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Signal transduction systems are influenced by positive and negative forces resulting in an output reflecting the sum of the opposing forces. The Rap family of regulatory protein modules control the output of two-component signal transduction systems through protein∶protein and protein∶peptide interactions. These modules and their peptide regulators are found in complex signaling pathways, including the bacterial developmental pathway to sporulation, competence, and protease secretion. Two articles published in the current issue of PLOS Biology reveal by means of crystallographic analyses how the Rap proteins of bacilli are regulated by their inhibitor Phr peptide and provide a mechanistic explanation for a genetic phenotype isolated decades earlier. The Rap-Phr module of bacterial regulators was the prototype of a family that now extends to other bacterial signaling proteins that involve the use of the tetratricopeptide repeat structural fold. The results invite speculation regarding the potential exploitation of this module as a molecular tool for applications in therapeutic design and biotechnology.

Magic-angle twisted bilayer graphene can host a variety of gate-tunable correlated states – including superconducting and correlated insulator states. Recently, junction-based superconducting moiré devices have been introduced, enabling the study of the charge, spin and orbital nature of superconductivity, as well as the coherence of moiré electrons in magic-angle twisted bilayer graphene. Complementary fundamental coherence effects—in particular, the Little–Parks effect in a superconducting ring and the Aharonov–Bohm effect in a normally conducting ring – have not yet been reported in moiré devices. Here, we observe both phenomena in a single gate-defined ring device, where we can embed a superconducting or normally conducting ring in a correlated or band insulator. The Little–Parks effect is seen in the superconducting phase diagram as a function of density and magnetic field, confirming the effective charge of 2 e . We also find that the coherence length of conducting moiré electrons exceeds several microns at 50 mK. In addition, we identify a regime characterized by h / e -periodic oscillations but with superconductor-like nonlinear transport. Gate-defined superconducting moiré devices offer high tunability for probing the nature of superconducting and correlated insulating states. Here, the authors report the Little–Parks and Aharonov–Bohm effects in a single gate-defined magic-angle twisted bilayer graphene device.

Superconducting magic-angle twisted-layer graphene (MATLG) is a promising candidate for superconducting electronics due to its electrical tunability. While the microscopic origins of superconductivity in MATLG have been intensively studied, many aspects of its phenomenology remain unexplored due to the challenges associated with studying two-dimensional (2D) materials. Here, we report the first direct experimental evidence of superconducting vortices in MATLG, a hallmark of type-II superconductors. Field-dependent critical current measurements in a gate-tuned Josephson junction reveal Fraunhofer-like patterns characteristic of ultrathin films with weak transverse screening. These patterns exhibit sudden shifts attributed to spontaneous vortex penetration into the leads. With the leads at the edge of the superconducting dome, we observe bistable V – I fluctuations linked to rapid vortex dynamics. Time-dependent measurements provide the vortex energy scale, the London penetration depth, and superfluid stiffness, consistent with recent kinetic inductance studies. These findings establish gate-defined Josephson junctions as versatile sensors of vortex dynamics in 2D superconductors. The authors study gate-defined Josephson junctions in four-layer twisted graphene. Field-dependent measurements of the critical current show a Fraunhofer-like pattern with sudden shifts, which they attribute to vortices jumping into and out of the superconducting leads.

Magic-Angle Twisted Bilayer Graphene (MATBG) shows a wide range of correlated phases which are electrostatically tunable. Despite a growing knowledge of the material, there is yet no consensus on the microscopic mechanisms driving its superconducting phase. A major obstacle to progress in this direction is that key thermodynamic properties, such as specific heat, electron-phonon coupling and superfluid stiffness, are challenging to measure due to the 2D nature of the material and its relatively low energy scales. Here, we use a gate-defined, radio frequency-biased, Josephson junction to probe the electronic dynamics of MATBG. We demonstrate evidence for two processes determining the low-frequency dynamics across the phase diagram: thermalization of electronic quasiparticles through phonon scattering and inductive response of the superconducting condensate. A phenomenological approach allows us to relate the experimentally observed dynamics to several thermodynamic properties of MATBG, including electron-phonon coupling and superfluid stiffness. Our findings support anisotropic or nodal superconductivity in MATBG and demonstrate a broadly applicable method for studying properties of 2D materials with out-of-equilibrium nanodevice dynamics. The mechanisms behind the superconducting phase in magic-angle twisted bilayer graphene (MATBG) remain debated. Here, the authors investigate radio frequency-biased Josephson junctions in MATBG, providing insights into the electron-phonon coupling and superfluid stiffness of correlated electrons.

Allograft vesicoureteral reflux (VUR) is a leading urological complication of kidney transplantation. Despite the relatively high incidence, there is a lack of consensus regarding VUR risk factors, impact on renal function, and management. Dialysis vintage and atrophic bladder have been recognized as the most relevant recipient-related determinants of post-transplant VUR, whilst possible relationships with sex, age, and ureteral implantation technique remain debated. Clinical manifestations vary from an asymptomatic condition to persistent or recurrent urinary tract infections (UTIs). Voiding cystourethrography is widely accepted as the gold standard diagnostic modality, and the reflux is generally graded following the International Reflux Study Committee Scale. Long-term transplant outcomes of recipients with asymptomatic grade I-III VUR are yet to be clarified. On the contrary, available data suggest that symptomatic grade IV-V VUR may lead to progressive allograft dysfunction and premature transplant loss. Therapeutic options include watchful waiting, prolonged antibiotic suppression, sub-mucosal endoscopic injection of dextranomer/hyaluronic acid copolymer at the site of the ureteral anastomosis, and surgery. Indication for specific treatments depends on recipient’s characteristics (age, frailty, compliance with antibiotics), renal function (serum creatinine concentration < 2.5 vs. ≥ 2.5 mg/dL), severity of UTIs, and VUR grading (grade I-III vs. IV-V). Current evidence supporting surgical referral over more conservative strategies is weak. Therefore, a tailored approach should be preferred. Properly designed studies, with adequate sample size and follow-up, are warranted to clarify those unresolved issues.

The phosphorelay signal transduction system activates developmental transcription in sporulation of Bacillus subtilis by phosphorylation of aspartyl residues of the Spo0F and Spo0A response regulators. The phosphorylation level of these response regulators is determined by the opposing activities of protein kinases and protein aspartate phosphatases that interpret positive and negative signals for development in a signal integration circuit. The RapA protein aspartate phosphatase of the phosphorelay is regulated by a peptide that directly inhibits its activity. This peptide is proteolytically processed from an inactive pre-inhibitor protein encoded in the phrA gene. The pre-inhibitor is cleaved by the protein export apparatus to a putative pro-inhibitor that is further processed to the active inhibitor peptide and internalized by the oligopeptide permease. This export-import circuit is postulated to be a mechanism for timing phosphatase activity where the processing enzymes regulate the rate of formation of the active inhibitor. The processing events may, in turn, be controlled by a regulatory hierarchy. Chromosome sequencing has revealed several other phosphatase--prepeptide gene pairs in B. subtilis, suggesting that the use of this mechanism may be widespread in signal transduction.

Background: Coronavirus disease 2019 (COVID-19) vaccination hesitancy is a threat as COVID-19 vaccines have reduced both viral transmission and virus-associated mortality rates, particularly in high-risk subgroups. Solid organ transplant recipients (SOTRs) are particularly vulnerable, as the underlying causes of their organ failure and the chronic immunosuppression are associated with a lower immune response to COVID-19 vaccines, and with an excessive risk of death due to SARS-CoV-2 infection. We aimed to evaluate COVID-19 vaccination hesitancy and its reasons in a population of SOTRs. Methods: All the SOTRs attending our post-transplant clinics were asked to fill in a vaccination status form with specific validated questions related to their willingness to receive a third vaccine dose. In the case of negative answers, the patients were encouraged to explain the reasons for their refusal. Among the SOTRs (1899), 1019 were investigated (53.7%). Results: Overall, 5.01% (51/1019) of the SOTRs raised concerns regarding the future third dose vaccination. In more detail, hesitancy rates were 3.3% (15/453), 4.2% (7/166), and 7.3% (29/400) among the investigated liver, lung, and kidney transplant recipients, respectively (p = 0.0018). The main reasons for hesitancy were fear of adverse events (30/51, 58.8%) and perceived lack of efficacy (21/51, 41.2%). Conclusions: Full adherence to ongoing or future vaccination campaigns is crucial to prevent, or at least reduce, COVID-19-related morbidity and mortality in fragile patients. The identification of the reasons influencing COVID-19 vaccination hesitancy in these patients is very important to establish appropriate and targeted patient–doctor communication strategies, and to further implement specific vaccination campaigns.

Since the declaration of the COVID-19 pandemic, the number of kidney transplants (KT) performed worldwide has plummeted. Besides the generalised healthcare crisis, this unprecedented drop has multiple explanations such as the risk of viral transmission through the allograft, the perceived increase in SARS-CoV-2-related morbidity and mortality in immunocompromised hosts, and the virtual “safety” of dialysis while awaiting effective antiviral prophylaxis or treatment. Our institution, operating at the epicentre of the COVID-19 pandemic in Italy, has continued the KT programme without pre-set limitations. In this single-centre retrospective observational study with one-year follow-up, we assessed the outcomes of patients who had undergone KT (KTR) or remained on the transplant waiting list (TWL), before (Pre-COV) or during (COV) the pandemic. The main demographic and clinical characteristics of the patients on the TWL or receiving a KT were very similar in the two periods. The pandemic did not affect post-transplant recipient and allograft loss rates. On the contrary, there was a trend toward higher mortality among COV-TWL patients compared to Pre-COV-TWL subjects. Such a discrepancy was primarily due to SARS-CoV-2 infections. Chronic exposure to immunosuppression, incidence of delayed allograft function, and rejection rates were comparable. However, after one year, COV-KTR showed significantly higher median serum creatinine than Pre-COV-KTR. Our data confirm that KT practice could be safely maintained during the COVID-19 pandemic, with excellent patient- and allograft-related outcomes. Strict infection control strategies, aggressive follow-up monitoring, and preservation of dedicated personnel and resources are key factors for the optimisation of the results in case of future pandemics.

COVID-19 is a life-threatening infection among elderly patients, comorbid patients, or transplanted patients. Lombardy (region of Italy), accounts for 786,324 cases as of 21 April 2021. We retrospectively describe our single Centre experience in 82 adult kidney-transplant patients with COVID-19 infection during two pandemic outbreaks: 27 (first outbreak) and 65 (second outbreak). Thirty-seven patients were hospitalized (HP) and sixty-five were home managed (HM). Infection presented with fever (80%), cough (51%), and dyspnea (33%). HP were older (60 ± 11 vs. 50 ± 14 years, p = 0.001), had more severe respiratory symptoms (dyspnea 62.1%, p < 0.0001–cough 67% p = 0.008), and a longer length of disease (30 ± 28 vs. 21 ± 10, p = 0.04). The incidence of acute kidney injury (AKI) was 29.7% (p < 0.0001). Steroid dosage was increased in 66% of patients (p = 0.0003), while calcineurin inhibitors were reduced by up to one third in 45% of cases, p < 0.0001. Eleven patients died (13%). HM patients recovered completely without sequelae. In the overall cohort, AKI development (p = 0.006 OR 50.4 CI 95% 3.0–836) and age (p = 0.04 OR 1.1 CI 95% 1.0–1.2) were the most important factors influencing the probability of death during the infection. Although we report a relatively low incidence of infection (5.1%) the incidence of death is almost four times higher than it is in the general population.

Bacillus anthracis lethal toxin (LT) is a key virulence factor of anthrax and contributes significantly to the in vivo pathology. The enzymatically active component is a Zn(2+)-dependent metalloprotease that cleaves most isoforms of mitogen-activated protein kinase kinases (MKKs). Using ex vivo differentiated human lung epithelium we report that LT destroys lung epithelial barrier function and wound healing responses by immobilizing the actin and microtubule network. Long-term exposure to the toxin generated a unique cellular phenotype characterized by increased actin filament assembly, microtubule stabilization, and changes in junction complexes and focal adhesions. LT-exposed cells displayed randomly oriented, highly dynamic protrusions, polarization defects and impaired cell migration. Reconstitution of MAPK pathways revealed that this LT-induced phenotype was primarily dependent on the coordinated loss of MKK1 and MKK2 signaling. Thus, MKKs control fundamental aspects of cytoskeletal dynamics and cell motility. Even though LT disabled repair mechanisms, agents such as keratinocyte growth factor or dexamethasone improved epithelial barrier integrity by reducing cell death. These results suggest that co-administration of anti-cytotoxic drugs may be of benefit when treating inhalational anthrax.