SGLT2 Inhibitors - The New Standard of Care for Cardiovascular, Renal and Metabolic Protection in Type 2 Diabetes: A Narrative Review.

A substantial evidence base supports the use of sodium-glucose cotransporter-2 inhibitors (SGLT2is) in the treatment of type 2 diabetes mellitus (T2DM). This class of medicines has demonstrated important benefits that extend beyond glucose-lowering efficacy to protective mechanisms capable of slowing or preventing the onset of long-term cardiovascular, renal and metabolic (CVRM) complications, making their use highly applicable for organ protection and the maintenance of long-term health outcomes. SGLT2is have shown cost-effectiveness in T2DM management and economic savings over other glucose-lowering therapies due to reduced incidence of cardiovascular and renal events. National and international guidelines advocate SGLT2i use early in the T2DM management pathway, based upon a plethora of supporting data from large-scale cardiovascular outcome trials, renal outcomes trials and real-world studies. While most people with T2DM would benefit from CVRM protection through SGLT2i use, prescribing hesitancy remains, potentially due to confusion concerning their place in the complex therapeutic paradigm, variation in licensed indications or safety perceptions/misunderstandings associated with historical data that have since been superseded by robust clinical evidence and long-term pharmacovigilance reporting. This latest narrative review developed by the Improving Diabetes Steering Committee (IDSC) outlines the place of SGLT2is within current evidence-informed guidelines, examines their potential as the standard of care for the majority of newly diagnosed people with T2DM and sets into context the perceived risks and proven advantages of SGLT2is in terms of sustained health outcomes. The authors discuss the cost-effectiveness case for SGLT2is and provide user-friendly tools to support healthcare professionals in the correct application of these medicines in T2DM management. The previously published IDSC SGLT2i Prescribing Tool for T2DM Management has undergone updates and reformatting and is now available as a Decision Tool in an interactive pdf format as well as an abbreviated printable A4 poster/wall chart.

A new variant of the inherent strain method for the prediction of distortion in powder bed fusion additive manufacturing processes.

A new variant of the inherent strain (IS) method is proposed to predict component distortion in powder bed fusion additive manufacturing (AM) that addresses some of the shortcomings of the previous work by accounting for both the compressive plastic strain formed adjacent to the melt pool and the thermal strain associated with the changing macroscale thermal field in the component during fabrication. A 3D thermomechanical finite element (FE) model using the new approach is presented and applied to predict the distortion of a component fabricated in an electron beam powder bed fusion (EB-PBF) machine. To improve computational efficiency, each computational layer is comprised of six powder layers. A time-averaged volumetric heat input based on beam voltage and current data obtained from the EB-PBF system was calculated and applied to each computational layer, consistent with the process timing. The inherent strains were applied per computational layer as an initial anisotropic contribution to the thermal strain at the time of activation of each computational layer, resulting in the sequential establishment of static equilibrium during component fabrication, which accounts for the variation in the local macroscale thermal field. The thermal field and distortion predicted by the thermomechanical model were verified using experimentally derived data. The model predicts in-plane compressive strains in the order of 10-3. Differences in the inherent strain were found at different locations in the component, consistent with differences in the macroscale thermal field. The proposed method is general and may also be applied to the laser powder bed fusion (L-PBF) process.

Mendelian randomization of chronic hepatitis B and cardiovascular disease.

Background: Evidence from observational studies suggests that chronic hepatitis B (CHB) is associated with cardiovascular disease (CVD). However, results have been inconsistent and causality remains to be established. We utilized two-sample Mendelian randomization (MR) to investigate potential causal associations between CHB and CVD, including atherosclerosis, coronary heart disease, hypertension, and ischemic stroke. Methods: The analysis was conducted through genome-wide association studies (GWAS), considering chronic hepatitis B as the exposure and cardiovascular disease as the endpoint. The primary method for evaluating causality in this analysis was the inverse-variance weighted (IVW) technique. Additionally, we employed the weighted median, MR-Egger regression, weighted mode, and simple mode methods for supplementary analyses. Finally, heterogeneity tests, sensitivity analyses, and multiple effects analyses were conducted. Results: In a random-effects IVW analysis, we found that genetic susceptibility to chronic hepatitis B was associated with an increased risk of atherosclerosis [OR = 1.048, 95% CI (1.022-1.075), P = 3.08E-04], as well as an increased risk of coronary heart disease [OR = 1.039, 95% CI (1.006-1.072), P = 0.020]. However, it was found to be inversely correlated with ischemic stroke risk [OR = 0.972, 95% CI (0.957-0.988), P = 4.13E-04]. There was no evidence that chronic hepatitis B was associated with hypertension [OR = 1.021, 95% CI (0.994-1.049), P = 0.121]. Conclusion: Our research indicates that chronic hepatitis B has a correlation with an elevated risk of developing atherosclerosis and coronary heart disease, while it is associated with a decreased risk of experiencing an ischemic stroke.

Caregiver perceptions of a pediatric produce prescription program during the COVID-19 pandemic.

Introduction: Produce prescription programs are rapidly expanding as a type of Food is Medicine intervention with prospects for mitigating food insecurity and reducing diet-related health disparities. Gaining insight into participant perspectives on program logistics and perceived impacts is crucial to program success and improvements. Methods: Between May and June 2021, we conducted individual and small group interviews with 23 caregivers with children aged 1-5 years who participated in a produce prescription program from 2020 to 2021 in Texas, U.S. They were provided with a gift card to a major national grocery retailer to purchase fresh produce. The card was reloaded $60 monthly for 8 months with automatic roll-over of unused funds to the next month. Participants also received nutrition education in the form of two videos. A deductive analysis approach was employed, and NVivo qualitative data analysis software was used to perform coding and to assist with subsequent analyses. Results: All 23 participants were female, with an average age of 37.5 years, and the majority identified as Hispanic/Latino (83%). About 43% of the families had three or more children. Six themes were generated from interviews. Three of these themes were related to program logistics: (1) ease of program use; (2) participant satisfaction with the incentive; and (3) desire for additional store options. The remaining main themes pertained to program impact: (1) the enhanced ability to purchase produce; (2) the usefulness of the nutrition education; and (3) persistent challenges encountered when preparing the produce for picky eaters and young children. Conclusion: A pediatric produce prescription program was perceived as logistically easy and a helpful source of financial support for accessing fresh produce. Program features such as card-based incentive system and partnership with major grocery retailer were favored by participants. For future program design, it may be beneficial to consider collaborating with multiple grocery outlets and enhancing the intensity and targeting of nutrition education.

Implementation of Food is Medicine Programs in Healthcare Settings: A Narrative Review.

Food is Medicine (FIM) programs to improve the accessibility of fruits and vegetables (FVs) or other healthy foods among patients with low income and diet-related chronic diseases are promising to improve food and nutrition security in the United States (US). However, FIM programs are relatively new and implementation guidance for healthcare settings using an implementation science lens is lacking. We used a narrative review to describe the evidence base on barriers and facilitators to FIM program integration in US healthcare settings following the Exploration, Preparation, Implementation, and Sustainment (EPIS) Framework. Evidence surrounding the EPIS Inner Context was a focus, including constructs Leadership, Organizational Characteristics, Quality and Fidelity Monitoring and Support, Organizational Staffing Processes, and Individual Characteristics. Peer-reviewed and grey literature about barriers and facilitators to FIM programs were of interest, defined as programs that screen and refer eligible patients with diet-related chronic disease experiencing food insecurity to healthy, unprepared foods. Thirty-one sources were included in the narrative review, including 22 peer-reviewed articles, four reports, four toolkits, and one thesis. Twenty-eight sources (90%) described EPIS Inner Context facilitators and 26 sources (84%) described FIM program barriers. The most common barriers and facilitators to FIM programs were regarding Quality and Fidelity Monitoring and Support (e.g., use of electronic medical records for tracking and evaluation, strategies to support implementation) and Organizational Staffing Processes (e.g., clear delineation of staff roles and capacity); although, barriers and facilitators to FIM programs were identified among all EPIS Inner Context constructs. We synthesized barriers and facilitators to create an EPIS-informed implementation checklist for healthcare settings for use among healthcare organizations/providers, partner organizations, and technical assistance personnel. We discuss future directions to align FIM efforts with implementation science terminology and theories, models, and frameworks to improve the implementation evidence base and support FIM researchers and practitioners.

Are prophylactic antibiotics required for combined intracavitary and interstitial brachytherapy of gynecologic cancers?

The purpose of this study is to evaluate the need for prophylactic antibiotic treatment prior to combined intracavitary and interstitial (hybrid) brachytherapy for gynecologic cancer. A total of 105 gynecologic cancer patients received 405 brachytherapy sessions, including 302 sessions of intracavitary brachytherapy and 103 sessions of hybrid brachytherapy. Prophylactic antibiotics were administered before 35% of the hybrid brachytherapy sessions. The incidence of postbrachytherapy fever and the frequency of subsequent antibiotic use for infection were compared between treatment groups. Among patients treated with hybrid brachytherapy, fever ≥37.5°C occurred in 16.4% of those not receiving prophylactic antibiotics and 16.7% of those receiving prophylactic antibiotics (P > 0.05). Similarly, fever ≥38.0°C occurred in 4.9% of patients not receiving prophylactic antibiotics and 2.4% of those receiving prophylactic antibiotics (P > 0.05). Additional antibiotics were used to treat postbrachytherapy infections in 4.8% of the group receiving prophylactic antibiotics and 0% of those not receiving prophylactic antibiotics, again without statistically significant difference. There were also no significant differences in posttreatment fever incidence and antibiotics use for infection between intracavitary brachytherapy and hybrid brachytherapy sessions. In conclusion, the incidences of infection and fever are low following hybrid brachytherapy, so prophylactic antibiotics are generally unnecessary.

Antecedents and outcomes of cyberbullying among Chinese university students: verification of a behavioral pathway model.

Introduction: Cyberbullying is a commonly-seen and hotly-debated social topic around the globe. This negative behavior is the source of many disastrous events, and so leading government bodies, organizations, schools and social communities attach great importance to addressing this topic. However, there is still much work to do in order to be clear about the causes of cyberbullying. Methods: The previous research cases were mostly viewed from the victims' perspectives; however, there is no comprehensive understanding of the perpetrators' viewpoints. Therefore, based on Social Cognitive Theory (SCT) and analysis of discussion in the literature, the following six variables were chosen as the focus of this study: overconfidence, excessive moral sense, cyberbullying, perceived value, happiness, and continued cyberbullying intention. This study established a research model of continued cyberbullying intention, which was verified by Structural Equation Modeling. In order to achieve the aims of the study, Chinese university students with an average age of 20.29 (SD = 1.43) were recruited as participants, from whom 1,048 valid questionnaires were collected. Results: The research results are as follows: 1. Overconfidence and excessive moral sense positively predicted cyberbullying behaviors; 2. Overconfidence positively predicted excessive moral sense; 3. Cyberbullying positively predicted perceived value and sense of happiness; and 4. Perceived value and sense of happiness positively predicted continued cyberbullying intentions. Conclusion: Students' biased self-perception significantly predicts their cyberbullying behaviors and continued cyberbullying intention. What is more, it is interesting to learn that perpetrators will continue to exhibit cyberbullying behaviors when they believe that what they do (cyberbullying) is valuable or allows them to experience positive feelings; this requires our attention.

Huang Lian Jie Du Decoction enhances the anti-tumor efficacy of immune checkpoint inhibitors by activating TLR7/8 signalling in melanoma.

BACKGROUND: The clinical application of immune checkpoint inhibitors (ICIs) is limited by their drug resistance, necessitating the development of ICI sensitizers to improve cancer immunotherapy outcomes. Huang Lian Jie Du Decoction (HLJD, Oren-gedoku-to in Japanese, Hwangryunhaedok-tang in Korean), a famous traditional Chinese medicinal prescription, has exhibited potential in the field of cancer treatment. This study aims to investigate the impact of HLJD on the efficacy of ICIs in melanoma and elucidate the underlying mechanisms. METHODS: The potential synergistic effects of HLJD and ICIs were investigated on the tumor-bearing mice model of B16F10 melanoma, and the tumor infiltration of immune cells was tested by flow cytometry. The differential gene expression in tumors between HLJD and ICIs group and ICIs alone group were analyzed by RNA-seq. The effects of HLJD on oxidative stress, TLR7/8, and type I interferons (IFN-Is) signaling were further validated by immunofluorescence, PCR array, and immunochemistry in tumor tissue. RESULTS: HLJD enhanced the anti-tumor effect of ICIs, significantly inhibited tumor growth, and prolonged the survival duration in melanoma. HLJD increased the tumor infiltration of anti-tumor immune cells, especially DCs, CD4+ T cells and CD8+T cells. Mechanically, HLJD activated the oxidative stress and TLR7/8 signaling pathway and IFN-Is-related genes in tumors. CONCLUSIONS: HLJD enhanced the therapeutic benefits of ICIs in melanoma, through increasing reactive oxygen species (ROS), promoting the TLR7/8 pathway, and activating IFN-Is signaling, which in turn activated DCs and T cells.

An explainable AI-assisted web application in cancer drug value prediction.

In recent years, there has been an increase in the interest in adopting Explainable Artificial Intelligence (XAI) for healthcare. The proposed system includes•An XAI model for cancer drug value prediction. The model provides data that is easy to understand and explain, which is critical for medical decision-making. It also produces accurate projections.•A model outperformed existing models due to extensive training and evaluation on a large cancer medication chemical compounds dataset.•Insights into the causation and correlation between the dependent and independent actors in the chemical composition of the cancer cell. While the model is evaluated on Lung Cancer data, the architecture offered in the proposed solution is cancer agnostic. It may be scaled out to other cancer cell data if the properties are similar. The work presents a viable route for customizing treatments and improving patient outcomes in oncology by combining XAI with a large dataset. This research attempts to create a framework where a user can upload a test case and receive forecasts with explanations, all in a portable PDF report.

Dosimetric comparison of intra-cavitary brachytherapy technique with free-hand (intra-cavitary + interstitial) technique in cervical cancer.

Purpose: The aim of the study was to dosimetrically compare intra-cavitary brachytherapy technique (ICBT) with free-hand (intra-cavitary + interstitial, IC + IS) technique. Material and methods: Twenty seven locally advanced carcinoma cervix patients were included in the study. Patients with more than medial 1/3rd parametrial residual disease without extending upto lateral pelvic wall were included, following external beam radiotherapy (EBRT), in which cobalt-60 high-dose-rate (60Co HDR) brachytherapy source was used. Dose for both plans were 6.5 Gy × 4 fractions, 2 fractions per day, 6 hours apart, over 2 days. Free-hand brachytherapy technique, consisted of placement of central tandem and 2 ovoids along with needles without using template, was applied. Two plans were generated by activating and deactivating the needles, and compared by normalizing to V100. Results: A total of 79 needles were applied. Using paired-t test, dosimetric comparison of both the plans was done. Free-hand plan had a significant higher mean V90 (volume receiving 90% of the dose) of 94.2% compared with 87.22% in ICBT plan (p ≤ 0.0001). Free-hand and ICBT plans presented a mean V100 values of 89.06% and 81.51% (p ≤ 0.0001), respectively, favoring free-hand plan. The mean D90 (dose to 90% volume), D98, and D100 of free-hand plan were 6.28 Gray (Gy), 4.91 Gy, and 3.62 Gy, respectively, but equivalent parameters in ICBT plan were 5.26 Gy, 3.72 Gy, and 2.61 Gy, with p value ≤ 0.0001. In both the plans, D2cc of the bladder, rectum, and sigmoid were 4.59 Gy, 3.98 Gy, 2.77 Gy, and 4.46 Gy, 3.90 Gy, 2.67 Gy, respectively, with no statistical significance. Conclusions: Free-hand brachytherapy (IC + IS) achieves a statistically significant better dose distribution to high-risk clinical target volume (HR-CTV) comparing with ICBT technique with similar dose to organs at risk.

Genomic Characterization of IS6110 Insertions in Mycobacterium orygis.

Mycobacterium orygis, a subspecies of the Mycobacterium tuberculosis complex (MTBC), has emerged as a significant concern in the context of One Health, with implications for zoonosis or zooanthroponosis or both. MTBC strains are characterized by the unique insertion element IS6110, which is widely used as a diagnostic marker. IS6110 transposition drives genetic modifications in MTBC, imparting genome plasticity and profound biological consequences. While IS6110 insertions are customarily found in the MTBC genomes, the evolutionary trajectory of strains seems to correlate with the number of IS6110 copies, indicating enhanced adaptability with increasing copy numbers. Here, we present a comprehensive analysis of IS6110 insertions in the M. orygis genome, utilizing ISMapper, and elucidate their genetic consequences in promoting successful host adaptation. Our study encompasses a panel of 67 paired-end reads, comprising 11 isolates from our laboratory and 56 sequences downloaded from public databases. Among these sequences, 91% exhibited high-copy, 4.5% low-copy, and 4.5% lacked IS6110 insertions. We identified 255 insertion loci, including 141 intragenic and 114 intergenic insertions. Most of these loci were either unique or shared among a limited number of isolates, potentially influencing strain behavior. Furthermore, we conducted gene ontology and pathway analysis, using eggNOG-mapper 5.0, on the protein sequences disrupted by IS6110 insertions, revealing 63 genes involved in diverse functions of Gene Ontology and 45 genes participating in various KEGG pathways. Our findings offer novel insights into IS6110 insertions, their preferential insertion regions, and their impact on metabolic processes and pathways, providing valuable knowledge on the genetic changes underpinning IS6110 transposition in M. orygis.

Indoxyl sulphate-TNFα axis mediates uremic encephalopathy in rodent acute kidney injury.

Acute kidney injury (AKI) is often accompanied by uremic encephalopathy resulting from accumulation of uremic toxins in brain possibly due to impaired blood-brain barrier (BBB) function. Anionic uremic toxins are substrates or inhibitors of organic anionic transporters (OATs). In this study we investigated the CNS behaviors and expression/function of BBB OAT3 in AKI rats and mice, which received intraperitoneal injection of cisplatin 8 and 20 mg/kg, respectively. We showed that cisplatin treatment significantly inhibited the expressions of OAT3, synaptophysin and microtubule-associated protein 2 (MAP2), impaired locomotor and exploration activities, and increased accumulation of uremic toxins in the brain of AKI rats and mice. In vitro studies showed that uremic toxins neither alter OAT3 expression in human cerebral microvascular endothelial cells, nor synaptophysin and MAP2 expressions in human neuroblastoma (SH-SY5Y) cells. In contrast, tumour necrosis factor alpha (TNFα) and the conditioned medium (CM) from RAW264.7 cells treated with indoxyl sulfate (IS) significantly impaired OAT3 expression. TNFα and CM from IS-treated BV-2 cells also inhibited synaptophysin and MAP2 expressions in SH-SY5Y cells. The alterations caused by TNFα and CMs in vitro, and by AKI and TNFα in vivo were abolished by infliximab, a monoclonal antibody designed to intercept and neutralize TNFα, suggesting that AKI impaired the expressions of OAT3, synaptophysin and MAP2 in the brain via IS-induced TNFα release from macrophages or microglia (termed as IS-TNFα axis). Treatment of mice with TNFα (0.5 mg·kg-1·d-1, i.p. for 3 days) significantly increased p-p65 expression and reduced the expressions of Nrf2 and HO-1. Inhibiting NF-κB pathway, silencing p65, or activating Nrf2 and HO-1 obviously attenuated TNFα-induced downregulation of OAT3, synaptophysin and MAP2 expressions. Significantly increased p-p65 and decreased Nrf2 and HO-1 protein levels were also detected in brain of AKI mice and rats. We conclude that AKI inhibits the expressions of OAT3, synaptophysin and MAP2 due to IS-induced TNFα release from macrophages or microglia. TNFα impairs the expressions of OAT3, synaptophysin and MAP2 partly via activating NF-κB pathway and inhibiting Nrf2-HO-1 pathway.

Development and evaluation of a single-tube nested PCR with colorimetric assay for Mycobacterium tuberculosis detection.

Molecular techniques have revolutionized tuberculosis (TB) diagnosis by offering a faster and more sensitive approach, detecting Mycobacterium tuberculosis (Mtb) DNA directly from samples. Single-tube nested PCR (STNPCR) combines two PCR reactions with separate oligonucleotide sets in a single tube. Moreover, colorimetric methods in PCR products have been studied for pathogen detection. Thus, this study aimed to establish a novel system based on colorimetric STNPCR for Mtb detection using microtiter plates with IS6110-amplified fragments. The results showed a general colorimetric STNPCR detection limit of 1 pg/µl. Its general sensitivity and specificity were 76.62 and 60.53%, respectively, with kappa index agreement of 0.166.

Finger printing-RFLP analysis of chromosomal IS6110 insertion sequence and PCR diagnosis of pulmonary tuberculosis, isolated from patients in El Hajeb region of Morocco.

Tuberculosis (TB) is one of the contagious diseases caused by M. tuberculosis (MTB) bacteria. Prompt diagnosis is one of the active solutions to control the spread of this infection. Besides, a targeted, specific and non-complex diagnosis can prove promising in this type of epidemic. This study was designed to compare the efficiencies of a diagnosis by Ziehl-Neelsen staining (ZN) and by the polymerase chain reaction (PCR) technique. Samples presented smear-positive pulmonary TB were subjected to Chromosomal restriction fragment length polymorphism of IS6110 (IS6110-RFLP) for fingerprinting profile determination. The results showed that out of 100 sputum samples of suspected case, 53 were positive. Numbers of positive individuals for tuberculosis obtained by the different diagnostic techniques, to know, (ZN staining; culture and PCR) were respectively: 6, 25 and 22. Chromosomal RFLP fingerprinting profile revealed the presence of five different genotypes obtained from seven tested isolates. These results suggest that molecular techniques are alternative tool for fast and specific diagnosis of pulmonary MTB from sputum.

Relationship Between Alexithymia, Smartphone Addiction, and Psychological Distress Among University Students: A Multi-country Study.

Objectives: Increasing dependence on smartphones results in the appearance of psychological problems, especially among young people. This study aims to determine the rates of alexithymia and its relationship with smartphone addiction and psychological distress in university students. Methods: A total of 2616 students (mean age = 22.5±3.5 years; 73.1% female) from universities in Egypt, Oman, and Pakistan were included in a cross-sectional and comparative study conducted through a web survey during the COVID-19 pandemic from October to December 2021. The following scales were used: Toronto Alexithymia Scale (TAS-20), Depression Anxiety Stress Scale (DASS-21), and Smartphone Addiction Scale-Short Version (SAS-SV). The survey also included questions related to sociodemographic and smartphone usage patterns.

[Primary pulmonary myxoid sarcoma with EWSR1-CREB1 fusion]. / Pervichnaya legochnaya miksoidnaya sarkoma so sliyaniem genov EWSR1-CREB1.

Primary pulmonary myxoid sarcoma with EWSR1-CREB1 fusion is an extremely rare tumor. Its clinical manifestation is unspecific and only molecular genetic method can proof this diagnosis. This paper describes an unusual clinical presentation of primary pulmonary myxoid sarcoma in a 68-year-old patient with involvement of both lungs.

Impact of COVID-19 public health restrictions on pregnant people's mental health, a mixed methods study.

The COVID-19 pandemic impacted the provision of obstetrical care. This mixed-methods study explores pregnant women's experiences during the COVID-19 pandemic using an explanatory sequential design. The experiences and opinions of obstetrical patients were elicited using an online questionnaire and semi-structured interview as a follow-up. There were 162 completed questionnaires, and 17 interviews. Qualitative analysis themes included worries about the intrapartum experience, impact on partners, and lack of postpartum support for breastfeeding and mental health. This study provides understanding of how the pandemic impacted pregnancy experiences, and the potential future repercussions of isolation and restrictions on wellbeing during public health crises. RéSUMé: La pandémie de COVID-19 a influencé la prestation de soins obstétricaux. Cette étude mixte explore les expériences des femmes enceintes pendant la pandémie de COVID-19 à l'aide d'un plan de recherche séquentiel explicatif. Les expériences et les opinions des patientes en obstétrique ont été recueillies par un questionnaire en ligne et par un entretien semi-structuré de suivi. Au total, 162 questionnaires ont été remplis et 17 entretiens ont eu lieu. Les thèmes de l'analyse qualitative portaient sur les inquiétudes liées à l'expérience d'accouchement, l'impact pour le partenaire et le manque de soutien post-partum pour l'allaitement et la santé mentale. Cette étude permet de comprendre l'impact de la pandémie sur les expériences de grossesse et les répercussions potentielles futures des restrictions et de l'isolement sur le bien-être pendant les crises de santé publique.

A metagenomics pipeline reveals insertion sequence-driven evolution of the microbiota.

Insertion sequence (IS) elements are mobile genetic elements in bacterial genomes that support adaptation. We developed a database of IS elements coupled to a computational pipeline that identifies IS element insertions in the microbiota. We discovered that diverse IS elements insert into the genomes of intestinal bacteria regardless of human host lifestyle. These insertions target bacterial accessory genes that aid in their adaptation to unique environmental conditions. Using IS expansion in Bacteroides, we show that IS activity leads to the insertion of "hot spots" in accessory genes. We show that IS insertions are stable and can be transferred between humans. Extreme environmental perturbations force IS elements to fall out of the microbiota, and many fail to rebound following homeostasis. Our work shows that IS elements drive bacterial genome diversification within the microbiota and establishes a framework for understanding how strain-level variation within the microbiota impacts human health.

The effect of DNA-binding proteins on insertion sequence element transposition upstream of the bgl operon in Escherichia coli.

The bglGFB operon in Escherichia coli K-12 strain BW25113, encoding the proteins necessary for the uptake and metabolism of ß-glucosides, is normally not expressed. Insertion of either IS1 or IS5 upstream of the bgl promoter activates expression of the operon only when the cell is starving in the presence of a ß-glucoside, drastically increasing transcription and allowing the cell to survive and grow using this carbon source. Details surrounding the exact mechanism and regulation of the IS insertional event remain unclear. In this work, the role of several DNA-binding proteins in how they affect the rate of insertion upstream of bgl are examined via mutation assays and protocols measuring transcription. Both Crp and IHF exert a positive effect on insertional Bgl+ mutations when present, active, and functional in the cell. Our results characterize IHF's effect in conjunction with other mutations, show that IHF's effect on IS insertion into bgl also affects other operons, and indicate that it may exert its effect by binding to and altering the DNA conformation of IS1 and IS5 in their native locations, rather than by directly influencing transposase gene expression. In contrast, the cAMP-CRP complex acts directly upon the bgl operon by binding upstream of the promoter, presumably altering local DNA into a conformation that enhances IS insertion.

The "Starting-Small" Effect in Phonology: Evidence From Biased Learning of Opaque and Transparent Vowel Harmony.

The starting-small effect is a cognitive advantage in language acquisition when learners begin by generalizing on regularities from structurally simple and shorter tokens in a skewed input distribution. Our study explored this effect as a potential explanation for the biased learning of opaque and transparent vowel harmony. In opaque vowel harmony, feature agreement occurs strictly between adjacent vowels, and an intervening "neutral vowel" blocks long-distance vowel harmony. Thus, opaque vowel harmony could be acquired even if learners start with structurally simpler and more frequent disyllabic tokens. Alternatively, transparent vowel harmony can only be observed in longer tokens demonstrating long-distance agreement by skipping a neutral vowel. Opaque vowel harmony is predicted to be learned more efficiently due to its compatibility with local dependency acquired via starting-small learning. In two artificial grammar learning experiments, learners were exposed to both vowel harmony patterns embedded in an equal number of disyllabic and trisyllabic tokens or a skewed distribution with twice as many disyllabic tokens. In Exp I, learners' test performance suggests the consistently biased learning of local and opaque vowel harmony with starting-small learning. Furthermore, in Exp II, the acquired vowel harmony patterns varied significantly by working memory capacity with a balanced but not skewed input distribution, presumably because of the ease of cognitive demand with starting-small learning.