Hypoxia-inducible transcription factors (HIFs) facilitate cellular adaptations to low-oxygen environments. However, it is increasingly recognised that HIFs may be activated in response to metabolic ...stimuli, even when oxygen is present. Understanding the mechanisms for the crosstalk that exists between HIF signalling and metabolic pathways is therefore important. This review focuses on the metabolic regulation of HIFs by small molecule metabolites and iron, highlighting the latest studies that explore how tricarboxylic acid (TCA) cycle intermediates, 2-hydroxyglutarate (2-HG) and intracellular iron levels influence the HIF response through modulating the activity of prolyl hydroxylases (PHDs). We also discuss the relevance of these metabolic pathways in physiological and disease contexts. Lastly, as PHDs are members of a large family of 2-oxoglutarate (2-OG) dependent dioxygenases that can all respond to metabolic stimuli, we explore the broader role of TCA cycle metabolites and 2-HG in the regulation of 2-OG dependent dioxygenases, focusing on the enzymes involved in chromatin remodelling.
Ovarian estrogens may influence the development of the human brain and behavior, but there are few opportunities to test this possibility. Isolated GnRH deficiency (IGD) is a rare endocrine disorder ...that could provide evidence for the role of estrogens in organizing sexually differentiated phenotypes: Unlike typical development, development in individuals with IGD is characterized by low or absent gonadal hormone production after the first trimester of gestation. Because external genitalia develop in the first trimester, external appearance is nevertheless concordant with gonadal sex in people with IGD. We therefore investigated the effects of gonadal hormones on sexual orientation by comparing participants with IGD (n = 97) to controls (n = 1670). Women with IGD reported lower male-attraction compared with typically developing women. In contrast, no consistent sexuality differences between IGD and typically developing men were evident. Ovarian hormones after the first trimester appear to influence female-typical dimensions of sexual orientation.
•Studied effects of perinatal gonadal hormones on human sexual orientation.•Participants were typically-developing or had isolated GnRH deficiency (IGD).•Women with IGD reported lower androphilia and higher levels of bisexuality.•There were no consistent differences between the two groups of men.•Results suggest a role of perinatal estrogens in organizing sexual orientation.
Productive biomolecular recognition requires exquisite control of affinity and specificity. Accordingly, nature has devised many strategies to achieve proper binding interactions. Bacterial ...multicomponent monooxygenases provide a fascinating example, where a diiron hydroxylase must reversibly interact with both ferredoxin and catalytic effector in order to achieve electron transfer and O2 activation during catalysis. Because these two accessory proteins have distinct structures, and because the hydroxylase-effector complex covers the entire surface closest to the hydroxylase diiron centre, how ferredoxin binds to the hydroxylase has been unclear. Here we present high-resolution structures of toluene 4-monooxygenase hydroxylase complexed with its electron transfer ferredoxin and compare them with the hydroxylase-effector structure. These structures reveal that ferredoxin or effector protein binding produce different arrangements of conserved residues and customized interfaces on the hydroxylase in order to achieve different aspects of catalysis.
We have investigated the ionospheric response close to the subsolar point in South America due to the strong solar flare (X2.8) that occurred on 13 May 2013. The present work discusses the sudden ...disturbances in the D region in the form of high‐frequency radio wave blackout recorded in ionograms, the E region disturbances in the form of the Sq current and equatorial electrojet intensifications, and the enhancement and decay in the ionospheric total electron content (TEC) as observed by a network of Global Navigation Satellite Systems receivers, the last of these manifestations constituting the main focuses of this study. The dayside ionosphere showed an abrupt increase of the TEC, with the region of the TEC increase being displaced away from the subsolar point toward the equatorial ionization anomaly (EIA) crest region. The decay in the ΔTEC following the decrease of the flare EUV flux varied at a slower ratio near the EIA crest than at the subsolar point. We used the Sheffield University Plasmasphere‐Ionosphere Model to simulate the TEC enhancement and the related variations as arising from the flare‐enhanced solar EUV flux and soft X‐rays. The simulations are compared with the observational data to validate our results, and it is found that a good part of the observed TEC variation features can be accounted for by the model simulation. The combined results from model and observational data can contribute significantly to advance our knowledge about ionospheric photochemistry and dynamics needed to improve our predictive capability on the low‐latitude ionospheric response to solar flares.
Key Points
During the solar flare occurrence, the TEC disturbance is larger at the EIA crest
At the flare initiation, the electron density increases faster at low altitudes
At half an hour after the flare, the F region electron density increase dominates
Bone collagen cross-links are now widely used to assess bone resorption levels in many metabolic bone diseases. The post-translational modifications of bone and other mineralizing collagens are ...significantly different from those of other type I collagen matrices, a fact that has been exploited during recent advances in the development of biochemical markers of bone resorption. The enzymatic collagen cross-linking mechanism is based upon aldehyde formation from specific telopeptide lysine or hydroxylysine residues. The immature ketoimine cross-links in bone form via the condensation of a telopeptide aldehyde with a helical lysine or hydroxylysine. Subsequent maturation to the pyridinoline and pyrrole cross-links occur by further reaction of the ketoimines with telopeptide aldehydes. In mineralizing tissues, a relatively low level of lysyl hydroxylation results in low levels of hydroxylysyl pyridinoline, and the occurrence of the largely bone specific lysyl pyridinoline and pyrrolic cross-links. The collagen post-translational modifications appear to play an integral role in matrix mineralization. The matrix of the turkey tendon only mineralizes after a remodeling of the collagen and the subsequent formation of a modified matrix more typical of bone than tendon. Further, disturbances in the post-translational modification of collagen can also affect the mineralization density and crystal structure of the tissue. In addition to their use as a convenient measure of matrix degradation, collagen cross-links are of significant importance for the biomechanical integrity of bone. Recent studies of osteoporotic bone, for example, have demonstrated that subtle perturbations in the pattern of lysine hydroxylation result in changes in the cross-link profile. These alterations, specifically changes in the level of the pyrrolic cross-link, also correlate with the strength of the bone. Further research into the biochemistry of bone collagen cross-links may expand current understanding and their clinical application in metabolic bone disease. This review also demonstrates the potential for further study into this area to provide more subtle information into the mechanisms and etiology of disease and aging of mineralizing tissues.
Background
Guidelines for urgent investigation of colorectal cancer (CRC) are based on age and symptom-based criteria. This study aims to compare the diagnostic value of clinical features and faecal ...immunochemical test (FIT) results to identify those at a higher risk of CRC, thereby facilitating effective triage of patients.
Methods
We undertook a review of all patients referred for investigation of CRC at our centre between September 2016 and June 2018. Patients were identified using a prospectively recorded local database. We performed a logistic regression analysis of factors associated with a diagnosis of CRC.
Results
One-thousand-and-seven-hundred-eighty-four patients with FIT results were included in the study. Change in bowel habit (CIBH) was the most common referring clinical feature (38.3%). Patients diagnosed with CRC were significantly older than those without malignancy (74.0 years vs 68.9 years,
p
= 0.0007). Male patients were more likely to be diagnosed with CRC than females (6.5% vs 2.5%, Chi-squared 16.93,
p
< 0.0001). CRC was diagnosed in 3.5% (24/684) with CIBH compared to 8.1% (6/74) with both CIBH and iron deficiency anaemia. No individual or combination of referring clinical features was associated with an increased diagnosis of CRC (Chi-squared, 8.03,
p
= 0.155). Three patients with negative FIT results (< 4 µg Hb/g faeces) were diagnosed with CRC (3/1027, 0.3%). The highest proportion of cancers detected was in the ≥ 100 µg Hb/g faeces group (55/181, 30.4%).
Conclusion
In a multivariate model, FIT outperforms age, sex and all symptoms prompting referral. FIT has greater stratification value than any referral symptoms. FIT does have value in patients with iron deficiency anaemia.
Clinical context:
Since 1979 and 1980 when the first reports of clinical feline hyperthyroidism (FHT) appeared in the literature, our understanding of the disease has evolved tremendously. Initially, ...FHT was a disease that only referral clinicians treated. Now it is a disease that primary clinicians routinely manage. Inclusion of the measurement of total thyroxine concentration in senior wellness panels, as well as in diagnostic work-ups for sick cats, now enables diagnosis of the condition long before the cat becomes the classic scrawny, unkempt, agitated patient with a bulge in its neck. However, earlier recognition of the problem has given rise to several related questions: how to recognize the health significance of the early presentations of the disease; how early to treat the disease; whether to treat FHT when comorbid conditions are present; and how to manage comorbid conditions such as chronic kidney disease and cardiac disease with treatment of FHT. The 2016 AAFP Guidelines for the Management of Feline Hyperthyroidism (hereafter referred to as the Guidelines) will shed light on these questions for the general practitioner and suggest when referral may benefit the cat.
Scope:
The Guidelines explain FHT as a primary disease process with compounding factors, and provide a concise explanation of what we know to be true about the etiology and pathogenesis of the disease.
The Guidelines also:
Distill the current research literature into simple recommendations for testing sequences that will avoid misdiagnosis and separate an FHT diagnosis into six clinical categories with associated management strategies.
Emphasize the importance of treating all hyperthyroid cats, regardless of comorbidities, and outline the currently available treatments for the disease.
Explain how to monitor the treated cat to help avoid exacerbating comorbid diseases.
Dispel some of the myths surrounding certain aspects of FHT and replace them with an evidence-based narrative that veterinarians and their practice teams can apply to feline patients and communicate to their owners.
Evidence base:
To help ensure better case outcomes, the Guidelines reflect currently available, evidenced-based knowledge. If research is lacking, or if a consensus does not exist, the expert panel of authors has made recommendations based on their extensive, cumulative clinical experience.
Although buprenorphine is an effective treatment for opioid use disorder (OUD), much remains to be understood about treatment non-response and methods for improving treatment retention. The addition ...of behavioral therapies to buprenorphine has not yielded consistent benefits for opioid outcomes, on average. However, several studies suggest that certain subgroups may benefit from the combination of buprenorphine and behavioral therapy, highlighting the potential for personalized approaches to treatment. Furthermore, little is known about whether behavioral therapies improve buprenorphine retention or non-opioid (e.g., functional) outcomes.
The objective of this project is to harmonize four previously conducted clinical trials testing the addition of behavioral therapy to buprenorphine maintenance for OUD and to use this larger dataset to answer critical clinical questions about the role of behavioral therapy in this population. Study aims include identifying potential moderators of the effect of the addition of behavioral therapy and quantifying the effect of behavioral therapy on buprenorphine retention and functional outcomes.
Analyses will consider outcomes of weeks of opioid use, weeks of retention in buprenorphine treatment, and functional outcomes as measured by the Addiction Severity Index. Analyses will include an indicator for each study to account for heterogeneity of samples and design.
Results will help to inform clinical and research efforts to optimize the use of behavioral therapies in the treatment of OUD.
•The efficacy of behavioral therapy added to buprenorphine for non-opioid outcomes is unclear.•This study will harmonize four clinical trials of treatment for opioid use disorder.•Outcomes include treatment retention and functional outcomes.•Moderators of treatment response will be examined.
PurposeThe Cook Stove Pregnancy Cohort Study (CSPCS) was designed to assess the effects of biomass fuel use on household air pollution (HAP) as well as the effects of HAP (fine particulate matter, ...PM2.5) on birth outcomes and acute lower respiratory infection (ALRI) among infants in Bangladesh.ParticipantsWe recruited 903 women within 18 weeks of pregnancy from rural and semiurban areas of Bangladesh between November 2016 and March 2017. All women and their infants (N=831 pairs) were followed until 12 months after delivery and a subset have undergone respiratory and gut microbiota analysis.MethodsQuestionnaires were administered to collect detailed sociodemographic, medical, nutritional and behavioural information on the mother–child dyads. Anthropometric measurements and biological samples were also collected, as well as household PM2.5 concentrations.Findings to datePublished work in this cohort showed detrimental effects of biomass fuel and health inequity on birth outcomes. Current analysis indicates high levels of household PM2.5 being associated with cooking fuel type and infant ALRI. Lastly, we identified distinct gut and respiratory microbial communities at 6 months of age.Future plansThis study provides an economical yet effective framework to conduct pregnancy cohort studies determining the health effects of adverse environmental exposures in low-resource countries. Future analyses in this cohort include assessing the effect of indoor PM2.5 levels on (1) physical growth, (2) neurodevelopment, (3) age of first incidence and frequency of ALRI in infants and (4) the development of the respiratory and gut microbiome. Additional support has allowed us to investigate the effect of in utero exposure to metals on infant neurodevelopment in the first year of life.
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