A COVID-19 peptide vaccine for the induction of SARS-CoV-2 T cell immunity.

T cell immunity is central for the control of viral infections. CoVac-1 is a peptide-based vaccine candidate, composed of SARS-CoV-2 T cell epitopes derived from various viral proteins1,2, combined with the Toll-like receptor 1/2 agonist XS15 emulsified in Montanide ISA51 VG, aiming to induce profound SARS-CoV-2 T cell immunity to combat COVID-19. Here we conducted a phase I open-label trial, recruiting 36 participants aged 18-80 years, who received a single subcutaneous CoVac-1 vaccination. The primary end point was safety analysed until day 56. Immunogenicity in terms of CoVac-1-induced T cell response was analysed as the main secondary end point until day 28 and in the follow-up until month 3. No serious adverse events and no grade 4 adverse events were observed. Expected local granuloma formation was observed in all study participants, whereas systemic reactogenicity was absent or mild. SARS-CoV-2-specific T cell responses targeting multiple vaccine peptides were induced in all study participants, mediated by multifunctional T helper 1 CD4+ and CD8+ T cells. CoVac-1-induced IFNγ T cell responses persisted in the follow-up analyses and surpassed those detected after SARS-CoV-2 infection as well as after vaccination with approved vaccines. Furthermore, vaccine-induced T cell responses were unaffected by current SARS-CoV-2 variants of concern. Together, CoVac-1 showed a favourable safety profile and induced broad, potent and variant of concern-independent T cell responses, supporting the presently ongoing evaluation in a phase II trial for patients with B cell or antibody deficiency.

Optimal Generators for Quantum Sensing.

We propose a computationally efficient method to derive the unitary evolution that a quantum state is most sensitive to. This allows one to determine the optimal use of an entangled state for quantum sensing, even in complex systems where intuition from canonical squeezing examples breaks down. In this paper we show that the maximal obtainable sensitivity using a given quantum state is determined by the largest eigenvalue of the quantum Fisher information matrix (QFIM) and the corresponding evolution is uniquely determined by the coinciding eigenvector. Since we optimize the process of parameter encoding rather than focusing on state preparation protocols, our scheme is relevant for any quantum sensor. This procedure naturally optimizes multiparameter estimation by determining, through the eigenvectors of the QFIM, the maximal set of commuting observables with optimal sensitivity.

Lindblad Master Equations for Quantum Systems Coupled to Dissipative Bosonic Modes.

We present a general approach to derive Lindblad master equations for a subsystem whose dynamics is coupled to dissipative bosonic modes. The derivation relies on a Schrieffer-Wolff transformation which allows us to eliminate the bosonic degrees of freedom after self-consistently determining their state as a function of the coupled quantum system. We apply this formalism to the dissipative Dicke model and derive a Lindblad master equation for the atomic spins, which includes the coherent and dissipative interactions mediated by the bosonic mode. This master equation accurately predicts the Dicke phase transition and gives the correct steady state. In addition, we compare the dynamics using exact diagonalization and numerical integration of the master equation with the predictions of semiclassical trajectories. We finally test the performance of our formalism by studying the relaxation of a NOON state and show that the dynamics captures quantum metastability.

Quantum Critical Behavior of Entanglement in Lattice Bosons with Cavity-Mediated Long-Range Interactions.

We analyze the ground-state entanglement entropy of the extended Bose-Hubbard model with infinite-range interactions. This model describes the low-energy dynamics of ultracold bosons tightly bound to an optical lattice and dispersively coupled to a cavity mode. The competition between on-site repulsion and global cavity-induced interactions leads to a rich phase diagram, which exhibits superfluid, supersolid, and insulating (Mott and checkerboard) phases. We use a slave-boson treatment of harmonic quantum fluctuations around the mean-field solution and calculate the entanglement entropy across the phase transitions. At commensurate filling, the insulator-superfluid transition is signaled by a singularity in the area-law scaling coefficient of the entanglement entropy, which is similar to the one reported for the standard Bose-Hubbard model. Remarkably, at the continuous Z_{2} superfluid-to-supersolid transition we find a critical logarithmic term, regardless of the filling. This behavior originates from the appearance of a roton mode in the excitation and entanglement spectrum, becoming gapless at the critical point, and it is characteristic of collective models.

Subradiant-to-Subradiant Phase Transition in the Bad Cavity Laser.

We show that the onset of steady-state superradiance in a bad cavity laser is preceded by a dissipative phase transition between two distinct phases of steady-state subradiance. The transition is marked by a nonanalytic behavior of the cavity output power and the mean atomic inversion, as well as a discontinuity in the variance of the collective atomic inversion. In particular, for repump rates below a critical value, the cavity output power is strongly suppressed and does not increase with the atom number, while it scales linearly with atom number above this value. Remarkably, we find that the atoms are in a macroscopically entangled steady state near the critical region with a vanishing fraction of unentangled atoms in the large atom number limit.

Rugged mHz-Linewidth Superradiant Laser Driven by a Hot Atomic Beam.

We propose a new type of superradiant laser based on a hot atomic beam traversing an optical cavity. We show that the theoretical minimum linewidth and maximum power are competitive with the best ultracoherent clock lasers. Also, our system operates naturally in continuous wave mode, which has been elusive for superradiant lasers so far. Unlike existing ultracoherent lasers, our design is simple and rugged. This makes it a candidate for the first widely accessible ultracoherent laser, as well as the first to realize sought-after applications of ultracoherent lasers in challenging environments.

Dynamical Phase Transitions to Optomechanical Superradiance.

We theoretically analyze superradiant emission of light from an ultracold gas of bosonic atoms confined in a bad cavity. A metastable dipolar transition of the atoms couples to the cavity field and is incoherently pumped, and the mechanical effects of cavity-atom interactions tend to order the atoms in the periodic cavity potential. By means of a mean-field model we determine the conditions on the cavity parameters and pump rate that lead to the buildup of a stable macroscopic dipole emitting coherent light. We show that this occurs when the superradiant decay rate and the pump rate exceed threshold values of the order of the photon recoil energy. Above these thresholds superradiant emission is accompanied by the formation of stable matter-wave gratings that diffract the emitted photons. Outside of this regime, instead, the optomechanical coupling can give rise to dephasing or chaos, for which the emitted light is respectively incoherent or chaotic. These behaviors exhibit the features of a dynamical phase transitions and emerge from the interplay between global optomechanical interactions, quantum fluctuations, and noise.

Dissipation-Assisted Prethermalization in Long-Range Interacting Atomic Ensembles.

We theoretically characterize the semiclassical dynamics of an ensemble of atoms after a sudden quench across a driven-dissipative second-order phase transition. The atoms are driven by a laser and interact via conservative and dissipative long-range forces mediated by the photons of a single-mode cavity. These forces can cool the motion and, above a threshold value of the laser intensity, induce spatial ordering. We show that the relaxation dynamics following the quench exhibits a long prethermalizing behavior which is first dominated by coherent long-range forces and then by their interplay with dissipation. Remarkably, dissipation-assisted prethermalization is orders of magnitude longer than prethermalization due to the coherent dynamics. We show that it is associated with the creation of momentum-position correlations, which remain nonzero for even longer times than mean-field predicts. This implies that cavity cooling of an atomic ensemble into the self-organized phase can require longer time scales than the typical experimental duration. In general, these results demonstrate that noise and dissipation can substantially slow down the onset of thermalization in long-range interacting many-body systems.

Supercooling of Atoms in an Optical Resonator.

We investigate laser cooling of an ensemble of atoms in an optical cavity. We demonstrate that when atomic dipoles are synchronized in the regime of steady-state superradiance, the motion of the atoms may be subject to a giant frictional force leading to potentially very low temperatures. The ultimate temperature limits are determined by a modified atomic linewidth, which can be orders of magnitude smaller than the cavity linewidth. The cooling rate is enhanced by the superradiant emission into the cavity mode allowing reasonable cooling rates even for dipolar transitions with ultranarrow linewidth.

Inflammatory bowel disease: an impaired barrier disease.

BACKGROUND: The intestinal barrier is a delicate structure composed of a single layer of epithelial cells, the mucus, commensal bacteria, immune cells, and antibodies. Furthermore, a wealth of antimicrobial peptides (AMPs) can be found in the mucus and defend the mucosa. Different lines of investigations now point to a prominent pathophysiological role of defensins, an important family of AMPs, in the pathogenesis of inflammatory bowel disease and, particularly, in small intestinal Crohn's disease. PURPOSE: In this review, we introduce the different antimicrobial peptides of the intestinal mucosa and describe their function, their expression pattern along the gastrointestinal tract, and their spatial relationship to the mucus layer. We then focus on the alterations found in inflammatory bowel disease. Small intestinal Crohn's disease (CD) is closely linked to defects in Paneth cells (specialized secretory epithelial cells at the bottom crypts) which secrete α-defensin human defensin (HD)-5 in huge quantities in healthy individuals. Decreased expression of these antimicrobial peptides is found in ileal CD, and single nucleotide polymorphisms with the highest linkage to CD affect genes involved in Paneth cell biology and defensin secretion. Additionally, antimicrobial peptides have a role in ulcerative colitis, where the depleted mucus layer cannot fulfill its crucial function of binding defensins and other AMPs to their proper site of action. CONCLUSION: Inflammatory bowel disease arises when the mucosal barrier is compromised in its defense against challenges from the intestinal microbiota. In ileal CD, a strong association can be found between diminished expression or defective function of defensins and the advent of intestinal inflammation.

[How to manage polypharmacia?] / Praxisrelevante pharmakogenetische Diagnostik zur Verbesserung der Arzneimitteltherapie.

Pharmacogenomics (PGx) is a key component of personalized medicine to improve clinical outcome of drug therapy and/or to avoid adverse drug reactions. Major efforts are currently spent internationally to implement PGx diagnostics into clinical practice. Evidence-based recommendations for dose-adjusted treatment which are established by international expert groups covering clinical and pharmacological expertise are publicly available. Clinical relevant examples for PGx diagnostics such as genetic testing for dihydropyrimidin-dehydrogenase and thiopurin-S-methyltransferase, as well as for various cytochrome P450 enzymes are summarized to promote the clinical implementation process of PGx in Germany.

Second-generation colon capsule endoscopy for detection of colorectal polyps: Systematic review and meta-analysis of clinical trials.

Background and study aims Adherence to colorectal cancer (CRC) screening is still unsatisfactory in many countries, thereby limiting prevention of CRC. Colon capsule endoscopy (CCE), a minimally invasive procedure, could be an alternative to fecal immunochemical tests or optical colonoscopy for CRC screening, and might increase adherence in CRC screening. This systematic review and meta-analysis evaluates the diagnostic accuracy of CCE compared to optical colonoscopy (OC) as the gold standard, adequacy of bowel preparation regimes and the patient perspective on diagnostic measures. Methods We conducted a systematic literature search in PubMed, EMBASE and the Cochrane Register for Clinical Trials. Pooled estimates for sensitivity, specificity and the diagnostic odds ratio with their respective 95 % confidence intervals (CI) were calculated for studies providing sufficient data. Results Of 840 initially identified studies, 13 were included in the systematic review and up to 9 in the meta-analysis. The pooled sensitivities and specificities for polyps ≥ 6 mm were 87 % (95 % CI: 83 %-90 %) and 87 % (95 % CI: 76 %-93 %) in 8 studies, respectively. For polyps ≥ 10 mm, the pooled estimates for sensitivities and specificities were 87 % (95 % CI: 83 %-90 %) and 95 % (95 % CI: 92 %-97 %) in 9 studies, respectively. A patients' perspective was assessed in 31 % (n = 4) of studies, and no preference of CCE over OC was reported. Bowel preparation was adequate in 61 % to 92 % of CCE exams. Conclusions CCE provides high diagnostic accuracy in an adequately cleaned large bowel. Conclusive findings on patient perspectives require further studies to increase acceptance/adherence of CCE for CRC screening.

Saturation mutagenesis reveals the importance of residues alphaR145 and alphaF146 of penicillin acylase in the synthesis of beta-lactam antibiotics.

Penicillin acylase (PA) from Escherichia coli can catalyze the coupling of an acyl group to penicillin- and cephalosporin-derived beta-lactam nuclei, a conversion that can be used for the industrial synthesis of beta-lactam antibiotics. The modest synthetic properties of the wild-type enzyme make it desirable to engineer improved mutants. Analysis of the crystal structure of PA has shown that residues alphaR145 and alphaF146 undergo extensive repositioning upon binding of large ligands to the active site, suggesting that these residues may be good targets for mutagenesis aimed at improving the catalytic performance of PA. Therefore, site-saturation mutagenesis was performed on both positions and a complete set of all 38 variants was subjected to rapid HPLC screening for improved ampicillin synthesis. Not less than 33 mutants showed improved synthesis, indicating the importance of the mutated residues in PA-catalyzed acyl transfer kinetics. In several mutants at low substrate concentrations, the maximum level of ampicillin production was increased up to 1.5-fold, and the ratio of the synthetic rate over the hydrolytic rate was increased 5-15-fold. Moreover, due to increased tendency of the acyl-enzyme intermediate to react with beta-lactam nucleophile instead of water, mutants alphaR145G, alphaR145S and alphaR145L demonstrated an enhanced synthetic yield over wild-type PA at high substrate concentrations. This was accompanied by an increased conversion of 6-APA to ampicillin as well as a decreased undesirable hydrolysis of the acyl donor. Therefore, these mutants are interesting candidates for the enzymatic production of semi-synthetic beta-lactam antibiotics.

Antimicrobial peptides in gastrointestinal inflammation.

Acute and chronic inflammations of mucosal surfaces are complex events in which the effector mechanisms of innate and adaptive immune systems interact with pathogenic and commensal bacteria. The role of constitutive and inducible antimicrobial peptides in intestinal inflammation has been investigated thoroughly over the recent years, and their involvement in various disease states is expanded ever more. Especially in the intestines, a critical balance between luminal bacteria and the antimicrobial peptides is essential, and a breakdown in barrier function by impaired production of defensins is already implicated in Crohn's disease. In this paper, we focus on the role of antimicrobial peptides in inflammatory processes along the gastrointestinal tract, while considering the resident and pathogenic flora encountered at the specific sites. The role of antimicrobial peptides in the primary events of inflammatory bowel diseases receives special attention.