Light-field control of real and virtual charge carriers.

Light-driven electronic excitation is a cornerstone for energy and information transfer. In the interaction of intense and ultrafast light fields with solids, electrons may be excited irreversibly, or transiently during illumination only. As the transient electron population cannot be observed after the light pulse is gone, it is referred to as virtual, whereas the population that remains excited is called real1-4. Virtual charge carriers have recently been associated with high-harmonic generation and transient absorption5-8, but photocurrent generation may stem from real as well as virtual charge carriers9-14. However, a link between the generation of the carrier types and their importance for observables of technological relevance is missing. Here we show that real and virtual charge carriers can be excited and disentangled in the optical generation of currents in a gold-graphene-gold heterostructure using few-cycle laser pulses. Depending on the waveform used for photoexcitation, real carriers receive net momentum and propagate to the gold electrodes, whereas virtual carriers generate a polarization response read out at the gold-graphene interfaces. On the basis of these insights, we further demonstrate a proof of concept of a logic gate for future lightwave electronics. Our results offer a direct means to monitor and excite real and virtual charge carriers. Individual control over each type of carrier will markedly increase the integrated-circuit design space and bring petahertz signal processing closer to reality15,16.

Process Development of a Macrocyclic Peptide Inhibitor of PD-L1.

This article outlines the process development leading to the manufacture of 800 g of BMS-986189, a macrocyclic peptide active pharmaceutical ingredient. Multiple N-methylated unnatural amino acids posed challenges to manufacturing due to the lability of the peptide to cleavage during global side chain deprotection and precipitation steps. These issues were exacerbated upon scale-up, resulting in severe yield loss and necessitating careful impurity identification, understanding the root cause of impurity formation, and process optimization to deliver a scalable synthesis. A systematic study of macrocyclization with its dependence on concentration and pH is presented. In addition, a side chain protected peptide synthesis is discussed where the macrocyclic protected peptide is extremely labile to hydrolysis. A computational study explains the root cause of the increased lability of macrocyclic peptide over linear peptide to hydrolysis. A process solution involving the use of labile protecting groups is discussed. Overall, the article highlights the advancements achieved to enable scalable synthesis of an unusually labile macrocyclic peptide by solid-phase peptide synthesis. The sustainability metric indicates the final preparative chromatography drives a significant fraction of a high process mass intensity (PMI).

Mitral bioprosthesis early dysfunction treated with transapical valvuloplasty during V-A ECMO.

We report the case of a 61-year-old male who had complications with a mitral valve (MV) bioprosthesis replacement by post-cardiotomy shock leading to VA ECMO implantation. The patient suffered early bioprosthetic valve failure owing to early thrombosis. The complication was successfully treated with a MV bioprosthesis transapical balloon valvuloplasty that restored normal leaflet mobility.

Triheptanoin for the treatment of long-chain fatty acid oxidation disorders: Final results of an open-label, long-term extension study.

Long-chain fatty acid oxidation disorders (LC-FAODs) result in life-threatening energy metabolism deficiencies/energy source depletion. Triheptanoin is an odd-carbon, medium chain triglyceride (that is an anaplerotic substrate of calories and fatty acids) for treating pediatric and adult patients with LC-FAODs. Study CL202 (NCT02214160), an open-label extension study of study CL201 (NCT01886378), evaluated the long-term safety/efficacy of triheptanoin in patients with LC-FAODs (N = 94), including cohorts who were triheptanoin naïve (n = 33) or had received triheptanoin in study CL201 (n = 24) or in investigator-sponsored trials/expanded access programs (IST/EAPs; n = 37). Primary endpoint was the annualized rate of LC-FAOD major clinical events (MCEs; rhabdomyolysis, hypoglycemia, cardiomyopathy). Mean ± standard deviation (SD) triheptanoin treatment durations were 27.4 ± 19.9, 46.9 ± 13.6, and 49.6 ± 21.4 months for the triheptanoin-naïve, CL201 rollover, and IST/EAP cohorts, respectively. In the triheptanoin-naïve cohort, median (interquartile range [IQR]) MCE rate significantly decreased from 2.00 (0.67-3.33) events/patient/year pre-triheptanoin to 0.28 (0.00-1.43) events/patient/year with triheptanoin (p = 0.0343), a reduction of 86%. In the CL201 rollover cohort, mean ± SD MCE rate significantly decreased from 1.76 ± 1.64 events/patient/year pre-triheptanoin to 1.00 ± 1.00 events/patient/year with triheptanoin (p = 0.0347), a reduction of 43%. In the IST/EAP cohort, mean ± SD MCE rate was 1.40 ± 2.37 (median [IQR] 0.57 [0.00-1.67]) events/patient/year with triheptanoin. Safety data were consistent with previous observations. Treatment-related treatment-emergent adverse events (TEAEs) occurred in 68.1% of patients and were mostly mild/moderate in severity. Five patients had seven serious treatment-related TEAEs; all resolved. Our results confirm the long-term efficacy of triheptanoin for patients with LC-FAOD.

Heart transplant in a Sars-CoV-2 positive recipient: Management protocol of the world's first case.

The advent of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in China at the end of 2019 has developed into a global outbreak, and COVID- 19 is an ongoing major public health issue. During the pandemic, transplant programs had to devise strategies to deal with the possibility of COVID-19-positive donors and recipients. We describe the case of a heart transplant recipient who tested positive with the SARS- CoV2 swab upon admission to our Unit of Cardiac Surgery when a suitable donor became available. Given his clinical status of end-stage heart failure and the absence of imaging and clinical signs suggestive of COVID-19, and his having been vaccinated with three doses, we decided to proceed with the transplant.

Development of a Crystallization-Induced Diastereomer Transformation of Oxime Isomers for the Asymmetric Synthesis of (1S,6R)-3,9-Diazabicyclo[4.2.1]nonane.

Herein we report a practical crystallization-induced diastereomer transformation (CIDT) of oxime isomers for the scalable asymmetric synthesis of the bicyclic diamine (1S,6R)-3,9-diazabicyclo[4.2.1]nonane derivative that serves as a valuable building block in medicinal chemistry. The developed approach utilizes (S)-phenylethylamine as a chiral auxiliary handle for CIDT, and the starting nortropinone derivative is prepared in one step from commercially available materials. The resulting E-oxime is subjected to a stereospecific Beckmann rearrangement, followed by reduction of the resulting lactam with LiAlH4 to afford the monoprotected (1S,6R)-3,9-diazabicyclo[4.2.1]nonane derivative. The development of the CIDT and understanding of the mechanistic implications leading to the high selectivity are reported.

Stark control of electrons across the molecule-semiconductor interface.

Controlling matter at the level of electrons using ultrafast laser sources represents an important challenge for science and technology. Recently, we introduced a general laser control scheme (the Stark control of electrons at interfaces or SCELI) based on the Stark effect that uses the subcycle structure of light to manipulate electron dynamics at semiconductor interfaces [A. Garzón-Ramírez and I. Franco, Phys. Rev. B 98, 121305 (2018)]. Here, we demonstrate that SCELI is also of general applicability in molecule-semiconductor interfaces. We do so by following the quantum dynamics induced by non-resonant few-cycle laser pulses of intermediate intensity (non-perturbative but non-ionizing) across model molecule-semiconductor interfaces of varying level alignments. We show that SCELI induces interfacial charge transfer regardless of the energy level alignment of the interface and even in situations where charge exchange is forbidden via resonant photoexcitation. We further show that the SCELI rate of charge transfer is faster than those offered by resonant photoexcitation routes as it is controlled by the subcycle structure of light. The results underscore the general applicability of SCELI to manipulate electron dynamics at interfaces on ultrafast timescales.

Co-Fermentation of Agri-Food Residues Using a Co-Culture of Yeasts as a New Bioprocess to Produce 2-Phenylethanol.

Whey is a dairy residue generated during the production of cheese and yogurt. Whey contains mainly lactose and proteins, contributing to its high chemical oxygen demand (COD). Current environmental regulations request proper whey disposal to avoid environmental pollution. Whey components can be transformed by yeast into ethanol and biomolecules with aroma and flavor properties, for example, 2-phenyethanol (2PE), highly appreciated in the industry due to its organoleptic and biocidal properties. The present study aimed to valorize agri-food residues in 2PE by developing suitable bioprocess. Cheese whey was used as substrate source, whereas crab headshells, residual soy cake, and brewer's spent yeast (BSY) were used as renewable nitrogen sources for the yeasts Kluyveromyces marxianus and Debaryomyces hansenii. The BSYs promoted the growth of both yeasts and the production of 2PE in flask fermentation. The bioprocess scale-up to 2 L bioreactor allowed for obtaining a 2PE productivity of 0.04 g2PE/L·h, twofold better productivity results compared to the literature. The bioprocess can save a treatment unit because the whey COD decreased under the detection limit of the analytical method, which is lower than environmental requirements. In this way, the bioprocess prevents environmental contamination and contributes to the circular economy of the dairy industry.

Response to triheptanoin therapy in critically ill patients with LC-FAOD: Report of patients treated through an expanded access program.

Long-chain fatty acid oxidation disorders (LC-FAOD) are a group of inborn errors of metabolism wherein patients are unable to process long-chain fatty acids into useable energy in the mitochondria. LC-FAOD commonly affects organ systems with high energy demand, manifesting as hypoketotic hypoglycemia, liver dysfunction, cardiomyopathy, rhabdomyolysis, and skeletal myopathy, as well as peripheral neuropathy and retinopathy in some subtypes. Collectively, LC-FAOD have a high mortality rate, especially in cases of early onset disease, and in the presence of cardiomyopathy. Triheptanoin is a synthetic medium-odd chain triglyceride, produced using a GMP-compliant process, which was designed to replenish mitochondrial metabolic deficits and restore energy homeostasis. Prior to its approval, triheptanoin was only available through clinical trials or to seriously ill patients as part of an expanded access program (EAP) following physician request. This retrospective study examined the impact of triheptanoin on cardiovascular parameters, in critically ill patients who participated in the EAP from February 2013 to January 2018. These patients persisted in critical condition despite receiving standard treatment in highly qualified centers by expert metabolic physicians and dietitians. Physician-completed questionnaires and narrative summaries were used to evaluate the disease presentation and management prior to the trigger event leading to triheptanoin request and use, and the response to triheptanoin treatment. Following triheptanoin initiation, most patients survived the initial trigger event (e.g., severe urinary tract infection, pneumonia) and demonstrated improvements in both short-term and long-term LC-FAOD manifestations. In patients with cardiomyopathy, stabilization or improvement from pretreatment levels was reported in left ventricular ejection fraction and left ventricular mass, in particular, all infants with cardiomyopathy showed improvement in cardiac function during triheptanoin therapy. Triheptanoin therapy was generally well tolerated. The study results are consistent with the existing positive benefit/risk profile of triheptanoin and reflect the effect of triheptanoin improving cardiac function in patients experiencing severe episodes of metabolic decompensation despite standard therapy.

Quadricuspid aortic valve repair with a modified-tricuspidization technique.

INTRODUCTION: Quadricuspid aortic valve (QAV) is an extremely rare developmental abnormality with an incidence of 0.006%. QAV is an incidental finding that in some patients (23%) may determine aortic regurgitation (AR). Altogether 16% of patients indeed require surgery with AR being the most frequent indication. METHODS AND RESULTS: We describe a case report of a 46 year-old female affected by severe aortic regurgitation due to QAV successfully treated with a  modified-tricuspidization technique associated with cusp extension, prolapsing commissure suturing, and sub-commissural annuloplasty. DISCUSSION: QAV repair represents an attractive perspective to overcome the drawbacks of either mechanical or biological prosthesis.

Primary malignant cardiac tumors: Sex-related therapy and multidisciplinary approach as a new challenge for the future.

Primary malignant cardiac tumors represent (PMCTs) a very rare disease with an incidence of 0.009%1 (up to 10% of primary cardiac neoplasms) and are related to a very poor prognosis. The study by Mohamed Rahouma tries to give us information on sex differences in PMCTs, their incidence, behavior, and outcomes. Females were significantly older and had a lower stage of cancer. Males are known to have a more aggressive course and present at an earlier age. Sarcoma is the most common type of PMCTs in both males and females. There was no gender disparity in late mortality and patients who underwent surgery had a better prognosis than those who did not undergo surgery. Significant predictors of late mortality were found to be patients' high comorbidity index, angiosarcoma histology, and Stage III/IV. A challenge for cardiac surgeons is to improve survival in patients with cardiac malignancies, involving a multidisciplinary approach with oncologists, cardiologists, and radiologists. To pave the way for a significant improvement in survival in the future, more advanced sex-specific medical therapies for cancer such as novel chemotherapy agents, targeted immune therapies, genetic engineering need to be standardized to PMCTs and combined with radiological therapies such as gamma-knife and very advanced surgery to effectively treat even very aggressive forms of malignant tumors, with a significant impact on the patient's quality of life and survival.

The best is the enemy of the good, a simple technique to treat a complex disease: Calamari procedure.

Infective endocarditis is a life-threatening condition and despite advances in antibiotic therapy, about one-third of patients require surgical treatment. The choice of the most appropriate surgical treatment is crucial. The study by Asen Petrov et al. paves the way for a new, safe, simple, and useful Calamari technique for the treatment of aortic valve endocarditis complicated by aortic root abscess (ARA). This technique was initially described in a series of five patients. The most interesting part of the study is that the procedure was effective (only one patient died 30 days after surgery) and fast (mean cardiopulmonary bypass time 90 ± 10.30 min; mean cross-clamp time 73.6 ± 12.12 min). As reported by Leontyev et al., the procedure of choice in ARA is represented by a wide range of procedures ranging from aortic valve replacement with debridement of the abscess to reconstruction of the intervalvular fibrous body and replacement of both the mitral valve and the aortic root. Alternatively, pericardial patch reconstruction is required in approximately one-third of cases. Radicality is key but a fast procedure is very important. In this scenario, the Calamari procedure is very useful, especially for its rapid execution (short cardiopulmonary bypass and cross-clamp time) which is associated with a reduction in mortality. A simple procedure to treat complex diseases. However, this procedure needs to be performed on more patients and its outcomes should be compared in trials with the other available techniques for the treatment of ARA.

Epidemiological and Clinical Characteristics of Hospitalized Pediatric Patients with SARS-CoV-2 Infection in Mexico City, Mexico.

Background: Evidence from across the world suggests that the pediatric population shows different clinical manifestations and has a lower risk of severe presentation of SARS-CoV-2 infection compared to adults. However, Mexico has one of the highest mortality rates in the pediatric population due to SARS-CoV-2 infection. Therefore, our objective was to explore the epidemiological and clinical characteristics associated with a positive confirmatory test in the Mexican pediatric population admitted to a tertiary care hospital in Mexico City. Methods: Clinical, imaging and laboratory data were retrospectively collected from 121 children hospitalized during the period from March 4th, 2020, to August 8th, 2021. The patients were identified as suspicious cases according to the guidelines of the General Directorate of Epidemiology of Mexico. Real-time polymerase chain reaction (RT-PCR) tests were used to confirm SARS-CoV-2 infection. Categorical variables were compared using the Chi-square test, and propensity score matching was performed to determine univariate and multivariate odds ratios of the population regarding a positive vs. negative SARS-CoV-2 result. Results: Of the 121 children, 36 had laboratory-confirmed SARS-CoV-2 infection. The main risk for SARS-CoV-2-associated pediatric hospitalization was contact with a family member with SARS-CoV-2. It was also found that fever and fatigue were statistically significantly associated with a positive SARS-CoV-2 test in multivariate models. Clinical and laboratory data in this Mexican hospitalized pediatric cohort differ from other reports worldwide; the mortality rate (1.6%) of the population studied was higher than that seen in reports from other countries. Conclusion: Our study found that fever and fatigue at hospital presentation as well as an antecedent exposure to a family member with SARS-CoV-2 infection were important risk factors for SARS-CoV-2 positivity in children at hospital admission.

Photocatalytic Dearomative Intermolecular [2 + 2] Cycloaddition of Heterocycles for Building Molecular Complexity.

Indole and indoline rings are important pharmacophoric scaffolds found in marketed drugs, agrochemicals, and biologically active molecules. The [2 + 2] cycloaddition reaction is a versatile strategy for constructing architecturally interesting, sp3-rich cyclobutane-fused scaffolds with potential applications in drug discovery programs. A general platform for visible-light mediated intermolecular [2 + 2] cycloaddition of indoles with alkenes has been realized. A substrate-based screening approach led to the discovery of tert-butyloxycarbonyl (Boc)-protected indole-2-carboxyesters as suitable motifs for the intermolecular [2 + 2] cycloaddition reaction. Significantly, the reaction proceeds in good yield with a wide variety of both activated and unactivated alkenes, including those containing free amines and alcohols, and the transformation exhibits excellent regio- and diastereoselectivity. Moreover, the scope of the indole substrate is very broad, extending to previously unexplored azaindole heterocycles that collectively afford fused cyclobutane containing scaffolds that offer unique properties with functional handles and vectors suitable for further derivatization. DFT computational studies provide insights into the mechanism of this [2 + 2] cycloaddition, which is initiated by a triplet-triplet energy transfer process. The photocatalytic reaction was successfully performed on a 100 g scale to provide the dihydroindole analog.

Feature Selection and Validation of a Machine Learning-Based Lower Limb Risk Assessment Tool: A Feasibility Study.

Early and self-identification of locomotive degradation facilitates us with awareness and motivation to prevent further deterioration. We propose the usage of nine squat and four one-leg standing exercise features as input parameters to Machine Learning (ML) classifiers in order to perform lower limb skill assessment. The significance of this approach is that it does not demand manpower and infrastructure, unlike traditional methods. We base the output layer of the classifiers on the Short Test Battery Locomotive Syndrome (STBLS) test used to detect Locomotive Syndrome (LS) approved by the Japanese Orthopedic Association (JOA). We obtained three assessment scores by using this test, namely sit-stand, 2-stride, and Geriatric Locomotive Function Scale (GLFS-25). We tested two ML methods, namely an Artificial Neural Network (ANN) comprised of two hidden layers with six nodes per layer configured with Rectified-Linear-Unit (ReLU) activation function and a Random Forest (RF) regressor with number of estimators varied from 5 to 100. We could predict the stand-up and 2-stride scores of the STBLS test with correlation of 0.59 and 0.76 between the real and predicted data, respectively, by using the ANN. The best accuracies (R-squared values) obtained through the RF regressor were 0.86, 0.79, and 0.73 for stand-up, 2-stride, and GLFS-25 scores, respectively.

An Improved PIII/PV═O-Catalyzed Reductive C-N Coupling of Nitroaromatics and Boronic Acids by Mechanistic Differentiation of Rate- and Product-Determining Steps.

Experimental, spectroscopic, and computational studies are reported that provide an evidence-based mechanistic description of an intermolecular reductive C-N coupling of nitroarenes and arylboronic acids catalyzed by a redox-active main-group catalyst (1,2,2,3,4,4-hexamethylphosphetane P-oxide, i.e., 1·[O]). The central observations include the following: (1) catalytic reduction of 1·[O] to PIII phosphetane 1 is kinetically fast under conditions of catalysis; (2) phosphetane 1 represents the catalytic resting state as observed by 31P NMR spectroscopy; (3) there are no long-lived nitroarene partial-reduction intermediates observable by 15N NMR spectroscopy; (4) the reaction is sensitive to solvent dielectric, performing best in moderately polar solvents (viz. cyclopentylmethyl ether); and (5) the reaction is largely insensitive with respect to common hydrosilane reductants. On the basis of the foregoing studies, new modified catalytic conditions are described that expand the reaction scope and provide for mild temperatures (T ≥ 60 °C), low catalyst loadings (≥2 mol%), and innocuous terminal reductants (polymethylhydrosiloxane). DFT calculations define a two-stage deoxygenation sequence for the reductive C-N coupling. The initial deoxygenation involves a rate-determining step that consists of a (3+1) cheletropic addition between the nitroarene substrate and phosphetane 1; energy decomposition techniques highlight the biphilic character of the phosphetane in this step. Although kinetically invisible, the second deoxygenation stage is implicated as the critical C-N product-forming event, in which a postulated oxazaphosphirane intermediate is diverted from arylnitrene dissociation toward heterolytic ring opening with the arylboronic acid; the resulting dipolar intermediate evolves by antiperiplanar 1,2-migration of the organoboron residue to nitrogen, resulting in displacement of 1·[O] and formation of the target C-N coupling product upon in situ hydrolysis. The method thus described constitutes a mechanistically well-defined and operationally robust main-group complement to the current workhorse transition-metal-based methods for catalytic intermolecular C-N coupling.

Serine-Selective Bioconjugation.

This Communication reports the first general method for rapid, chemoselective, and modular functionalization of serine residues in native polypeptides, which uses a reagent platform based on the P(V) oxidation state. This redox-economical approach can be used to append nearly any kind of cargo onto serine, generating a stable, benign, and hydrophilic phosphorothioate linkage. The method tolerates all other known nucleophilic functional groups of naturally occurring proteinogenic amino acids. A variety of applications can be envisaged by this expansion of the toolbox of site-selective bioconjugation methods.

Synthesis of Cyclobutane-Fused Tetracyclic Scaffolds via Visible-Light Photocatalysis for Building Molecular Complexity.

We describe the synthesis through visible-light photocatalysis of novel functionalized tetracyclic scaffolds that incorporate a fused azabicyclo[3.2.0]heptan-2-one motif, which are structurally interesting cores with potential in natural product synthesis and drug discovery. The synthetic approach involves an intramolecular [2 + 2] cycloaddition with concomitant dearomatization of the heterocycle via an energy transfer process promoted by an iridium-based photosensitizer, to build a complex molecular architecture with at least three stereogenic centers from relatively simple, achiral precursors. These fused azabicyclo[3.2.0]heptan-2-one-based tetracycles were obtained in high yield (generally >99%) and with excellent diastereoselectivity (>99:1). The late-stage derivatization of a bromine-substituted, tetracyclic indoline derivative with alkyl groups, employing a mild Negishi C-C bond forming protocol as a means of increasing structural diversity, provides additional modularity that will enable the delivery of valuable building blocks for medicinal chemistry. Density functional theory calculations were used to compute the T1-S0 free energy gap of the olefin-tethered precursors and also to predict their reactivities based on triplet state energy transfer and transition state energy feasibility.

Yeast-driven whey biorefining to produce value-added aroma, flavor, and antioxidant compounds: technologies, challenges, and alternatives.

Whey is a liquid residue generated during the production of cheese and yogurt. It has a pH between 3.9 and 5.6, and a high chemical oxygen demand (COD), from 60 to 80 g/L. Whey contains lactose, proteins, and minerals. Globally, approximately 50% of the whey generated is untreated and is released directly into the environment, which represents an environmental risk. To overcome whey management problems, conventional thermo-physical valorization treatments have been explored, which are complex, costly and energy-intensive. As an alternative, whey fermentation processes employing bacteria, fungi and yeast are economical and promising methods. Among them, yeast fermentation creates value-added products such as antimicrobials, biofuels, aromas, flavors, and antioxidants with no need for previous conditioning of the whey, such as hydrolysis of the lactose, prior to whey biorefining. The biorefining concept applied to whey is discussed using chemical and biological transformation pathways, showing their pluses and minuses, such as technical drawbacks. The main challenges and solutions for the production of fusel alcohols, specifically for 2-phenylethanol, are also discussed in this review.

Synthesis of functionalized derivatives of the gamma-secretase modulator BMS-932481 and identification of its major metabolite.

In an effort to improve physical properties by introducing polar functionality into the bicyclic pyrimidine gamma-secretase modulator (GSM) clinical candidate BMS-932481, we prepared several oxidative products of BMS-932481. Among the analogs that were prepared, the C-5 alcohol 3 was identified as the predominant metabolite of BMS-932481 found in rat and human liver microsomes. Alcohol 3 was determined to be chemically unstable, leading to the hypothesis that 3 may lead to the production of reactive species both in vitro and in vivo.