Precise Photoexcitation Measurement of Tan's Contact in the Entire BCS-BEC Crossover.

We study two-body correlations in a spin-balanced ultracold harmonically trapped Fermi gas of ^{6}Li atoms in the crossover from the Bardeen-Cooper-Schrieffer (BCS) to the Bose-Einstein-Condensate (BEC) regime. For this, we precisely measure Tan's contact using a novel method based on photoexcitation of atomic pairs, which was recently proposed by Wang et al. [Photoexcitation measurement of Tan's contact for a strongly interacting Fermi gas, Phys. Rev. A 104, 063309 (2021).PLRAAN2469-992610.1103/PhysRevA.104.063309]. We map out the contact in the entire phase diagram of the BCS-BEC crossover for various temperatures and interaction strengths, probing regions in phase space that have not been investigated yet. Our measurements reach an uncertainty of ≈2% at the lowest temperatures and thus represent a precise quantitative benchmark. By comparison to our data, we localize the regions in phase space where theoretical predictions and interpolations give valid results. In regions where the contact is already well known we find excellent agreement with our measurements. Thus, our results demonstrate that photoinduced loss is a precise probe to measure quantum correlations in a strongly interacting Fermi gas.

Identification of inhibitors targeting the energy-coupling factor (ECF) transporters.

The energy-coupling factor (ECF) transporters are a family of transmembrane proteins involved in the uptake of vitamins in a wide range of bacteria. Inhibition of the activity of these proteins could reduce the viability of pathogens that depend on vitamin uptake. The central role of vitamin transport in the metabolism of bacteria and absence from humans make the ECF transporters an attractive target for inhibition with selective chemical probes. Here, we report on the identification of a promising class of inhibitors of the ECF transporters. We used coarse-grained molecular dynamics simulations on Lactobacillus delbrueckii ECF-FolT2 and ECF-PanT to profile the binding mode and mechanism of inhibition of this novel chemotype. The results corroborate the postulated mechanism of transport and pave the way for further drug-discovery efforts.

Treatment of aseptic facial granuloma as a manifestation of pediatric rosacea with oral macrolides.

Aseptic facial granuloma is a rare pediatric disease, presenting with asymptomatic facial nodules on the cheeks or the eyelids and may represent a form of granulomatous rosacea in children. In this retrospective case series, 12 children with aseptic facial granuloma were treated with oral macrolides (erythromycin or roxithromycin) resulting in a healing of the lesions within a mean treatment time of 5.25 months with no recurrences. The treatment was mainly well tolerated. Oral macrolides may be effective in the treatment of patients with aseptic facial granuloma.

[Quality of life of patients with mycosis fungoides and Sézary syndrome]. / Lebensqualität von Patienten mit Mycosis fungoides und Sézary-Syndrom.

Mycosis fungoides as the most common type and Sézary syndrome as a leukemic variant belong to the rare group of cutaneous T­cell lymphomas. Both diseases are considered incurable and show a chronic course. Since there is no curative treatment, maintaining quality of life and relief of symptoms should be important elements when treating patients with mycosis fungoides and Sézary syndrome. Pruritus, which is a common and burdensome symptom of cutaneous T­cell lymphoma, may negatively impact quality of life. Pruritus and quality of life can be assessed with established measurement tools. Consistent recording enables physicians to recognize restrictions in physical and psychosocial aspects of quality of life early so that therapy can be adapted.

Late-Stage Modification of Aminoglycoside Antibiotics Overcomes Bacterial Resistance Mediated by APH(3') Kinases.

The continuous emergence of antimicrobial resistance is causing a threat to patients infected by multidrug-resistant pathogens. In particular, the clinical use of aminoglycoside antibiotics, broad-spectrum antibacterials of last resort, is limited due to rising bacterial resistance. One of the major resistance mechanisms in Gram-positive and Gram-negative bacteria is phosphorylation of these amino sugars at the 3'-position by O-phosphotransferases [APH(3')s]. Structural alteration of these antibiotics at the 3'-position would be an obvious strategy to tackle this resistance mechanism. However, the access to such derivatives requires cumbersome multi-step synthesis, which is not appealing for pharma industry in this low-return-on-investment market. To overcome this obstacle and combat bacterial resistance mediated by APH(3')s, we introduce a novel regioselective modification of aminoglycosides in the 3'-position via palladium-catalyzed oxidation. To underline the effectiveness of our method for structural modification of aminoglycosides, we have developed two novel antibiotic candidates overcoming APH(3')s-mediated resistance employing only four synthetic steps.

Second sound in the crossover from the Bose-Einstein condensate to the Bardeen-Cooper-Schrieffer superfluid.

Second sound is an entropy wave which propagates in the superfluid component of a quantum liquid. Because it is an entropy wave, it probes the thermodynamic properties of the quantum liquid. Here, we study second sound propagation for a large range of interaction strengths within the crossover between a Bose-Einstein condensate (BEC) and the Bardeen-Cooper-Schrieffer (BCS) superfluid, extending previous work at unitarity. In particular, we investigate the strongly-interacting regime where currently theoretical predictions only exist in terms of an interpolation in the crossover. Working with a quantum gas of ultracold fermionic 6Li atoms with tunable interactions, we show that the second sound speed varies only slightly in the crossover regime. By varying the excitation procedure, we gain deeper insight on sound propagation. We compare our measurement results with classical-field simulations, which help with the interpretation of our experiments.

Real-World Experience of Talimogene Laherparepvec (T-VEC) in Old and Oldest-Old Patients with Melanoma: A Retrospective Single Center Study.

PURPOSE: Rising melanoma incidences lead to an increasing need for individual therapy strategies in old patients. Talimogene laherparepvec (T-VEC) is a modified herpes simplex virus, approved for the local treatment of unresectable metastatic melanoma. Since data on the efficacy and safety of geriatric patients are sparse, this study was conducted to gain further real-world experience in the treatment of old and oldest-old patients with T-VEC and to obtain data on therapy costs in this population in Germany. PATIENTS AND METHODS: We performed a retrospective analysis, including all patients with a minimum age of 75 years who were treated with T-VEC from August 2016 to September 2020 in the Skin Cancer Center of the University Hospital Frankfurt, Germany. Patient clinicopathological data, treatment responses, toxicities, treatment-specific data and therapy costs were assessed. RESULTS: Twelve patients with a median age of 83 years (75-89 years) at the start of treatment were identified. By the end of the study, three (25%) patients experienced complete remission (CR), four (33%) experienced partial response (PR), two patients (17%) remained at stable disease (SD) and three (25%) patients suffered from progressive disease (PD). Overall response rate was 58.3%, and durable response rate was 41.7%. There were no treatment-related adverse events grade 3 or higher. The median duration of treatment was seventeen weeks (3-57 weeks). Median medication costs in the patients who had completed treatment (n=10) were calculated to be 27,325 Euros in Germany. CONCLUSION: This study provides further evidence for an effective use of T-VEC in old and oldest-old patients. The low rate of adverse events seems to be favorable compared to other systemic melanoma therapies. Furthermore, duration of treatment was short and therapy costs were lower than would have been expected from clinical trial data. Altogether, these data encourage the use of T-VEC in this special patient cohort.

C6 Ceramide (d18:1/6:0) as a Novel Treatment of Cutaneous T Cell Lymphoma.

Cutaneous T cell lymphomas (CTCLs) represent a heterogeneous group of T cell lymphomas that primarily affect the skin. The most frequent forms of CTCL are mycosis fungoides and Sézary syndrome. Both are characterized by frequent recurrence, developing chronic conditions and high mortality with a lack of a curative treatment. In this study, we evaluated the effect of short-chain, cell-permeable C6 Ceramide (C6Cer) on CTCL cell lines and keratinocytes. C6Cer significantly reduced cell viability of CTCL cell lines and induced cell death via apoptosis and necrosis. In contrast, primary human keratinocytes and HaCaT keratinocytes were less affected by C6Cer. Both keratinocyte cell lines showed higher expressions of ceramide catabolizing enzymes and HaCaT keratinocytes were able to metabolize C6Cer faster and more efficiently than CTCL cell lines, which might explain the observed protective effects. Along with other existing skin-directed therapies, C6Cer could be a novel well-tolerated drug for the topical treatment of CTCL.

Interventions for mycosis fungoides.

BACKGROUND: Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma, a malignant, chronic disease initially affecting the skin. Several therapies are available, which may induce clinical remission for a time. This is an update of a Cochrane Review first published in 2012: we wanted to assess new trials, some of which investigated new interventions. OBJECTIVES: To assess the effects of interventions for MF in all stages of the disease. SEARCH METHODS: We updated our searches of the following databases to May 2019: the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS. We searched 2 trials registries for additional references. For adverse event outcomes, we undertook separate searches in MEDLINE in April, July and November 2017. SELECTION CRITERIA: Randomised controlled trials (RCTs) of local or systemic interventions for MF in adults with any stage of the disease compared with either another local or systemic intervention or with placebo. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. The primary outcomes were improvement in health-related quality of life as defined by participants, and common adverse effects of the treatments. Key secondary outcomes were complete response (CR), defined as complete disappearance of all clinical evidence of disease, and objective response rate (ORR), defined as proportion of patients with a partial or complete response. We used GRADE to assess the certainty of evidence and considered comparisons of psoralen plus ultraviolet A (PUVA) light treatment as most important because this is first-line treatment for MF in most guidelines. MAIN RESULTS: This review includes 20 RCTs (1369 participants) covering a wide range of interventions. The following were assessed as either treatments or comparators: imiquimod, peldesine, hypericin, mechlorethamine, nitrogen mustard and intralesional injections of interferon-α (IFN-α) (topical applications); PUVA, extracorporeal photopheresis (ECP: photochemotherapy), and visible light (light applications); acitretin, bexarotene, lenalidomide, methotrexate and vorinostat (oral agents); brentuximab vedotin; denileukin diftitox; mogamulizumab; chemotherapy with cyclophosphamide, doxorubicin, etoposide, and vincristine; a combination of chemotherapy with electron beam radiation; subcutaneous injection of IFN-α; and intramuscular injections of active transfer factor (parenteral systemics). Thirteen trials used an active comparator, five were placebo-controlled, and two compared an active operator to observation only. In 14 trials, participants had MF in clinical stages IA to IIB. All participants were treated in secondary and tertiary care settings, mainly in Europe, North America or Australia. Trials recruited both men and women, with more male participants overall. Trial duration varied from four weeks to 12 months, with one longer-term study lasting more than six years. We judged 16 trials as at high risk of bias in at least one domain, most commonly performance bias (blinding of participants and investigators), attrition bias and reporting bias. None of our key comparisons measured quality of life, and the two studies that did presented no usable data. Eighteen studies reported common adverse effects of the treatments. Adverse effects ranged from mild symptoms to lethal complications depending upon the treatment type. More aggressive treatments like systemic chemotherapy generally resulted in more severe adverse effects. In the included studies, CR rates ranged from 0% to 83% (median 31%), and ORR ranged from 0% to 88% (median 47%). Five trials assessed PUVA treatment, alone or combined, summarised below. There may be little to no difference between intralesional IFN-α and PUVA compared with PUVA alone for 24 to 52 weeks in CR (risk ratio (RR) 1.07, 95% confidence interval (CI) 0.87 to 1.31; 2 trials; 122 participants; low-certainty evidence). Common adverse events and ORR were not measured. One small cross-over trial found once-monthly ECP for six months may be less effective than twice-weekly PUVA for three months, reporting CR in two of eight participants and ORR in six of eight participants after PUVA, compared with no CR or ORR after ECP (very low-certainty evidence). Some participants reported mild nausea after PUVA but no numerical data were given. One participant in the ECP group withdrew due to hypotension. However, we are unsure of the results due to very low-certainty evidence. One trial comparing bexarotene plus PUVA versus PUVA alone for up to 16 weeks reported one case of photosensitivity in the bexarotene plus PUVA group compared to none in the PUVA-alone group (87 participants; low-certainty evidence). There may be little to no difference between bexarotene plus PUVA and PUVA alone in CR (RR 1.41, 95% CI 0.71 to 2.80) and ORR (RR 0.94, 95% CI 0.61 to 1.44) (93 participants; low-certainty evidence). One trial comparing subcutaneous IFN-α injections combined with either acitretin or PUVA for up to 48 weeks or until CR indicated there may be little to no difference in the common IFN-α adverse effect of flu-like symptoms (RR 1.32, 95% CI 0.92 to 1.88; 82 participants). There may be lower CR with IFN-α and acitretin compared with IFN-α and PUVA (RR 0.54, 95% CI 0.35 to 0.84; 82 participants) (both outcomes: low-certainty evidence). This trial did not measure ORR. One trial comparing PUVA maintenance treatment to no maintenance treatment, in participants who had already had CR, did report common adverse effects. However, the distribution was not evaluable. CR and OR were not assessable. The range of treatment options meant that rare adverse effects consequently occurred in a variety of organs. AUTHORS' CONCLUSIONS: ​​There is a lack of high-certainty evidence to support decision making in the treatment of MF. Because of substantial heterogeneity in design, missing data, small sample sizes, and low methodological quality, the comparative safety and efficacy of these interventions cannot be reliably established on the basis of the included RCTs. PUVA is commonly recommended as first-line treatment for MF, and we did not find evidence to challenge this recommendation. There was an absence of evidence to support the use of intralesional IFN-α or bexarotene in people receiving PUVA and an absence of evidence to support the use of acitretin or ECP for treating MF. Future trials should compare the safety and efficacy of treatments to PUVA, as the current standard of care, and should measure quality of life and common adverse effects.

AMPK activation protects astrocytes from hypoxia­induced cell death.

Adenosine monophosphate (AMP)­activated protein kinase (AMPK) is a major cellular energy sensor that is activated by an increase in the AMP/adenosine triphosphate (ATP) ratio. This causes the initiation of adaptive cellular programs, leading to the inhibition of anabolic pathways and increasing ATP synthesis. AMPK indirectly inhibits mammalian target of rapamycin (mTOR) complex 1 (mTORC1), a serine/threonine kinase and central regulator of cell growth and metabolism, which integrates various growth inhibitory signals, such as the depletion of glucose, amino acids, ATP and oxygen. While neuroprotective approaches by definition focus on neurons, that are more sensitive under cell stress conditions, astrocytes play an important role in the cerebral energy homeostasis during ischemia. Therefore, the protection of astrocytic cells or other glial cells may contribute to the preservation of neuronal integrity and function. In the present study, it was thus hypothesized that a preventive induction of energy deprivation­activated signaling pathways via AMPK may protect astrocytes from hypoxia and glucose deprivation. Hypoxia­induced cell death was measured in a paradigm of hypoxia and partial glucose deprivation in vitro in the immortalized human astrocytic cell line SVG. Both the glycolysis inhibitor 2­deoxy­d­glucose (2DG) and the AMPK activator A­769662 induced the phosphorylation of AMPK, resulting in mTORC1 inhibition, as evidenced by a decrease in the phosphorylation of the target ribosomal protein S6 (RPS6). Treatment with both 2DG and A­769662 also decreased glucose consumption and lactate production. Furthermore, A­769662, but not 2DG induced an increase in oxygen consumption, possibly indicating a more efficient glucose utilization through oxidative phosphorylation. Hypoxia­induced cell death was profoundly reduced by treatment with 2DG or A­769662. On the whole, the findings of the present study demonstrate, that AMPK activation via 2DG or A­769662 protects astrocytes under hypoxic and glucose­depleted conditions.

Heavy Water Affects Vital Parameters of Human Melanoma Cells in vitro.

PURPOSE: Although regular water is composed of two hydrogens and one oxygen, referred to as H2O, a small amount of water on this planet contains alternative forms of elements with different molecular weights because of the addition of neutrons. The present study was dedicated to studying the effect of heavy water (D2O), in which the two hydrogens become substituted by deuterium, on the cell physiology of different human cells with particular focus on malignant melanoma cells. METHODS: Cells were cultured in regular medium in which the content of H2O was gradually substituted by D2O or deuterium-depleted water (DDW). Following this, the changes of basic cellular parameters, such as morphology, migration, proliferation, cell cycle, apoptosis and microtubule integrity were examined. RESULTS: It was found that raising the D2O content above the standard levels led to a concentration-dependent decrease in proliferation. Lowering the D2O levels below this level had no effect. Likewise, elevated D2O levels hampered migration. Moreover, cell-cycle analysis showed an increase of sub-G1 cells. Corroboratively, markers for apoptosis were induced (histone-associated DNA fragments, Bax, and PARP). In regard to microtubule integrity, only very high levels of D2O (75%) caused partial filament condensation. CONCLUSION: D2O, although chemically identical with H2O, shows proapoptotic and antiproliferative effects on melanoma cells. These findings give a closer look of this interesting compound.

Collagen I Promotes Adipocytogenesis in Adipose-Derived Stem Cells In Vitro.

A hallmark of ageing is the redistribution of body fat. Particularly, subcutaneous fat decreases paralleled by a decrease of skin collagen I are typical for age-related skin atrophy. In this paper, we hypothesize that collagen I may be a relevant molecule stimulating the differentiation of adipose-derived stem cells (ASCs) into adipocytes augmenting subcutaneous fat. In this context lipogenesis, adiponectin, and collagen I receptor expression were determined. Freshly isolated ASCs were characterized by stemness-associated surface markers by FACS analysis and then transdifferentiated into adipocytes by specific medium supplements. Lipogenesis was evaluated using Nile Red staining and documented by fluorescence microscopy or quantitatively measured by using a multiwell spectrofluorometer. Expression of adiponectin was measured by real-time RT-PCR and in cell-free supernatants by ELISA, and expression of collagen I receptors was observed by western blot analysis. It was found that supports coated with collagen I promote cell adhesion and lipogenesis of ASCs. Interestingly, a reverse correlation to adiponectin expression was observed. Moreover, we found upregulation of the collagen receptor, discoidin domain-containing receptor 2; receptors of the integrin family were absent or downregulated. These findings indicate that collagen I is able to modulate lipogenesis and adiponectin expression and therefore may contribute to metabolic dysfunctions associated with ageing.

Glucansucrase (mutant) enzymes from Lactobacillus reuteri 180 efficiently transglucosylate Stevia component rebaudioside A, resulting in a superior taste.

Steviol glycosides from the leaves of the plant Stevia rebaudiana are high-potency natural sweeteners but suffer from a lingering bitterness. The Lactobacillus reuteri 180 wild-type glucansucrase Gtf180-ΔN, and in particular its Q1140E-mutant, efficiently α-glucosylated rebaudioside A (RebA), using sucrose as donor substrate. Structural analysis of the products by MALDI-TOF mass spectrometry, methylation analysis and NMR spectroscopy showed that both enzymes exclusively glucosylate the Glc(ß1→C-19 residue of RebA, with the initial formation of an (α1→6) linkage. Docking of RebA in the active site of the enzyme revealed that only the steviol C-19 ß-D-glucosyl moiety is available for glucosylation. Response surface methodology was applied to optimize the Gtf180-ΔN-Q1140E-catalyzed α-glucosylation of RebA, resulting in a highly productive process with a RebA conversion of 95% and a production of 115 g/L α-glucosylated products within 3 h. Development of a fed-batch reaction allowed further suppression of α-glucan synthesis which improved the product yield to 270 g/L. Sensory analysis by a trained panel revealed that glucosylated RebA products show a significant reduction in bitterness, resulting in a superior taste profile compared to RebA. The Gtf180-ΔN-Q1140E glucansucrase mutant enzyme thus is an efficient biocatalyst for generating α-glucosylated RebA variants with improved edulcorant/organoleptic properties.

Furoates and thenoates inhibit pyruvate dehydrogenase kinase 2 allosterically by binding to its pyruvate regulatory site.

The last decade has witnessed the reawakening of cancer metabolism as a therapeutic target. In particular, inhibition of pyruvate dehydrogenase kinase (PDK) holds remarkable promise. Dichloroacetic acid (DCA), currently undergoing clinical trials, is a unique PDK inhibitor in which it binds to the allosteric pyruvate site of the enzyme. However, the safety of DCA as a drug is compromised by its neurotoxicity, whereas its usefulness as an investigative tool is limited by the high concentrations required to exert observable effects in cell culture. Herein, we report the identification - by making use of saturation-transfer difference NMR spectroscopy, enzymatic assays and computational methods - of furoate and thenoate derivatives as allosteric pyruvate-site-binding PDK2 inhibitors. This work substantiates the pyruvate regulatory pocket as a druggable target.

Deuteration enhances catalyst lifetime in palladium-catalysed alcohol oxidation.

The catalyst palladium/2,9-CD3-phenanthroline has a 1.8 times higher turnover number than its non-deuterated counterpart in the aerobic alcohol oxidation of methyl glucoside and allows the regioselective oxidation with dioxygen as the terminal oxidant.

Regioselective modification of unprotected glycosides.

Selective modification of unprotected carbohydrates is difficult due to the similar reactivity of the hydroxyl groups. In carbohydrate synthesis, therefore, even straightforward transformations often require multiple synthetic steps. The development of selective methods for carbohydrate modification is consequently highly desired. This review describes the methods for the regio- and chemoselective carbohydrate modification, with a focus on novel approaches that mainly apply transition metal catalysis and organocatalysis, and discusses the challenges and opportunities in this field.

Downregulation of sphingosine 1-phosphate (S1P) receptor 1 by dexamethasone inhibits S1P-induced mesangial cell migration.

Sphingosine 1-phosphate (S1P) is generated by sphingosine kinase (SK)-1 and -2 and acts mainly as an extracellular ligand at five specific receptors, denoted S1P1-5. After activation, S1P receptors regulate important processes in the progression of renal diseases, such as mesangial cell migration and survival. Previously, we showed that dexamethasone enhances SK-1 activity and S1P formation, which protected mesangial cells from stress-induced apoptosis. Here we demonstrate that dexamethasone treatment lowered S1P1 mRNA and protein expression levels in rat mesangial cells. This effect was abolished in the presence of the glucocorticoid receptor antagonist RU-486. In addition, in vivo studies showed that dexamethasone downregulated S1P1 expression in glomeruli isolated from mice treated with dexamethasone (10 mg/kg body weight). Functionally, we identified S1P1 as a key player mediating S1P-induced mesangial cell migration. We show that dexamethasone treatment significantly lowered S1P-induced migration of mesangial cells, which was again reversed in the presence of RU-486. In summary, we suggest that dexamethasone inhibits S1P-induced mesangial cell migration via downregulation of S1P1. Overall, these results demonstrate that dexamethasone has functional important effects on sphingolipid metabolism and action in renal mesangial cells.