Control of stereogenic oxygen in a helically chiral oxonium ion.

The control of tetrahedral carbon stereocentres remains a focus of modern synthetic chemistry and is enabled by their configurational stability. By contrast, trisubstituted nitrogen1, phosphorus2 and sulfur compounds3 undergo pyramidal inversion, a fundamental and well-recognized stereochemical phenomenon that is widely exploited4. However, the stereochemistry of oxonium ions-compounds bearing three substituents on a positively charged oxygen atom-is poorly developed and there are few applications of oxonium ions in synthesis beyond their existence as reactive intermediates5,6. There are no examples of configurationally stable oxonium ions in which the oxygen atom is the sole stereogenic centre, probably owing to the low barrier to oxygen pyramidal inversion7 and the perception that all oxonium ions are highly reactive. Here we describe the design, synthesis and characterization of a helically chiral triaryloxonium ion in which inversion of the oxygen lone pair is prevented through geometric restriction to enable it to function as a determinant of configuration. A combined synthesis and quantum calculation approach delineates design principles that enable configurationally stable and room-temperature isolable salts to be generated. We show that the barrier to inversion is greater than 110 kJ mol-1 and outline processes for resolution. This constitutes, to our knowledge, the only example of a chiral non-racemic and configurationally stable molecule in which the oxygen atom is the sole stereogenic centre.

Catalytic Enantioselective 6π Photocyclization of Acrylanilides.

Controlling absolute stereochemistry in catalytic photochemical reactions is generally challenging owing to high rates of background reactivity. Successful strategies broadly rely on selective excitation of the reaction substrate when associated with a chiral catalyst. Recent studies have demonstrated that chiral Lewis acid complexes can enable selective energy transfer from a photosensitizer to facilitate enantioselective triplet state reactions. Here, we apply this approach to the enantioselective catalysis of a 6π photocyclization through the design of an iridium photosensitizer optimized to undergo energy transfer to a reaction substrate only in the presence of a chiral Lewis acid complex. Among a group of iridium(III) sensitizers, enantioselectivity and yield closely correlate with photocatalyst triplet energy within a narrow window enabled by a modest reduction in substrate triplet energy upon binding a scandium/ligand complex. These results demonstrate that photocatalyst tuning offers a means to suppress background reactivity and improve enantioselectivity in photochemical reactions.

Iridium-Catalyzed Asymmetric Difunctionalization of C-C σ-Bonds Enabled by Ring-Strained Boronate Complexes.

Enantioenriched organoboron intermediates are important building blocks in organic synthesis and drug discovery. Recently, transition metal-catalyzed enantioselective 1,2-metalate rearrangements of alkenylboronates have emerged as an attractive protocol to access these valuable reagents by installing two different carbon fragments across C═C π-bonds. Herein, we report the development of an iridium-catalyzed asymmetric allylation-induced 1,2-metalate rearrangement of bicyclo[1.1.0]butyl (BCB) boronate complexes enabled by strain release, which allows asymmetric difunctionalization of C-C σ-bonds, including dicarbonation and carboboration. This protocol provides a variety of enantioenriched three-dimensional 1,1,3-trisubstituted cyclobutane products bearing a boronic ester that can be readily derivatized. Notably, the reaction gives trans diastereoisomers that result from an anti-addition across the C-C σ-bond, which is in contrast to the syn-additions observed for reactions promoted by PdII-aryl complexes and other electrophiles in our previous works. The diastereoselectivity has been rationalized based on a combination of experimental data and density functional theory calculations, which suggest that the BCB boronate complexes are highly nucleophilic and react via early transition states with low activation barriers.

Clinical characteristics and factors associated with ICU mortality during the first year of the SARS-Cov-2 pandemic in Romania: A prospective, cohort, multicentre study of 9000 patients.

BACKGROUND: The epidemiology of critically ill patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may be different worldwide. Despite similarities in medicine quality and formation, there are also significant differences concerning healthcare and ICU organisation, staffing, financial resources and population compliance and adherence. Large cohort data of critically ill patients from Central and Eastern Europe are also lacking. OBJECTIVES: The study objectives were to describe the clinical characteristics of patients admitted to Romanian ICUs with SARS-CoV-2 infection and to identify the factors associated with ICU mortality. DESIGN: Prospective, cohort, observational study. SETTING: National recruitment, multicentre study, between March 2020 to March 2021. PATIENTS: All patients with SARS-CoV-2 infection admitted to Romanian ICUs were eligible. There were no exclusion criteria. INTERVENTION: None. MAIN OUTCOME MEASURE: ICU mortality. RESULTS: The statistical analysis included 9058 patients with definitive ICU outcome. The multivariable mixed effects logistic regression model found that age [odds ratio (OR) 1.27; 95% confidence interval (CI), 1.23 to 1.31], male gender (OR 1.21; 95% CI 1.05 to 1.4), medical history of neoplasia (OR 1.74; 95% CI, 1.36 to 2.22), chronic kidney disease (OR 1.54; 95% CI, 1.27 to 1.88), type II diabetes (OR 1.23; 95% CI, 1.06 to 1.43), chronic heart failure (OR 1.24; 95% CI, 1.03 to 1.49), dyspnoea (OR 1.3; 95% CI, 1.1 to 1.5), SpO2 less than 90% (OR 3; 95% CI, 2.5 to 3.5), admission SOFA score (OR 1.07; 95% CI, 1.05 to 1.09), acute respiratory distress syndrome (ARDS) on ICU admission (OR 1.35; 95% CI, 1.1 to 1.63) and the need for noninvasive (OR 1.8, 95% CI, 1.5 to 1.22) or invasive ventilation (OR 28; 95% CI, 22 to 35) and neuromuscular blockade (OR 3.5; 95% CI, 2.6 to 4.8), were associated with larger ICU mortality.Higher GCS on admission (OR 0.81; 95% CI, 0.79 to 0.83), treatment with hydroxychloroquine (OR 0.78; 95% CI, 0.64 to 0.95) and tocilizumab (OR 0.58; 95% CI, 0.48 to 0.71) were inversely associated with ICU mortality. CONCLUSION: The SARS-CoV-2 critically ill Romanian patients share common personal and clinical characteristics with published European cohorts. Public health measures and vaccination campaign should focus on patients at risk.

The Influence of Fixed Dental Prostheses on the Expression of Inflammatory Markers and Periodontal Status-Narrative Review.

A dental prosthesis will only be successful if the restoration lasts for a long period and does not cause any illness. The presence of permanent prosthetic restorations has been linked to an increased risk of periodontal infections, according to a large body of research that has been gathered. When chronic inflammation is brought on by fixed prosthetic constructions, both cellular and noncellular immunity are activated as adaptive immune mechanisms. It has previously been stated that both clinically adequate and inadequate restorations might cause gingival inflammation. Areas surrounding the abutment teeth presented periodontal pockets, attachment loss, congestion, bleeding on probing, and gingival hyperplasia after fixed restorations were removed. The depth of pockets, bleeding on probing, and bone loss are all closely correlated with disease's severity and IL-1ß concentration in gingival crevicular fluid; IL-1ß shows higher values in disease sites than in healthy ones. hs-CRP and TNF-α blood levels showed a considerable reduction one day after fixed restorations were applied, in comparison with the pre-treatment values. Collaboration between prosthodontists and periodontists is essential for a good treatment outcome since it will increase the restoration's lifespan, enhance periodontal health, and improve the quality of life for dental patients.

Metal-Free Arylation of Benzothiophenes at C4 by Activation as their Benzothiophene S-Oxides.

Benzothiophenes, activated by oxidation to the corresponding S-oxides, undergo C-H/C-H-type coupling with phenols to give C4 arylation products. While an electron-withdrawing group at C3 of the benzothiophene is important, the process operates without a directing group and a metal catalyst, thus rendering it compatible with sensitive functionalities-e.g. halides and formyl groups. Quantum chemical calculations suggest a formal stepwise mechanism involving heterolytic cleavage of an aryloxysulfur species to give a π-complex of the corresponding benzothiophene and a phenoxonium cation. Subsequent addition of the phenoxonium cation to the C4 position of the benzothiophene is favored over the addition to C3; Fukui functions predict that the major regioisomer is formed at the more electron-rich position between C3 and C4. Varied selective manipulation of the benzothiophene products showcase the synthetic utility of the metal-free arylation process.

Electrochemical Modification of Polypeptides at Selenocysteine.

Mild strategies for the selective modification of peptides and proteins are in demand for applications in therapeutic peptide and protein discovery, and in the study of fundamental biomolecular processes. Herein, we describe the development of an electrochemical selenoetherification (e-SE) platform for the efficient site-selective functionalization of polypeptides. This methodology utilizes the unique reactivity of the 21st amino acid, selenocysteine, to effect formation of valuable bioconjugates through stable selenoether linkages under mild electrochemical conditions. The power of e-SE is highlighted through late-stage C-terminal modification of the FDA-approved cancer drug leuprolide and assembly of a library of anti-HER2 affibody conjugates bearing complex cargoes. Following assembly by e-SE, the utility of functionalized affibodies for in vitro imaging and targeting of HER2 positive breast and lung cancer cell lines is also demonstrated.

Lung mechanics during video-assisted abdominal surgery in Trendelenburg position: a cross-sectional propensity-matched comparison between classic laparoscopy and robotic-assisted surgery.

BACKGROUND: Video-assisted surgery has become an increasingly used surgical technique in patients undergoing major thoracic and abdominal surgery and is associated with significant perioperative respiratory and cardiovascular changes. The aim of this study was to investigate the effect of intraoperative pneumoperitoneum during video-assisted surgery on respiratory physiology in patients undergoing robotic-assisted surgery compared to patients undergoing classic laparoscopy in Trendelenburg position. METHODS: Twenty-five patients undergoing robotic-assisted surgery (RAS) were compared with twenty patients undergoing classic laparoscopy (LAS). Intraoperative ventilatory parameters (lung compliance and plateau airway pressure) were recorded at five specific timepoints: after induction of anesthesia, after carbon dioxide (CO2) insufflation, one-hour, and two-hours into surgery and at the end of surgery. At the same time, arterial and end-tidal CO2 values were noted and arterial to end-tidal CO2 gradient was calculated. RESULTS: We observed a statistically significant difference in plateau pressure between RAS and LAS at one-hour (26.2 ± 4.5 cmH2O vs. 20.2 ± 3.5 cmH2O, p = 0.05) and two-hour intervals (25.2 ± 5.7 cmH2O vs. 17.9 ± 3.1 cmH2O, p = 0.01) during surgery and at the end of surgery (19.9 ± 5.0 cmH2O vs. 17.0 ± 2.7 cmH2O, p = 0.02). Significant changes in lung compliance were also observed between groups at one-hour (28.2 ± 8.5 mL/cmH2O vs. 40.5 ± 13.9 mL/cmH2O, p = 0.01) and two-hour intervals (26.2 ± 7.8 mL/cmH2O vs. 54.6 ± 16.9 mL/cmH2O, p = 0.01) and at the end of surgery (36.3 ± 9.9 mL/cmH2O vs. 58.2 ± 21.3 mL/cmH2O, p = 0.01). At the end of surgery, plateau pressures remained higher than preoperative values in both groups, but lung compliance remained significantly lower than preoperative values only in patients undergoing RAS with a mean 24% change compared to 1.7% change in the LAS group (p = 0.01). We also noted a more significant arterial to end-tidal CO2 gradient in the RAS group compared to LAS group at one-hour (12.9 ± 4.5 mmHg vs. 7.4 ± 4.4 mmHg, p = 0.02) and two-hours interval (15.2 ± 4.5 mmHg vs. 7.7 ± 4.9 mmHg, p = 0.02), as well as at the end of surgery (11.0 ± 6.6 mmHg vs. 7.0 ± 4.6 mmHg, p = 0.03). CONCLUSION: Video-assisted surgery is associated with significant changes in lung mechanics after induction of pneumoperitoneum. The observed changes are more severe and longer-lasting in patients undergoing robotic-assisted surgery compared to classic laparoscopy.

Can SARS-CoV-2 Induce Uterine Vascular Anomalies and Poor Contractile Response?-A Case Report.

We are reporting a case of a 36 year-old Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) positive hypertensive primigravida with postpartum uterine atony that required emergency subtotal hysterectomy at Saint John Hospital Bucur Maternity Bucharest. The maternity was designated as the Coronavirus Disease 2019 (COVID-19) Maternity for Bucharest and Ilfov County since March 2020. The patient was mildly symptomatic for SARS-CoV-2, infection confirmed with reverse transcription polymerase chain reaction (RT-PCR). The caesarean section was performed and a live male fetus was born, 2630 g and Apgar Score of 9 (the male fetus was negative for SARS-CoV-2). Postpartum hysterectomy with adnexal preservation was performed because of uterine atony. The postoperative evolution was favorable. The patient was discharged with her baby 10 days after birth. Given the limited resources, the placenta, the umbilical cord and the uterus were not tested for SARS-CoV-2. The pathology exam revealed that on the maternal side there were specific uterine atony lesions as well as endometrial and miometrial ischaemia. The placenta had nonspecific findings: chronic ischemic lesions with small villi, fibrin deposits in the materno-fetal interface. The peculiarity of the case is that we report the morphological findings of the placenta and uterus resulted from intrapartum uterine atonia in a patient with gestational arterial hypertension, premature birth and COVID-19. Further studies are required to characterize the pattern of such intricate conditions.

Continuous Noninvasive Hemoglobin Monitoring Reflects the Development of Acute Hemodilution After Consecutive Fluid Challenges.

BACKGROUND: Consecutive fluid challenges (FCs) are frequently administered to maximize the stroke volume (SV) as part of a goal-directed therapy (GDT) strategy. However, fluid administration may also cause acute hemodilution that might lead to an actual paradoxical decrease in oxygen delivery (DO2). The aim of this study was to examine whether continuous noninvasive hemoglobin (SpHb) monitoring can be used to detect the development of acute hemodilution after graded fluid administration. METHODS: In 40 patients who underwent major vascular or gastrointestinal surgery, an FC, consisting of 250 mL colloid solution, was administered. When the SV increased by ≥10%, the FC was repeated up to a maximum of 3 times. Laboratory-measured hemoglobin concentrations (BHb), SpHb, SV, cardiac output (CO), and DO2 values were recorded after each FC. RESULTS: All 40 patients received the first FC, 32 patients received the second FC, and 20 patients received the third FC (total of 750 mL). Out of the 92 administered FCs, only 55 (60%) caused an increase in SV ≥10% ("responders"). The first and the second FCs were associated with a significant increase in the mean CO and DO2, while the mean SpHb and BHb decreased significantly. However, the third and last FC was associated with no statistical difference in CO and SV, a further significant decrease in mean SpHb and BHb, and a significant decrease in DO2 in these patients. Compared to their baseline values (T0), BHb and SpHb decreased by a mean of 5.3% ± 4.9% and 4.4% ± 5.2%, respectively, after the first FC (T1; n = 40), by 9.7% ± 8.4% and 7.9% ± 6.9% after the second FC (T2; n = 32), and by 14.5% ± 6.2% and 14.6% ± 5.7% after the third FC (T3; n = 20). Concordance rates between the changes in SpHb and in BHb after the administration of 250, 500, and 750 mL colloids were 83%, 90%, and 100%, respectively. CONCLUSIONS: Fluid loading aimed at increasing the SV and the DO2 as part of GDT strategy is associated with acute significant decreases in both BHb and SpHb concentrations. When the administration of an FC is not followed by a significant increase (≥10%) in the SV, the DO2 decreases significantly due to the development of acute hemodilution. Continuous noninvasive monitoring of SpHb does not reflect accurately absolute BHb values, but may be reliably used to detect the development of acute hemodilution especially after the administration of at least 500 mL of colloids.

Visible-Light-Mediated Heterocycle Functionalization via Geometrically Interrupted [2+2] Cycloaddition.

The [2+2] photocycloaddition is the most valuable and intensively investigated photochemical process. Here we demonstrate that irradiation of N-acryloyl heterocycles with blue LED light (440 nm) in the presence of an IrIII complex leads to efficient and high yielding fused γ-lactam formation across a range of substituted heterocycles. Quantum calculations show that the reaction proceeds via cyclization in the triplet excited state to yield a 1,4-diradical; intersystem crossing leads preferentially to the closed shell singlet zwitterion. This is geometrically restricted from undergoing recombination to yield a cyclobutane by the planarity of the amide substituent. A prototropic shift leads to the observed bicyclic products in what can be viewed as an interrupted [2+2] cycloaddition.

Synthesis of Triarylamines via Sequential C-N Bond Formation.

A one-pot domino N-arylation protocol is described using diaryliodonium reagents under copper catalysis. The reaction uses both aryl groups of the diaryliodonium reagent to generate triarylamines starting from simple anilines, representing an atom-economical preparation of an important class of organic material building blocks.

Obesity is associated with decreased lung compliance and hypercapnia during robotic assisted surgery.

Robotic assisted surgery (RAS) represents a great challenge for anesthesiology due to the increased intraabdomial pressures required for surgical optimal approach. The changes in lung physiology are difficult to predict and require fast decision making in order to prevent altered gas exchange. The aim of this study was to document the combined effect of patient physical status, medical history and intraoperative position during RAS on lung physiology and to determine perioperative risk factors for hypercapnia. We prospectively analyzed 62 patients who underwent elective RAS. Age, co-morbidities and body mass index (BMI) were recorded before surgery. Ventilatory parameters and arterial blood gas analysis were determined before induction of anesthesia, after tracheal intubation and on an hourly basis until the end of surgery. In RAS, the induction of pneumoperitoneum was associated with a significant decrease in lung compliance from a mean of 42.5-26.7 ml cm H2O-1 (p = 0.001) and an increase in plateau pressure from a mean of 16.1 mmHg to a mean of 23.6 mmHg (p = 0.001). Obesity, demonstrated by a BMI over 30, significantly correlates with a decrease in lung compliance after induction of anesthesia (p = 0.001). A significant higher increase in arterial CO2 tension was registered in patients undergoing RAS in steep Trendelenburg position (p = 0.05), but no significant changes in end-tidal CO2 were recorded. A higher arterial to end-tidal CO2 tension gradient was observed in patients with a BMI > 30 (p < 0.001). In conclusion, patients' physical status, especially obesity, represents the main risk factor for decreased lung compliance during RAS and patient positioning in either Trendelenburg or steep Trendelenburg during surgery has limited effects on respiratory physiology.

Ventriculoportal Shunt, a New Transomphalic Extraperitoneal Surgical Technique in Treatment of Hydrocephalus.

AIM: The aim of this article was to report a new transomphalic extraperitoneal surgical technique for treatment of hydrocephalus, called ventriculoportal shunt. MATERIALS AND METHODS: We performed ventriculoportal shunt on an experimental animal (pig). The particularity of ventriculoportal shunt consists in the fact that the distal end of the catheter is inserted transomphalic extraperitoneally in the portal system through reopened umbilical vein. We present technical details regarding this new surgical technique. RESULTS AND DISCUSSION: The animal had favorable outcome, without any postoperative early or late morbidity. We discuss indications, contraindications, possible complications in humans and advantages of ventriculoportal shunt compared with ventriculocardiac and ventriculoperitoneal drainages and possibilities to avoid complications specific to classic shunt procedures. CONCLUSIONS: Ventriculoportal shunt is a new surgical technique for treatment of hydrocephalus. The distal end of the catheter introduced into reopened umbilical vein, drains cerebrospinal fluid into the portal system. Ventriculoportal shunt is safe and easy to perform. With ventriculoportal shunt specific complications of ventriculoperitoneal or ventriculocardiac drainages can be potentially avoided. Ventriculoportal shunt combines advantages of vascular shunt with those of having an immunological barrier for cerebrospinal fluid before entering the systemic circulation. Theoretically, indications for surgery are extended, and ventriculoportal shunt can be performed in patients former contraindicated for ventriculoperitoneal shunt. Further research is needed and this surgical technique must be performed on human subjects with hydrocephalus.

Our initial experience with ventriculo-epiplooic shunt in treatment of hydrocephalus in two centers.

INTRODUCTION: Hydrocephalus represents impairment in cerebrospinal fluid (CSF) dynamics. If the treatment of hydrocephalus is considered difficult, the repeated revisions of ventriculo-peritoneal (VP) shunts are even more challenging. OBJECTIVE: The aim of this article is to evaluate the efficiency of ventriculo-epiplooic (VEp) shunt as a feasible alternative in hydrocephalic patients. MATERIAL AND METHODS: A technical modification regarding the insertion of peritoneal catheter was imagined: midline laparotomy 8-10cm long was performed in order to open the peritoneal cavity; the great omentum was dissected between its two layers; we placed the distal end of the catheter between the two epiplooic layers; a fenestration of 4cm in diameter into the visceral layer was also performed. A retrospective study of medical records of 15 consecutive patients with hydrocephalus treated with VEp shunt is also presented. RESULTS: Between 2008 and 2014 we performed VEp shunt in 15 patients: 5 with congenital hydrocephalus, 8 with secondary hydrocephalus and 2 with normal pressure hydrocephalus. There were 7 men and 8 women. VEp shunt was performed in 13 patients with multiple distal shunt failures and in 2 patients, with history of abdominal surgery, as de novo extracranial drainage procedure. The outcome was favorable in all cases, with no significant postoperative complications. CONCLUSIONS: VEp shunt is a new, safe and efficient surgical technique for the treatment of hydrocephalus. VEp shunt is indicated in patients with history of recurrent distal shunt failures, and in patients with history of open abdominal surgery and high risk for developing abdominal complications.

The Romanian National Program for Liver Transplantation - 852 Procedures in 815 Patients over 17 Years (2000-2017): A Continuous Evolution to Success.

Background: Liver transplantation (LT) has become an established treatment for end-stage liver disease, with more than 20.000 procedures yearly worldwide. The aim of this study was to analyze the results of Romanian National Program of LT. Methods: Between April 2000 and April 2017, 817 pts received 852 LTs in Romania. Male/female ratio was 487/330, while adult/pediatric ratio was 753/64, with a mean age of 46 years (median 50 yrs; range 7 months - 68 yrs). Main LT indications were HBV cirrhosis (230 pts; 28.2%), HCC (173 pts; 21.2%), and HCV cirrhosis (137 pts; 16.8%). Waiting time and indications for LT, patient and donor demographics, graft features, surgical procedures, and short and long-term outcomes were analyzed. Results: DDLT was performed in 682 pts (83.9%): whole LT in 662 pts (81%), split LT in 16 pts (2.3%), reduced LT in 2 pts (0.2%), and domino LT in 1 pts (0.1%). LDLT was performed in 135 pts (16.5%): right hemiliver in 93 pts (11.4%), left lateral section in 28 pts (3.4%), left hemiliver in 8 pts (1%), left hemiliver with segment 1 in 4 pts (0.5%), and dual graft LDLT in 2 pts (0.2%). Overall major morbidity rate was 31.4% (268 pts), while perioperative mortality was 7.9% (65 pts). Retransplantation rate was 4.3% (35 pts): 27 whole LTs, 3 reduced LTs, 3 split LTs, and 2 LDLT. Long-term overall 1-, 3-, and 5-year estimated survival rates for patients were 87.9%, 81.5%, and 79.1%, respectively. One-, 3-, and 5-year overall mortality on waiting list also decreased significantly over time from 31.4%, 54.1% and 63.5%, to 4.4%, 13.9% and 23.6%, respectively. Conclusions: The Romanian National program for liver transplantation addresses all causes of acute and chronic liver failure or liver tumors in adults and children, using all surgical techniques, with good long-term outcome. The program constantly evolved over time, leading to decreased mortality rate on the waiting list.

Integrated approach for studying adaptation mechanisms in the human somatosensory cortical network.

Magnetoencephalography and independent component analysis (ICA) was utilized to study and characterize neural adaptation in the somatosensory cortical network. Repetitive punctate tactile stimuli were applied unilaterally to the dominant hand and face using a custom-built pneumatic stimulator called the TAC-Cell. ICA-based source estimation from the evoked neuromagnetic responses indicated cortical activity in the contralateral primary somatosensory cortex (SI) for face stimulation, while hand stimulation resulted in robust contralateral SI and posterior parietal cortex (PPC) activation. Activity was also observed in the secondary somatosensory cortical area (SII) with reduced amplitude and higher variability across subjects. There was a significant difference in adaptation rate between SI and higher-order somatosensory cortices for hand stimulation. Adaptation was significantly dependent on stimulus frequency and pulse index within the stimulus train for both hand and face stimulation. The peak latency of the activity was significantly dependent on stimulation site (hand vs. face) and cortical area (SI vs. PPC). The difference in the peak latency of activity in SI and PPC is presumed to reflect a hierarchical serial-processing mechanism in the somatosensory cortex.

Altered long-range functional connectivity in PTSD: Role of the infraslow oscillations of cortical activity amplitude envelopes.

OBJECTIVE: Coupling between the amplitude envelopes (AEs) of regional cortical activity reflects mechanisms that coordinate the excitability of large-scale cortical networks. We used resting-state MEG recordings to investigate the association between alterations in the coupling of cortical AEs and symptoms of post-traumatic stress disorder (PTSD). METHODS: Participants (n = 96) were service members with combat exposure and various levels of post-traumatic stress severity (PTSS). We assessed the correlation between PTSS and (1) coupling of broadband cortical AEs of beta band activity, (2) coupling of the low- (<0.5 Hz) and high-frequency (>0.5 Hz) components of the AEs, and (3) their time-varying patterns. RESULTS: PTSS was associated with widespread hypoconnectivity assessed from the broadband AE fluctuations, which correlated with subscores for the negative thoughts and feelings/emotional numbing (NTF/EN) and hyperarousal clusters of symptoms. Higher NTF/EN scores were also associated with smaller increases in resting-state functional connectivity (rsFC) with time during the recordings. The distinct patterns of rsFC in PTSD were primarily due to differences in the coupling of low-frequency (infraslow) fluctuations of the AEs of beta band activity. CONCLUSIONS: Our findings implicate the mechanisms underlying the regulation/coupling of infraslow oscillations in the alterations of rsFC assessed from broadband AEs and in PTSD symptomatology. SIGNIFICANCE: Altered coordination of infraslow amplitude fluctuations across large-scale cortical networks can contribute to network dysfunction and may provide a target for treatment in PTSD.

Late-stage benzenoid-to-troponoid skeletal modification of the cephalotanes exemplified by the total synthesis of harringtonolide.

Skeletal modifications enable elegant and rapid access to various derivatives of a compound that would otherwise be difficult to prepare. They are therefore a powerful tool, especially in the synthesis of natural products or drug discovery, to explore different natural products or to improve the properties of a drug candidate starting from a common intermediate. Inspired by the biosynthesis of the cephalotane natural products, we report here a single-atom insertion into the framework of the benzenoid subfamily, providing access to the troponoid congeners - representing the reverse of the proposed biosynthesis (i.e., a contra-biosynthesis approach). Computational evaluation of our designed transformation prompted us to investigate a Büchner-Curtius-Schlotterbeck reaction of a p-quinol methylether, which ultimately results in the synthesis of harringtonolide in two steps from cephanolide A, which we had previously prepared. Additional computational studies reveal that unconventional selectivity outcomes are driven by the choice of a Lewis acid and the nucleophile, which should inform further developments of these types of reactions.