Orbital- and millennial-scale Asian winter monsoon variability across the Pliocene-Pleistocene glacial intensification.

Intensification of northern hemisphere glaciation (iNHG), ~2.7 million years ago (Ma), led to establishment of the Pleistocene to present-day bipolar icehouse state. Here we document evolution of orbital- and millennial-scale Asian winter monsoon (AWM) variability across the iNHG using a palaeomagnetically dated centennial-resolution grain size record between 3.6 and 1.9 Ma from a previously undescribed loess-palaeosol/red clay section on the central Chinese Loess Plateau. We find that the late Pliocene-early Pleistocene AWM was characterized by combined 41-kyr and ~100-kyr cycles, in response to ice volume and atmospheric CO2 forcing. Northern hemisphere ice sheet expansion, which was accompanied by an atmospheric CO2 concentration decline, substantially increased glacial AWM intensity  and its orbitally oscillating amplitudes across the iNHG. Superposed on orbital variability, we find that millennial AWM intensity fluctuations persisted during both the warmer (higher-CO2) late Pliocene and colder (lower-CO2) early Pleistocene, in response to both external astronomical forcing and internal climate dynamics.

How comparable are patient outcomes in the "real-world" with populations studied in pivotal AML trials?

Despite an increasing desire to use historical cohorts as "synthetic" controls for new drug evaluation, limited data exist regarding the comparability of real-world outcomes to those in clinical trials. Governmental cancer data often lacks details on treatment, response, and molecular characterization of disease sub-groups. The Australasian Leukaemia and Lymphoma Group National Blood Cancer Registry (ALLG NBCR) includes source information on morphology, cytogenetics, flow cytometry, and molecular features linked to treatment received (including transplantation), response to treatment, relapse, and survival outcome. Using data from 942 AML patients enrolled between 2012-2018, we assessed age and disease-matched control and interventional populations from published randomized trials that led to the registration of midostaurin, gemtuzumab ozogamicin, CPX-351, oral azacitidine, and venetoclax. Our analyses highlight important differences in real-world outcomes compared to clinical trial populations, including variations in anthracycline type, cytarabine intensity and scheduling during consolidation, and the frequency of allogeneic hematopoietic cell transplantation in first remission. Although real-world outcomes were comparable to some published studies, notable differences were apparent in others. If historical datasets were used to assess the impact of novel therapies, this work underscores the need to assess diverse datasets to enable geographic differences in treatment outcomes to be accounted for.

Outcomes and Costs in Patients with Immune Thrombotic Thrombocytopenic Purpura Receiving Front-Line Versus Delayed Caplacizumab: A US Hospital Database Study.

European real-world data indicate that front-line treatment with caplacizumab is associated with improved clinical outcomes compared with delayed caplacizumab treatment. The objective of the study was to describe the characteristics, treatment patterns, and outcomes in hospitalized patients with an immune-mediated thrombotic thrombocytopenic purpura (iTTP) episode treated with front-line versus delayed caplacizumab in the US. This retrospective cohort analysis of a US hospital database included adult patients (≥18 years) with an acute iTTP episode (a diagnosis of thrombotic microangiopathy and ≥1 therapeutic plasma exchange [TPE] procedure) from January 21, 2019, to February 28, 2021. Unadjusted baseline characteristics, treatment patterns, healthcare resource utilization, and costs were compared between patients who received front-line versus delayed (<2 vs ≥2 days after TPE initiation) caplacizumab treatment. Out of 39 patients, 16 (41.0%) received front-line and 23 (59.0%) received delayed treatment with caplacizumab. Baseline characteristics and symptoms were similar between the two groups. Patients who received front-line caplacizumab treatment had significantly fewer TPE administrations (median: 5.0 vs 12.0); and a significantly shorter hospital stay (median: 9.0 days vs 16.0 days) than patients receiving delayed caplacizumab therapy. Both of these were significantly lower in comparison of means (t-test P < .01). Median inpatient costs (inclusive of caplacizumab costs) were 54% higher in the delayed treated patients than in the front-line treated patients (median: $112 711 vs $73 318). TPE-specific cost was lower in the front-line treated cohort (median: $6 989 vs $10 917). In conclusion, front-line treatment with caplacizumab had shorter hospitalizations, lower healthcare resource utilization, and lower costs than delayed caplacizumab treatment after TPE therapy.

Sleep duration and perceptions of sleep quality in British Army recruits during basic training - an observational analysis.

Introduction: Sleep is critical to the health, wellbeing and performance of military personnel during basic training. This two-part study evaluated sleep-wake patterns and sleep disturbances in junior soldiers (JS) and infantry recruits in Autumn 2021 (study 1), and non-infantry recruits in spring 2022 (study 2). Methods: During studies 1 and 2, validated wearable technology combined with a sleep diary was used to quantify sleep-wake indices, sleep disturbances and perceptions of sleep quality. Sleep diary data was analysed descriptively. A series of repeated-measures ANOVAs examined differences in objective sleep-wake indices. Correlation analysis determined associations between time in bed (TIB) and total sleep time (TST). Results: Significant (p < 0.05) differences in most sleep-wake indices were observed between weeks of basic training for all cohorts. Strong positive correlations between TIB and TST were observed for each cohort across basic training (r = 0.681 - 0.970, p < 0.001), with longer TST associated with greater TIB. The mean±SD sleep duration (hours and mins [hm]) for JS (06:22 ± 00:27hm), non-infantry (05:41 ± 00:47hm) and infantry (05:46 ± 00:34hm) recruits across basic training was consistently below national recommendations. The mean±SD bed and wake times for JS (bedtime: 23:01 ± 00:32hm; awake: 05:34 ± 00:10hm), non-infantry (bedtime: 23:38 ± 01:09hm; awake: 04:47 ± 00:58hm), and infantry (bedtime: 23:13 ± 00:29hm; awake: 05:38 ± 00:26hm) recruits varied across weeks of basic training, with over 80% reporting "fairly bad" or "very bad" sleep quality and frequent periods of "dozing off" during daytime activity. The most commonly reported sleep disturbing factors identified during basic training involved: late-night military admin (e.g., ironing, boot cleaning, kit set up etc), early morning wake times, extraneous noise, light and hot room temperatures within the primary sleeping environment, bed/mattress discomfort, muscle soreness and feelings of stress and anxiety. Discussion/Conclusion: Our findings contribute to the existing evidence that long-term sleep loss is pervasive during initial military training programmes. The average sleep durations indicate chronic and unrecoverable sleep loss which would be expected to significantly impair physical and cognitive military performance, and increase the risk of injury, illness and attrition rates during basic training. Changes in the design and scheduling of basic training programmes to enable, at the least, minimum sleep recommendations to be met, and to improve sleep hygiene in the primary sleeping environment are warranted.

Introduction and scientific justification of data transportability for confined field testing for the ERA of GM plants.

The concept of Data Transportability (DT) of Confined Field Testing (CFT) to support the Environmental Risk Assessment (ERA) of Genetically Modified (GM) plants was first introduced in the literature by Garcia-Alonso et al., in 2014. Since then, DT has been discussed in many countries and regions as a concept to prevent duplication of regulatory studies without compromising quality of the ERA. However, despite its usefulness and scientific justification, DT is not well adopted at this time and many regulatory agencies around the world require additional in-country CFT be conducted before approving GM plants. Based on the current circumstances, the authors organized a parallel session entitled "Introduction and Scientific Justification of DT for CFT for the ERA of GM plants" at 16th ISBR (the International Society for Biosafety Research). This session mainly consisted of the following three parts. The first two speakers, Andrew Roberts and Abigail Simmons provided an overview of DT and examples of conditions for the transportability of field data/conclusions advocated in the peer-reviewed scientific journals. Next, the current status of DT adoption in some countries/regions such as Japan and Africa, and a theoretical case study for Argentina were introduced by Kazuyuki Hiratsuka, Douglas Miano, and Facundo Vesprini, respectively. Lastly, a risk hypothesis-based approach for DT which was developed in advance by the five speakers of this parallel session, was introduced. During the discussion, there was a common understanding that transition to the risk hypothesis-based approach for DT was scientifically appropriate, considering the accumulated evidences that several countries have conducted confirmatory local CFT for more than 20 years but they have not detected any differences related to the ERA assessment endpoints in GM crops. The risk hypothesis-based approach for DT introduced here is expected to play an important role in discussions on the implementation of DT in various parts of the world in the future.

The Consequences of Anthropomorphic and Teleological Beliefs in a Global Pandemic.

To describe something in terms of its purpose or function is to describe its teleology. Previous studies have found that teleological beliefs are positively related to anthropomorphism, and that anthropomorphism decreases the perceived unpredictability of non-human agents. In the current study, we explore these relationships using the highly salient example of beliefs about the coronavirus pandemic. Results showed that both anthropomorphism and teleology were negatively associated with perceived uncertainty and threat, and positively associated with self-reported behavioural change in response to the pandemic. These findings suggest that highly anthropomorphic and teleological individuals may view coronavirus as agentive and goal-directed. While anthropomorphic and teleological beliefs may facilitate behavioural change in response to the pandemic, we also found that the associated reduction in uncertainty and threat may be detrimental to behavioural change. We discuss the implications of these findings for messaging about global events more broadly.

Six-year follow-up and subgroup analyses of a phase 2 trial of venetoclax for del(17p) chronic lymphocytic leukemia.

ABSTRACT: Chromosome 17p deletion (del[17p]) is associated with poor prognosis in patients with chronic lymphocytic leukemia (CLL). Venetoclax is approved for treatment of previously untreated and relapsed/refractory (R/R) CLL, including patients with del(17p), based on the open-label, multicenter, phase 2 M13-982 trial (NCT01889186). Here, we detail the 6-year follow-up analysis for M13-982. A total of 158 patients with previously untreated (n = 5) or R/R (n = 153) del(17p) CLL received 400 mg venetoclax daily after initial ramp-up until progressive disease. After a median follow-up of 70 months, the best objective response rate (ORR) was 77% (21% complete remission [CR] and 49% partial remission [PR]), with a median duration of response (DOR) of 39.3 months (95% confidence interval [CI], 31.1-50.5). The median progression-free survival (PFS) was 28.2 months (95% CI, 23.4-37.6), and median overall survival (OS) was 62.5 months (95% CI, 51.7-not reached), with 16% of patients remaining on treatment after 6 years. Multivariable analysis did not identify statistically significant correlation between patient subgroups defined by clinical or laboratory variables and ORR or PFS. The most common grade ≥3 adverse events were neutropenia (42%), infections (33%), anemia (16%), and thrombocytopenia (16%). Post hoc comparative analyses of PFS and OS from treatment initiation, from a 24-month landmark, and by minimal residual disease status were performed between patients with del(17p) in the M13-982 and MURANO studies in the interest of understanding these data in another context. These long-term data show the continued benefits of venetoclax in patients with del(17p) CLL. The trial was registered at www.clinicaltrials.gov as #NCT01889186.

Lasso Peptides: Exploring the Folding Landscape of Nature's Smallest Interlocked Motifs.

Lasso peptides make up a class of natural products characterized by a threaded structure. Given their small size and stability, chemical synthesis would offer tremendous potential for the development of novel therapeutics. However, the accessibility of the pre-folded lasso architecture has limited this advance. To better understand the folding process de novo, simulations are used herein to characterize the folding propensity of microcin J25 (MccJ25), a lasso peptide known for its antimicrobial properties. New algorithms are developed to unambiguously distinguish threaded from nonthreaded precursors and determine handedness, a key feature in natural lasso peptides. We find that MccJ25 indeed forms right-handed pre-lassos, in contrast to past predictions but consistent with all natural lasso peptides. Additionally, the native pre-lasso structure is shown to be metastable prior to ring formation but to readily transition to entropically favored unfolded and nonthreaded structures, suggesting that de novo lasso folding is rare. However, by altering the ring forming residues and appending thiol and thioester functionalities, we are able to increase the stability of pre-lasso conformations. Furthermore, conditions leading to protonation of a histidine imidazole side chain further stabilize the modified pre-lasso ensemble. This work highlights the use of computational methods to characterize lasso folding and demonstrates that de novo access to lasso structures can be facilitated by optimizing sequence, unnatural modifications, and reaction conditions like pH.

A widespread methylotroph acyl-homoserine lactone synthase produces a new quorum sensing signal that regulates swarming in Methylobacterium fujisawaense.

IMPORTANCE: Bacteria known as pink-pigmented facultative methylotrophs colonize many diverse environments on earth, play an important role in the carbon cycle, and in some cases promote plant growth. However, little is known about how these organisms interact with each other and their environment. In this work, we identify one of the chemical signals commonly used by these bacteria and discover that this signal controls swarming motility in the pink-pigmented facultative methylotroph Methylobacterium fujisawaense DSM5686. This work provides new molecular details about interactions between these important bacteria and will help scientists predict these interactions and the group behaviors they regulate from genomic sequencing information.

Nonthreaded Isomers of Sungsanpin and Ulleungdin Lasso Peptides Inhibit H1299 Cancer Cell Migration.

Lasso peptides are a structurally distinct class of biologically active natural products defined by their short sequences with impressively interlocked tertiary structures. Their characteristic peptide [1]rotaxane motif confers marked proteolytic and thermal resiliency, and reports on their diverse biological functions have been credited to their exceptional sequence variability. Because of these unique properties, taken together with improved technologies for their biosynthetic production, lasso peptides are emerging as a designable scaffold for peptide-based therapeutic discovery and development. Although the defined structure of lasso peptides is recognized for its remarkable properties, the role of the motif in imparting bioactivity is less understood. For example, sungsanpin and ulleungdin are natural lasso peptides that similarly exhibit encouraging cell migration inhibitory activities in A549 lung carcinoma epithelial cells, despite sharing only one-third of the sequence homology. We hypothesized that the shape of the lasso motif is beneficial for the preorganization of the conserved residues, which might be partially retained in variants lacking the threaded structure. Herein, we describe solid-phase peptide synthesis strategies to prepare acyclic, head-to-side chain (branched), and head-to-tail (macrocyclic) cyclic variants based on the sungsanpin (Sun) and ulleungdin (Uln) sequences. Proliferation assays and time-lapse cell motility imaging studies were used to evaluate the cell inhibitory properties of natural Sun compared with the synthetic Sun and Uln isomers. These studies demonstrate that the lasso motif is not a required feature to slow cancer cell migration and more generally show that these nonthreaded isomers can retain similar activity to the natural lasso peptide despite the differences in their overall structures.

Pre-sleep protein supplementation does not improve performance, body composition, and recovery in British Army recruits (part 1).

Dietary protein is crucial for optimising physical training adaptations such as muscular strength and mass, which are key aims for athletic populations, including British Army recruits. New recruits fail to meet the recommended protein intake during basic training (BT), with negligible amounts consumed in the evening. This study assessed the influence of a daily bolus of protein prior to sleep on performance adaptations, body composition and recovery in British Army recruits. 99 men and 23 women [mean ± standard deviation (SD): age: 21.3 ± 3.5 years, height: 174.8 ± 8.4 cm, body mass 75.4 ± 12.2 kg] were randomised into a dietary control (CON), carbohydrate placebo (PLA), moderate (20 g) protein (MOD) or high (60 g) protein (HIGH) supplementation group. Supplements were isocaloric and were consumed on weekday evenings between 2000 and 2100 for 12 weeks during BT. Performance tests (mid-thigh pull, medicine ball throw, 2 km run time, maximal push-up, and maximal vertical jump) and body composition were assessed at the start and end of BT. Dietary intake, energy expenditure, salivary hormones, urinary nitrogen balance, perceived muscle soreness, rating of perceived exertion, mood, and fatigue were assessed at the start, middle and end of BT. Protein supplementation increased protein intake in HIGH (2.16 ± 0.50 g⸱kg-1⸱day-1) and MOD (1.71 ± 0.48 g⸱kg-1⸱day-1) compared to CON (1.17 ± 0.24 g⸱kg-1⸱day-1) and PLA (1.31 ± 0.29 g⸱kg-1⸱day-1; p < 0.001). Despite this, there was no impact of supplementation on mid-thigh pull performance (CON = 7 ± 19%, PLA = 7 ± 19%, MOD = 0 ± 16%, and HIGH = 4 ± 14%; p = 0.554) or any other performance measures (p > 0.05). Fat-free mass changes were also similar between groups (CON = 4 ± 3%, PLA = 4 ± 4%, MOD = 3 ± 3%, HIGH = 5 ± 4%, p = 0.959). There was no impact of protein supplementation on any other body composition or recovery measure. We conclude no benefits of pre-bed protein supplementation to improve performance, body composition and recovery during BT. It is possible the training stimulus was great enough, limiting the impact of protein supplementation. However, the high degree of inter-participant variability suggests an individualised use of protein supplementation should be explored, particularly in those who consume sub-optimal (<1.6 g⸱kg-1⸱day-1) habitual amounts of protein. Clinical trial registration: The study was registered with ClinicalTrials.gov, U.S. national institutes (identifier: NCT05998590).

Pre-sleep protein supplementation does not improve recovery from load carriage in British Army recruits (part 2).

British Army basic training (BT) is physically demanding with new recruits completing multiple bouts of physical activity each day with limited recovery. Load carriage is one of the most physically demanding BT activities and has been shown to induce acute exercise-induced muscle damage (EIMD) and impair muscle function. Protein supplementation can accelerate muscle recovery by attenuating EIMD and muscle function loss. This study investigated the impact of an additional daily bolus of protein prior to sleep throughout training on acute muscle recovery following a load carriage test in British Army recruits. Ninety nine men and 23 women (mean ± SD: age: 21.3 ± 3.5 yrs., height: 174.8 ± 8.4 cm, body mass 75.4 ± 12.2 kg) were randomized to dietary control (CON), carbohydrate placebo (PLA), moderate (20 g; MOD) or high (60 g; HIGH) protein supplementation. Muscle function (maximal jump height), perceived muscle soreness and urinary markers of muscle damage were assessed before (PRE), immediately post (POST), 24-h post (24 h-POST) and 40-h post (40 h-POST) a load carriage test. There was no impact of supplementation on muscle function at POST (p = 0.752) or 40 h-POST (p = 0.989) load carriage but jump height was greater in PLA compared to HIGH at 24 h-POST (p = 0.037). There was no impact of protein supplementation on muscle soreness POST (p = 0.605), 24 h-POST (p = 0.182) or 40 h-POST (p = 0.333). All groups had increased concentrations of urinary myoglobin and 3-methylhistidine, but there was no statistical difference between groups at any timepoint (p > 0.05). We conclude that pre-sleep protein supplementation does not accelerate acute muscle recovery following load carriage in British Army recruits during basic training. The data suggests that consuming additional energy in the form of CHO or protein was beneficial at attenuating EIMD, although it is acknowledged there were no statistical differences between groups. Although EIMD did occur as indicated by elevated urinary muscle damage markers, it is likely that the load carriage test was not arduous enough to reduce muscle function, limiting the impact of protein supplementation. Practically, protein supplementation above protein intakes of 1.2 g⸱kg-1⸱day-1 following load carriage over similar distances (4 km) and carrying similar loads (15-20 kg) does not appear to be warranted.

A Promiscuous rSAM Enzyme Enables Diverse Peptide Cross-linking.

Ribosomally produced and post-translationally modified polypeptides (RiPPs) are a diverse group of natural products that are processed by a variety of enzymes to their biologically relevant forms. PapB is a member of the radical S-adenosyl-l-methionine (rSAM) superfamily that introduces thioether cross-links between Cys and Asp residues in the PapA RiPP. We report that PapB has high tolerance for variations in the peptide substrate. Our results demonstrate that branched side chains in the thiol- and carboxylate-containing residues are processed and that lengthening of these groups to homocysteine and homoglutamate does not impair the ability of PapB to form thioether cross-links. Remarkably, the enzyme can even cross-link a peptide substrate where the native Asp carboxylate moiety is replaced with a tetrazole. We show that variations to residues embedded between the thiol- and carboxylate-containing residues are tolerated by PapB, as peptides containing both bulky (e.g., Phe) and charged (e.g., Lys) side chains in both natural L- and unnatural D-forms are efficiently cross-linked. Diastereomeric peptides bearing (2S,3R)- and (2S,3S)-methylaspartate are processed by PapB to form cyclic thioethers with markedly different rates, suggesting the enzymatic hydrogen atom abstraction event for the native Asp-containing substrate is diastereospecific. Finally, we synthesized two diastereomeric peptide substrates bearing E- and Z-configured γ,δ-dehydrohomoglutamate and show that PapB promotes addition of the deoxyadenosyl radical (dAdo•) instead of hydrogen atom abstraction. In the Z-configured γ,δ-dehydrohomoglutamate substrate, a fraction of the dAdo-adduct peptide is thioether cross-linked. In both cases, there is evidence for product inhibition of PapB, as the dAdo-adducts likely mimic the native transition state where dAdo• is poised to abstract a substrate hydrogen atom. Collectively, these findings provide critical insights into the arrangement of reacting species in the active site of the PapB, reveal unusual promiscuity, and highlight the potential of PapB as a tool in the development peptide therapeutics.

The incidence of personal importation of prescription medicines among Australians 45 and older: a cross-sectional survey.

Objective This study is the first to investigate the incidence of personal importation of prescription medicines among Australians aged 45 years or older, and the reasons driving this behaviour. Methods An online survey was distributed to Australians, aged 45 years or older, who were taking prescription medicines. Recruitment was conducted via Qualtrics. The survey was completed by 1180 respondents. Results In our sample, 1.8% of respondents had imported prescription medicines in the previous 12 months, 21.9% had not taken, or had delayed taking, a prescribed medicine due to cost, 21.9% described medicines as unaffordable/very unaffordable, and 17.7% took some budgetary measure to pay for their medicines. The most significant predictors (P < 0.001) of importation were doctors raising it as an option (1.0% vs 42.9%), awareness of the Personal Importation Scheme (0.8% vs 22.6%), believing that importing was safe (1.6% vs 20.9%), paying more than the maximum PBS co-payment for any individual medicine (0.4% vs 8.1%), higher monthly spend on medicines (1.0% vs 6%), and delaying or not taking a medicine due to cost (0.9% vs 5.0%). Almost half (44.4%) would consider importing medicines to save money. Conclusions Potentially hundreds of thousands of Australians are importing prescription medicines from abroad, and many Australians indicate they are willing to import medicines to save money.

Statin-induced Mitochondrial Priming Sensitizes Multiple Myeloma Cells to BCL2 and MCL-1 Inhibitors.

The BCL2 inhibitor venetoclax promotes apoptosis in blood cancer cells and is approved for treatment of chronic lymphocytic leukemia and acute myeloid leukemia. However, multiple myeloma cells are frequently more dependent on MCL-1 for survival, conferring resistance to venetoclax. Here we report that mevalonate pathway inhibition with statins can overcome resistance to venetoclax in multiple myeloma cell lines and primary cells. In addition, statins sensitize to apoptosis induced by MCL-1 inhibitor, S63845. In retrospective analysis of venetoclax clinical studies in multiple myeloma, background statin use was associated with a significantly enhanced rate of stringent complete response and absence of progressive disease. Statins sensitize multiple myeloma cells to venetoclax by upregulating two proapoptotic proteins: PUMA via a p53-independent mechanism and NOXA via the integrated stress response. These findings provide rationale for prospective testing of statins with venetoclax regimens in multiple myeloma. SIGNIFICANCE: BH3 mimetics including venetoclax hold promise for treatment of multiple myeloma but rational combinations are needed to broaden efficacy. This study presents mechanistic and clinical data to support addition of pitavastatin to venetoclax regimens in myeloma. The results open a new avenue for repurposing statins in blood cancer.

Phylogenetics and biomineralization of a novel magnetotactic Gammaproteobacterium from a freshwater lake in Beijing, China.

Magnetotactic bacteria (MTB) have the remarkable capability of producing intracellularly membrane-enveloped magnetic nanocrystals (i.e. magnetosomes) and swimming along geomagnetic field lines. Despite more than 50 years of research, bacterial diversity and magnetosome biomineralization within MTB are relatively less known in the Gammaproteobacteria class than other groups. This is incompatible with the status of Gammaproteobacteria as the most diverse class of gram-negative bacteria with a number of ecologically important bacteria. Here, we identify a novel MTB strain YYHR-1 affiliated with the Gammaproteobacteria class of the Pseudomonadota phylum from a freshwater lake. In YYHR-1, most magnetosome crystals are organized into a long chain aligned along the cell long axis; unusually, a few small superparamagnetic crystals are located at the side of the chain, off the main chain axis. Micromagnetic simulations indicate that magnetostatic interactions among adjacent crystals within a chain reduce the Gibbs energy to enhance chain stability. Genomic analysis suggests that duplication of magnetosome gene clusters may result in off-chain magnetosomes formation. By integrating available genomic data from Gammaproteobacteria, the phylogenetic position of MTB in this class is reassigned here. Our new findings expand knowledge about MTB diversity and magnetosome biomineralization, and deepen understanding of the phylogenetics of the Gammaproteobacteria.

Deaminative ring contraction for the synthesis of polycyclic heteroaromatics: a concise total synthesis of toddaquinoline.

A concise strategy to prepare polycyclic heteroaromatics involving a deaminative contraction cascade is detailed. The efficient deaminative ring contraction involves the in situ methylation of a biaryl-linked dihydroazepine to form a cyclic ammonium cation that undergoes a base-induced [1,2]-Stevens rearrangement/dehydroamination sequence. The presence of pseudosymmetry guides the retrosynthetic analysis of pyridyl-containing polycyclic heteroaromatics, enabling their construction by the reductive cyclization and deaminative contraction of tertiary amine precursors.