just to study the fundamental interplay between crystal structure, symmetry operations and nonlinear transport; but also to develop wireless rectifiers and energy-harvesting chiral devices.

The Italian Multicentric Randomized OPTkIMA Trial on Fixed vs Progressive Intermittent TKI Therapy in CML Elderly Patients: 3-Years of Molecular Response and Quality of Life Monitoring After Completing the Treatment Plan.

BACKGROUND: Intermittent treatment with tyrosine kinase inhibitors (TKIs) is an option for elderly chronic myeloid leukemia (CML) patients who are often candidates for life-long treatment. MATERIALS AND METHODS: The Italian phase III multicentric randomized Optimize TKIs Multiple Approaches (OPTkIMA) study aimed to evaluate if a progressive de-escalation of TKIs is able to maintain the molecular remission (MR)3.0 and to improve Health-Related Quality of Life (HRQoL) in CML elderly patients. RESULTS: A total of 215 patients in stable MR3.0/MR4.0 were randomized to receive an intermittent TKI schedule 1 month ON-1 month OFF for 3 years (FIXED arm; n = 111) vs. a progressive de-escalation TKI dose up to one-third of the starting dose at the 3rd year (PROGRESSIVE arm; n = 104). Two hundred three patients completed the 3rd year of OPTkIMA study. At the last follow-up, MR3.0 loss was 27% vs. 46% (P = .005) in the FIXED vs PROGRESSIVE arm, respectively. None of these patients experienced disease progression. The 3-year probability of maintaining the MR3.0 was 59% vs. 53%, respectively (P = .13). HRQoL globally improved from the baseline to the 3rd year, without any significant difference between the 2 arms. After the 3rd year, the proportion of patients who was address to TKI discontinuation in the 2 arms was 36% (FIXED) vs. 58% (PROGRESSIVE) (P = .03). CONCLUSIONS: The intensification of intermittent TKI therapy is associated with a higher incidence of MR3.0 loss, but those patients who maintain the MR3.0 molecular response at the end of the study have been frequently considered eligible for TFR. The HRQoL generally improved during the de-escalation therapy in both randomization arms.

Development of a Bispecific IgG1 Antibody Targeting BCMA and PDL1.

We designed, produced, and purified a novel IgG1-like, bispecific antibody (bsAb) directed against B-cell maturation antigen (BCMA), expressed by multiple myeloma (MM) cells, and an immune checkpoint inhibitor (ICI), PDL1, expressed in the MM microenvironment. The BCMA×PDL1 bsAb was fully characterized in vitro. BCMA×PDL1 bound specifically and simultaneously, with nM affinity, to both native membrane-bound antigens and to the recombinant soluble antigen fragments, as shown by immunophenotyping analyses and surface plasmon resonance (SPR), respectively. The binding affinity of bsAb for PDL1 and BCMA was similar to each other, but PDL1 affinity was about 10-fold lower in the bsAb compared to parent mAb, probably due to the steric hindrance associated with the more internal anti-PDL1 Fab. The bsAb was also able to functionally block both antigen targets with IC50 in the nM range. The bsAb Fc was functional, inducing human-complement-dependent cytotoxicity as well as ADCC by NK cells in 24 h killing assays. Finally, BCMA×PDL1 was effective in 7-day killing assays with peripheral blood mononuclear cells as effectors, inducing up to 75% of target MM cell line killing at a physiologically attainable, 6 nM, concentration. These data provide the necessary basis for future optimization and in vivo testing of this novel bsAb.

SEPN1-related myopathy depends on the oxidoreductase ERO1A and is druggable with the chemical chaperone TUDCA.

Selenoprotein N (SEPN1) is a protein of the endoplasmic reticulum (ER) whose inherited defects originate SEPN1-related myopathy (SEPN1-RM). Here, we identify an interaction between SEPN1 and the ER-stress-induced oxidoreductase ERO1A. SEPN1 and ERO1A, both enriched in mitochondria-associated membranes (MAMs), are involved in the redox regulation of proteins. ERO1A depletion in SEPN1 knockout cells restores ER redox, re-equilibrates short-range MAMs, and rescues mitochondrial bioenergetics. ERO1A knockout in a mouse background of SEPN1 loss blunts ER stress and improves multiple MAM functions, including Ca2+ levels and bioenergetics, thus reversing diaphragmatic weakness. The treatment of SEPN1 knockout mice with the ER stress inhibitor tauroursodeoxycholic acid (TUDCA) mirrors the results of ERO1A loss. Importantly, muscle biopsies from patients with SEPN1-RM exhibit ERO1A overexpression, and TUDCA-treated SEPN1-RM patient-derived primary myoblasts show improvement in bioenergetics. These findings point to ERO1A as a biomarker and a viable target for intervention and to TUDCA as a pharmacological treatment for SEPN1-RM.

Detection and molecular analysis of Pseudorabies virus from free-ranging Italian wolves (Canis lupus italicus) in Italy - a case report.

BACKGROUND: The only natural hosts of Pseudorabies virus (PRV) are members of the family Suidae (Sus scrofa scrofa). In mammals, the infection is usually fatal and typically causes serious neurologic disease. This study describes four Aujeszky's disease cases in free-ranging Italian wolves (Canis lupus italicus). In Italy, the wolf is a strictly protected species and is in demographic expansion. CASE PRESENTATION: Three wolves (Wolf A, B, and C) were found in a regional park in Northern Italy, and one (Wolf D) was found in Central Italy. Wolf A and D were alive at the time of the finding and exhibited a fatal infection with epileptic seizures and dyspnoea, dying after a few hours. Wolf B presented scratching lesions under the chin and a detachment of the right earlobe, whilst Wolf C was partially eaten. The wolves showed hepatic congestion, diffuse enteritis, moderate pericardial effusion, severe bilateral pneumonia, and diffuse hyperaemia in the brain. The diagnostic examinations included virological analyses and detection of toxic molecules able to cause serious neurological signs. All four wolves tested positive for pseudorabies virus (PrV). The analysed sequences were placed in Italian clade 1, which is divided into two subclades, "a" and "b". The sequences of Wolf A, B, and C were closely related to other Italian sequences in the subclade b, originally obtained from wild boars and hunting dogs. The sequence from Wolf D was located within the same clade and was closely related to the French hunting dog sequences belonging to group 4. CONCLUSION: Results showed the presence of PrV strains currently circulating in wild boars and free-ranging Italian wolves. The genetic characterisation of the PrV UL44 sequences from the four wolves confirmed the close relationship with the sequences from wild boars and hunting dogs. This fact supports a possible epidemiological link with the high PrV presence in wild boars and the possibility of infection in wolves through consumption of infected wild boar carcasses or indirect transmission. To the best of our knowledge, this study is the first detection of Pseudorabies virus in free-ranging Italian wolves in northern and central Italy.

Control of Charge-Spin Interconversion in van der Waals Heterostructures with Chiral Charge Density Waves.

A charge density wave (CDW) represents an exotic state in which electrons are arranged in a long-range ordered pattern in low-dimensional materials. Although the understanding of the fundamental character of CDW is enriched after extensive studies, its practical application remains limited. Here, an unprecedented demonstration of a tunable charge-spin interconversion (CSI) in graphene/1T-TaS2 van der Waals heterostructures is shown by manipulating the distinct CDW phases in 1T-TaS2. Whereas CSI from spins polarized in all three directions is observed in the heterostructure when the CDW phase does not show commensurability, the output of one of the components disappears, and the other two are enhanced when the CDW phase becomes commensurate. The experimental observation is supported by first-principles calculations, which evidence that chiral CDW multidomains in the heterostructure are at the origin of the switching of CSI. The results uncover a new approach for on-demand CSI in low-dimensional systems, paving the way for advanced spin-orbitronic devices.

Erratum: A tetracationic porphyrin with dual anti-prion activity.

[This corrects the article DOI: 10.1016/j.isci.2023.107480.].

Local control of superconductivity in a NbSe2/CrSBr van der Waals heterostructure.

Two-dimensional magnets and superconductors are emerging as tunable building-blocks for quantum computing and superconducting spintronic devices, and have been used to fabricate all two-dimensional versions of traditional devices, such as Josephson junctions. However, novel devices enabled by unique features of two-dimensional materials have not yet been demonstrated. Here, we present NbSe2/CrSBr van der Waals superconducting spin valves that exhibit infinite magnetoresistance and nonreciprocal charge transport. These responses arise from a unique metamagnetic transition in CrSBr, which controls the presence of localized stray fields suitably oriented to suppress the NbSe2 superconductivity in nanoscale regions and to break time reversal symmetry. Moreover, by integrating different CrSBr crystals in a lateral heterostructure, we demonstrate a superconductive spin valve characterized by multiple stable resistance states. Our results show how the unique physical properties of layered materials enable the realization of high-performance quantum devices based on novel working principles.

Antimicrobial Susceptibility of Commensal E. coli Isolated from Wild Birds in Umbria (Central Italy).

The role of wildlife, including birds, in antimicrobial resistance is nowadays a speculative topic for the scientific community as they could be spreaders/sources of antimicrobial resistance genes. In this respect, we aimed to investigate the antimicrobial susceptibility of 100 commensal Escherichia coli strains, isolated from wild birds from an Umbrian rescue centre and admitted to the Veterinary Teaching Hospital of Perugia (Central Italy) mainly for traumatic injuries. The possible presence of Salmonella spp. and ESBL-producing E. coli was also estimated. The highest prevalence of resistance was observed for ampicillin (85%) and amoxicillin/clavulanic acid (47%), probably due to their extensive use in human and veterinary medicine. Seventeen out of the one hundred E. coli isolates (17%) displayed a multidrug-resistance profile, including the beta-lactam category, with the most common resistance patterns to three or four classes of antibiotics. Resistance to ciprofloxacin, cefotaxime and ceftazidime exhibited values of 18%, 17% and 15%, respectively. Eight out of the hundred E. coli isolates (8%) were ESBL and seven showed multidrug resistance profiles. Salmonella spp. was not isolated. Resistance to third-generation cephalosporins, also detected in long-distance migratory birds, suggests the need for monitoring studies to define the role of wild birds in antimicrobial resistance circuits.

Clinical impact of the genomic landscape and leukemogenic trajectories in non-intensively treated elderly acute myeloid leukemia patients.

To characterize the genomic landscape and leukemogenic pathways of older, newly diagnosed, non-intensively treated patients with AML and to study the clinical implications, comprehensive genetics analyses were performed including targeted DNA sequencing of 263 genes in 604 patients treated in a prospective Phase III clinical trial. Leukemic trajectories were delineated using oncogenetic tree modeling and hierarchical clustering, and prognostic groups were derived from multivariable Cox regression models. Clonal hematopoiesis-related genes (ASXL1, TET2, SRSF2, DNMT3A) were most frequently mutated. The oncogenetic modeling algorithm produced a tree with five branches with ASXL1, DDX41, DNMT3A, TET2, and TP53 emanating from the root suggesting leukemia-initiating events which gave rise to further subbranches with distinct subclones. Unsupervised clustering mirrored the genetic groups identified by the tree model. Multivariable analysis identified FLT3 internal tandem duplications (ITD), SRSF2, and TP53 mutations as poor prognostic factors, while DDX41 mutations exerted an exceptionally favorable effect. Subsequent backwards elimination based on the Akaike information criterion delineated three genetic risk groups: DDX41 mutations (favorable-risk), DDX41wildtype/FLT3-ITDneg/TP53wildtype (intermediate-risk), and FLT3-ITD or TP53 mutations (high-risk). Our data identified distinct trajectories of leukemia development in older AML patients and provide a basis for a clinically meaningful genetic outcome stratification for patients receiving less intensive therapies.

Nature of the Interaction of Alpha-D-Mannose and Escherichia coli Bacteria, and Implications for its Regulatory Classification. A Delphi Panel European Consensus Based on Chemistry and Legal Evidence.

The nature of alpha-D-mannose-natural aldohexose sugar, C-2 glucose epimer, whose intended use is for preventing urinary tract infections-in the interaction with E. coli is addressed in order to drive the issue of its regulatory classification as a medicinal product or medical device. PRISMA systematic review approach was applied; Delphi Panel method was used to target consensus on statements retrieved from evidence. Based on regulatory definitions and research evidence, the mechanism of D-mannose does not involve a metabolic or immunological action while there is uncertainty regarding the pharmacological action. Specific interaction between the product and the bacteria within the body occurs, but its nature is inert: it does not induce a direct response activating or inhibiting body processes. Moreover, the action of D-mannose takes place, even if inside the bladder, outside the epithelium on bacteria that have not yet invaded the urothelial tissue. Therefore, its mechanism of action is not directed to host structures but to structures (bacteria) external to the host's tissues. On the basis of current regulation, the uncertainty as regard a pharmacological action of alpha-D-mannose makes possible its medical device classification: new regulations and legal judgments can add further considerations. From a pharmacological perspective, research is driven versus synthetic mannosides: no further considerations are expected on alpha-D-mannose.

A Comprehensive Technology Platform for the Rapid Discovery of Peptide Inhibitors against SARS-CoV-2 Pseudovirus Infection.

We developed and validated a technology platform for designing and testing peptides inhibiting the infectivity of SARS-CoV-2 spike protein-based pseudoviruses. This platform integrates target evaluation, in silico inhibitor design, peptide synthesis, and efficacy screening. We generated a cyclic peptide library derived from the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein and the angiotensin-converting enzyme 2 (ACE2) receptor. The cell-free validation process by ELISA competition assays and Surface Plasmon Resonance (SPR) studies revealed that the cyclic peptide c9_05, but not its linear form, binds well to ACE2. Moreover, it effectively inhibited the transduction in HEK293, stably expressing the human ACE2 receptor of pseudovirus particles displaying the SARS-CoV-2 spike in the Wuhan or UK variants. However, the inhibitory efficacy of c9_05 was negligible against the Omicron variant, and it failed to impede the entry of pseudoviruses carrying the B.1.351 (South African) spike. These variants contain three or more mutations known to increase affinity to ACE2. This suggests further refinement is needed for potential SARS-CoV-2 inhibition. Our study hints at a promising approach to develop inhibitors targeting viral infectivity receptors, including SARS-CoV-2's. This platform also promises swift identification and evaluation of inhibitors for other emergent viruses.

The role of Mycoplasma ovipneumoniae and Mycoplasma arginini in the respiratory mycoplasmosis of sheep and goats in Italy: Correlation of molecular data with histopathological features.

Mycoplasma infections are commonly found in the respiratory system of small ruminants; the species most commonly detected are Mycoplasma ovipneumoniae and Mycoplasma arginini, associated with the so-called "atypical non-progressive pneumonia". The pathogenic role of M. ovipneumoniae in pneumonia has been demonstrated in sheep but still needs to be verified in goats; on the other hand, the role of M. arginini in sheep is not well understood, while in goats seems to be of low pathogenic value. The present study aims to investigate the aetiology of pneumonia in sheep and goats that died from respiratory disease using anatomopathological, histopathological, and molecular investigations and to clarify the role of respiratory mycoplasmas by the association of molecular data with histopathological features. First, to better understand which histological changes are actually suggestive of atypical pneumonia in sheep and goats, the study identified the histological lesions significantly associated with Mycoplasma spp. infection. Then, the histological score of lesions considered suggestive of atypical pneumonia was used to estimate the pathogenicity of each mycoplasma detected. The results showed that M. ovipneumoniae and M. arginini (alone or in mixed infections) are pathogenic both in sheep, as well as in goats with similar histology and severity of lesions. Moreover, young animals were statistically more susceptible to M.ovipneumoniae and M. arginini infection than adults. Animals appeared more at risk to the development of M. ovipneumoniae and M. arginini infection in summer.

A tetracationic porphyrin with dual anti-prion activity.

Prions are deadly infectious agents made of PrPSc, a misfolded variant of the cellular prion protein (PrPC) which self-propagates by inducing misfolding of native PrPC. PrPSc can adopt different pathogenic conformations (prion strains), which can be resistant to potential drugs, or acquire drug resistance, hampering the development of effective therapies. We identified Zn(II)-BnPyP, a tetracationic porphyrin that binds to distinct domains of native PrPC, eliciting a dual anti-prion effect. Zn(II)-BnPyP binding to a C-terminal pocket destabilizes the native PrPC fold, hindering conversion to PrPSc; Zn(II)-BnPyP binding to the flexible N-terminal tail disrupts N- to C-terminal interactions, triggering PrPC endocytosis and lysosomal degradation, thus reducing the substrate for PrPSc generation. Zn(II)-BnPyP inhibits propagation of different prion strains in vitro, in neuronal cells and organotypic brain cultures. These results identify a PrPC-targeting compound with an unprecedented dual mechanism of action which might be exploited to achieve anti-prion effects without engendering drug resistance.

Acute Promyelocytic Leukemia and Brugada Syndrome: A Report on the Safety of Arsenic Trioxide/All-Trans-Retinoic Acid Therapy.

Acute promyelocytic leukemia (APL) is a rare and aggressive form of acute myeloid leukemia (AML). Instead of cytotoxic chemotherapy, a combination of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) represents front-line therapy in low-risk patients. However, the therapeutic approach could be challenging in the case of a concomitant diagnosis of Brugada syndrome (BrS), a genetic disease characterized by an increased risk of arrhythmias and sudden cardiac death. Here, we present the case of a BrS patient who has been diagnosed with low-risk APL and treated with ATRA and ATO without observing arrhythmic events. In particular, we highlight the difficulties encountered by clinicians during the diagnostic work-up and the choice of the best treatment for these patients.

Indoleamine 2,3-Dioxygenase Deletion to Modulate Kynurenine Pathway and to Prevent Brain Injury after Cardiac Arrest in Mice.

BACKGROUND: The catabolism of the essential amino acid tryptophan to kynurenine is emerging as a potential key pathway involved in post-cardiac arrest brain injury. The aim of this study was to evaluate the effects of the modulation of kynurenine pathway on cardiac arrest outcome through genetic deletion of the rate-limiting enzyme of the pathway, indoleamine 2,3-dioxygenase. METHODS: Wild-type and indoleamine 2,3-dioxygenase-deleted (IDO-/-) mice were subjected to 8-min cardiac arrest. Survival, neurologic outcome, and locomotor activity were evaluated after resuscitation. Brain magnetic resonance imaging with diffusion tensor and diffusion-weighted imaging sequences was performed, together with microglia and macrophage activation and neurofilament light chain measurements. RESULTS: IDO-/- mice showed higher survival compared to wild-type mice (IDO-/- 11 of 16, wild-type 6 of 16, log-rank P = 0.036). Neurologic function was higher in IDO-/- mice than in wild-type mice after cardiac arrest (IDO-/- 9 ± 1, wild-type 7 ± 1, P = 0.012, n = 16). Indoleamine 2,3-dioxygenase deletion preserved locomotor function while maintaining physiologic circadian rhythm after cardiac arrest. Brain magnetic resonance imaging with diffusion tensor imaging showed an increase in mean fractional anisotropy in the corpus callosum (IDO-/- 0.68 ± 0.01, wild-type 0.65 ± 0.01, P = 0.010, n = 4 to 5) and in the external capsule (IDO-/- 0.47 ± 0.01, wild-type 0.45 ± 0.01, P = 0.006, n = 4 to 5) in IDO-/- mice compared with wild-type ones. Increased release of neurofilament light chain was observed in wild-type mice compared to IDO-/- (median concentrations [interquartile range], pg/mL: wild-type 1,138 [678 to 1,384]; IDO-/- 267 [157 to 550]; P < 0.001, n = 3 to 4). Brain magnetic resonance imaging with diffusion-weighted imaging revealed restriction of water diffusivity 24 h after cardiac arrest in wild-type mice; indoleamine 2,3-dioxygenase deletion prevented water diffusion abnormalities, which was reverted in IDO-/- mice receiving l-kynurenine (apparent diffusion coefficient, µm2/ms: wild-type, 0.48 ± 0.07; IDO-/-, 0.59 ± 0.02; IDO-/- and l-kynurenine, 0.47 ± 0.08; P = 0.007, n = 6). CONCLUSIONS: The kynurenine pathway represents a novel target to prevent post-cardiac arrest brain injury. The neuroprotective effects of indoleamine 2,3-dioxygenase deletion were associated with preservation of brain white matter microintegrity and with reduction of cerebral cytotoxic edema.