Era Of Biology Research Articles

In remembrance: Joseph Gall

ABSTRACT A 14-year boy is given a microscope by his parents. It is not a toy – but a real microscope. He deploys it to rediscover the biology he had known before, but now in a magnified world. With extraordinary intellectual gifts he then, and manifestly later becomes absorbed by the idea that all this, however mysterious at first glance, might be subject to rational understanding, with painstaking study. Thus, was the genesis of one of the greatest cell biologists of the 20th century, Joseph Grafton Gall, who died 12 September 2024, at 96. He had been professionally active up until only a few years ago. There was no one like him in the modern era of cell biology and there will not be another figure like him anytime soon.

Recurrence rates after strictureplasty for small bowel Crohn's disease remain high in the era of biologics.

Despite advancements in therapeutic options for Crohn's disease (CD), strictureplasty is a mainstay bowel-preserving technique for small bowel CD. We sought to audit international practice across three high-volume centres since the widespread use of biologic medication. A retrospective audit was performed for all strictureplasties undertaken for small bowel CD, over a 15-year period (2006-2021), in three high-volume centres in the United Kingdom and Italy. Primary endpoints were clinical recurrence and reoperation for recurrence. In all, 123 patients were included; 58% were men, 25% smoked and 60% had previous abdominal surgery for CD. Median age was 40 years (interquartile range 30-52 years), mean body mass index 22 (15-31) and median disease duration 138 months (81-255 months). 42% had been treated with biologics preoperatively. In total 338 strictureplasties were performed in 123 patients, with a median of two per patient (interquartile range 1-3). Complications occurred in 35%, with 8% scoring Clavien-Dindo Grade 3. There were no Grade 4/5 complications. Postoperative biologic treatment was administered to 84/123 patients (68.3%). Median follow-up was 54 months. 41/123 patients (33.3%) developed clinical recurrence. Reoperation for recurrent stricturing was performed in 26/123 patients (21%). Clinical recurrence and reoperation rates were significantly higher in patients who continued to smoke after their index surgery. Strictureplasty remains a safe and effective surgical treatment for small bowel CD. Recurrence and reoperation rates remain high, regardless of postoperative biologic therapy. Smoking significantly increases the risk of recurrence.

Stable Cu (I) Complexes for Intracellular Cu-Catalyzed Azide Alkyne Cycloaddition.

The copper-catalyzed azide-alkyne cycloaddition (CuAAC) has heralded a new era of chemical biology and biomedicine. However, caveats of CuAAC include formation of reactive oxygen species (ROS) and other copper-related toxicity. This limits utility in sensitive biological samples and matrices. Towards addressing these caveats, we synthesized and fully characterized two air and water stable trinuclear Cu (I) dimer complexes. The complexes were stable to oxidation in the presence of hydrogen peroxide, acid, base, and other chelators, which was reasoned to be due to the linear benzimidazole-Cu-benzimidazole geometry. Computational investigations of the catalytic cycle implicated two of the three coppers in the trimer complex as the active metal centers. The complexes were shown to catalyze the reaction at far below sub-toxic concentrations for intracellular click reactions to label triple negative breast cancer cells and compared to the current CuSO-4-THPTA standard.

Prevalence and incidence of uveitis in patients with spondyloarthritis: the impact of the biologics era. Data from International ASAS-COMOSPA Study.

Uveitis is a common extra-musculoskeletal manifestation in Spondyloarthritis (SpA). The aim of this study was to analyze the prevalence of uveitis in SpA patients, its association with geographical areas and to determine whether its incidence was different before and after the biological era. ASAS-COMOSPA is a retrospective study that includes patients fulfilling ASAS SpA classification criteria from 22 countries. The overall prevalence of uveitis was calculated, and factors associated with the onset of a first episode of uveitis were evaluated using a Cox regression. A Log-Rank test was performed to compare the new onset of uveitis in the no biological era (SpA onset before 2000) vs biological era (SpA onset after 2000). 3984 patients were included. The likelihood of presenting a first uveitis episode increased over time, from a prevalence of 10.5% (95%CI 9.5%-11.4%) at the time of the SpA diagnosis to 46.6% (41.6%-51.5%) after 30 years since the SpA diagnosis. HLA-B27 positivity, family history of uveitis, peripheral enthesitis and IBD were associated with higher risk of uveitis. Patients with SpA disease onset after year 2000 showed a lower prevalence of uveitis compared with disease onset before year 2000 (8.2% vs 25.5%, p< 0.01), as well as a lower incidence (2.8 per 100 PY vs 6.1 per 100 PY, respectively). In our study the risk of having suffered from at least one episode of uveitis ranged from 10% at the time of the diagnosis of axSpA to 47% after 30 years of disease duration. Patients with disease onset after biologic therapy introduction showed a significantly lower prevalence and incidence of first episodes of uveitis.

Preserving Fertility in People With Rheumatic Diseases.

Rheumatology patients historically were told they "can't" or "shouldn't" become pregnant. Improved rheumatic diagnostics and treatments have led to decreased morbidity and mortality and increased quality of life resulting in an opportunity to focus on fertility and its preservation. In the same vein as rheumatic disease care, assisted reproductive technology (ART), which includes freezing of egg and sperm as well as in vitro fertilization, has made considerable strides in the recent past. ART is safe for those with rheumatic diseases and has comparable outcomes to the general public, but may take additional effort due to optimal timing, rheumatic medications, and other nuances. In a specialty that treats chronic inflammatory diagnoses using teratogens and gonadotoxins, it is important to address family building desires with patients so their goals can be met.Rheumatologists have little knowledge of ART and how it impacts or applies to their patients; however, patients want their rheumatologist to be the source of knowledge for this information (Arthritis Rheumatol. 2022;74:suppl 9). Many barriers to ART exist and will be explored, with the financial burden being paramount (Glob J Health Sci. 6;1:181-191). Future efforts to examine the future fertility of rheumatology patients in an era of biologics and "treat-to-target" are needed to better understand who would most benefit from this costly and not without risk medical treatment. Given the changing landscape of financial support for ART due to insurance mandates, rheumatologists should not modify counseling based on the anticipated ability of patients to afford care. Preservation should also be broached with patients without partners and those from the LGBTQAI+ community. In addition to expanding the education of rheumatologists regarding this topic and its incorporation into clinical care, advocacy for ART access and insurance coverage is a much-needed future direction.

Fate of ileorectal anastomosis for treating Crohn's disease in the era of biologics: Results from a French retrospective multicentre cohort study.

The rate of surgical recurrence following ileorectal anastomosis (IRA) in patients with Crohn's disease (CD) remains poorly understood. Most studies were conducted before the advent of biologics. Our aim was to assess the fate of IRA in patients with CD during the biologics era and identify risk factors for endoscopic, clinical, and surgical recurrence. This retrospective multicentre cohort study included patients with CD who underwent IRA between 2006 and 2022. The association of patient characteristics and postoperative measures with each type of postoperative recurrence and need for a definitive stoma was investigated using the chi-square test or Fisher's exact test. During a median follow-up period of 60 months, the rates of endoscopic, clinical, and surgical postoperative recurrence were 70%, 59%, and 35%, respectively. The rate of perianal lesions was higher in patients who underwent a definitive stoma (70% vs. 35%, p = 0.007) and with endoscopic (50% vs. 25%, p = 0.038), clinical (54% vs. 24%, p = 0.006), and surgical (63% vs. 34%, p = 0.015) recurrence. The incidence of residual microscopic disease at the rectal margin was higher in patients with endoscopic recurrence (p = 0.047). Biologics were identified as protective factors against the need for a definitive stoma (p = 0.044). IRA is a good treatment option for extensive colitis in patients with CD. However, its consideration should be weighed in the presence of perianal lesions, which have been shown to be a risk factor for delayed proctectomy.

Progress and opportunities of foundation models in bioinformatics.

Bioinformatics has undergone a paradigm shift in artificial intelligence (AI), particularly through foundation models (FMs), which address longstanding challenges in bioinformatics such as limited annotated data and data noise. These AI techniques have demonstrated remarkable efficacy across various downstream validation tasks, effectively representing diverse biological entities and heralding a new era in computational biology. The primary goal of this survey is to conduct a general investigation and summary of FMs in bioinformatics, tracing their evolutionary trajectory, current research landscape, and methodological frameworks. Our primary focus is on elucidating the application of FMs to specific biological problems, offering insights to guide the research community in choosing appropriate FMs for tasks like sequence analysis, structure prediction, and function annotation. Each section delves into the intricacies of the targeted challenges, contrasting the architectures and advancements of FMs with conventional methods and showcasing their utility across different biological domains. Further, this review scrutinizes the hurdles and constraints encountered by FMs in biology, including issues of data noise, model interpretability, and potential biases. This analysis provides a theoretical groundwork for understanding the circumstances under which certain FMs may exhibit suboptimal performance. Lastly, we outline prospective pathways and methodologies for the future development of FMs in biological research, facilitating ongoing innovation in the field. This comprehensive examination not only serves as an academic reference but also as a roadmap for forthcoming explorations and applications of FMs in biology.

When the microbiome meets One Health principle: Leading to the Holy Grail of biology and contributing to overall well‐being and social sustainability

AbstractThe convergence of microbiome science with the One Health principle heralds a transformative era in biology, prioritizing the collective well‐being of humans, animals, and the environment. This review delves into the intricate dance between microbiomes and their hosts, revealing their profound impact on health, nutrient cycles, and climate change. Championing a unified approach to health issues across diverse kingdoms of life, One Health emerges as a holistic strategy, underscored by a proposed universal balance theory, “Balance of Dynamic Factors.” This theory spotlights the equilibrium within microbial and human‐animal‐environment interactions, offering a revolutionary pathway to global health and social well‐being. It paves the way for disease prevention, health equity, and sustainability, all of which are purviews of a balanced ecological system. We navigate the challenges and opportunities of this integrative approach, culminating in a call for action for the incorporation of microbiome science into health policies, precision medicine, legislation, eco‐health projects, and education, thereby setting the stage for harmonious coexistence with our planet.

Differences in disease characteristics and treatment exposures between paediatric and adult-onset inflammatory bowel disease using a registry-based cohort.

Previous studies highlighted a more extensive phenotype for paediatric-onset than adult-onset inflammatory bowel disease (IBD). However, most lacked long-term follow-up, and some were conducted before the era of biologics. The aim of this study is to compare disease characteristics and treatment exposures between paediatric-onset and adult-onset IBD. From a registry that periodically and uniformly retrieves demographics, disease characteristics/phenotype, and treatments, we compared the characteristics of paediatric-onset (diagnosed at ≥6 and <18 years) and adult-onset IBD, diagnosed during 2000-2022 and with ≥12 months follow-up. Of the 2837 patients with Crohn's disease and 1332 with ulcerative colitis, 3316 had adult-onset and 853 paediatric-onset IBD. The median follow-up was 6 years. Patients with paediatric-onset presented with more extensive disease and received more intensified therapies, including biologics and JAK inhibitors than those with adult-onset IBD. Paediatric-onset ulcerative colitis showed a higher prevalence of E3 extensive colitis including pancolitis and a greater requirement for systemic steroids, immunomodulators, and biologics than adult-onset ulcerative colitis. Paediatric-onset versus adult-onset Crohn's disease exhibited greater L3 ileocolonic involvement and perianal disease phenotype, and higher exposure to immunomodulators and biologics. Kaplan-Meier curve and Cox proportional hazards analyses showed significantly lower 15-year biologic-free survival from diagnosis among those with paediatric-onset IBD than with adult-onset IBD (p = <0.001), indicating greater and earlier use of biologics in the former. Paediatric-onset presents with more extensive disease with higher exposures to immunomodulators and biologic therapies than adult-onset IBD.

Risk Factors for Recurrence of Crohn's Disease After Ileocecal Resection and Management Strategies

IntroductionPediatric patients with ileocecal Crohn's Disease (CD) refractory to medical management frequently require ileocecectomy. However, risk factors for post-operative ileocecal recurrence and appropriate management strategies are poorly defined in the pediatric literature in the biologic era. MethodsWe queried our institutional database from 1/1/2012–12/31/2022 for patients aged 1–21 who underwent primary ileocecectomy for CD. We analyzed baseline characteristics, operative details, medical management, recurrence patterns, and management patterns. ResultsWe identified 208 patients who underwent primary ileocecal resection, of which 66 (23%) demonstrated endoscopic recurrence at 2.1 ± 0.5 years and 28 (13%) developed clinical recurrence at 2.5 ± 0.8 years. Recurrence was at the surgical anastomosis in 43 (21%). Before surgery, 138 (66%) were treated with a biologic, of which 25 (18%) were transitioned to a second line biologic pre-operatively. Requiring a separate intervention for perianal or intestinal disease increased the odds of recurrence on multivariable analysis, as did requiring a second line biologic. Of those with endoscopic recurrence, most [62/66 (94%)] were successfully managed with medical optimization alone. Only four (6.7%) required procedural intervention with two being managed with endoscopic balloon dilation and two requiring repeat resection and re-anastomosis. Median follow up was 2.6 years [IQR 1.2–4.5]. ConclusionRequiring separate interventions for perianal or intestinal disease and demonstrating disease difficult to medically control may increase the risk of recurrent post-operative ileocecal CD. Such patients should be closely surveilled for endoscopic recurrence and may warrant more aggressive medical regimens. Recurrence can typically be managed medically with few patients requiring procedural intervention. Level of EvidenceIII.

IL1RL1variant may affect the response to type 2 biologics in patients with severe asthma

BackgroundAsthma is a heterogeneous disease with variable response to treatment. Genetic backgrounds are involved in the severity of type 2 asthma, but their effects on responses to biologics remain unknown. This study aimed to clarify the role of genetic factors in response to biologics in patients with severe asthma.MethodsAdults with severe asthma receiving biologics were enrolled in this multicenter, observational, real-world study. The responses to biologics were evaluated using Physicians’ Global Evaluation of Treatment Effectiveness (GETE). Optimal biologic for each patient was also determined based on the best GETE score for the biologic used or currently used biologic. Three single nucleotide polymorphisms (IL1RL1, rs1420101;IL4RA, rs8832; andTSLP, rs1837253) were examined.ResultsAmong the 113 patients analysed, 53 (46.9%) had an excellent GETE score for at least one biologic. These patients with an excellent GETE score for at least one biologic, particularly for benralizumab, had the risk genotype of rs1420101 more frequently than the remaining patients, independent of the clinical demographics. Regarding the optimal biologic for each patient, anti-IL-5 drugs were optimal for patients with the rs1420101 TT or rs8832 GG genotype. Furthermore, dupilumab was similarly effective, regardless of the risk genotypes examined in this study.ConclusionIL1RL1rs1420101 TT genotype and/orIL4RArs8832 GG genotype may predict an excellent or optimal response to biologic therapy in each patient, particularly to anti-IL-5 targeted therapy. The elucidation of genetic predisposition may improve the management of severe asthma in the era of biologics.

Extending computational protein design to intrinsically disordered proteins.

Advances in the accuracy and throughput of molecular simulations usher in a new era in the structural biology of disordered proteins.

Comparative morphology at a crossroads.

Morphology has been the fundamental and most important source of information in biology. We strongly believe that in the current molecular era of biology, comparative morphology still has an important role to play in understanding life on Earth and ecosystem functioning, bridging the knowledge gap between evolution, systematics, and ecology.

An Updated Reappraisal of Dupilumab in Children and Adolescents with Severe Asthma.

Severe asthma (SA) is still a demanding challenge in clinical practice. Type 2 inflammation is the most common phenotype in children and adolescents with SA. As a result, anti-inflammatory drugs, mainly corticosteroids (CSs), represent the first choice to reduce type 2 inflammation. However, SA patients may require high inhaled and oral CS doses to achieve and maintain asthma control. Some SA patients, despite the highest CS dosages, can even display uncontrolled asthma. Therefore, the biological era constituted a breakthrough in managing this condition. Dupilumab is a monoclonal antibody directed against the IL-4 receptor α-subunit (IL-4Rα), antagonizing against both IL-4 and IL-13, and has been approved for pediatric severe type 2 asthma. This review presents and discusses the most recent published studies on dupilumab in children and adolescents with SA. There is convincing evidence that dupilumab is a safe and effective option in managing SA as it can reduce asthma exacerbations, reduce CS use, and improve lung function, asthma control, and quality of life, also for caregivers. However, a thorough diagnostic pathway is mandatory, mainly concerning phenotyping. In fact, the ideal eligible candidate is a child or adolescent with a type 2 allergic phenotype.

A Population-Based Matched Cohort Study of Digestive System Cancer Incidence and Mortality in Individuals With and Without Inflammatory Bowel Disease.

To study digestive system cancer risks in individuals with inflammatory bowel diseases (IBDs) in the biologic era. We used population-level administrative and cancer registry data from Ontario, Canada, (1994-2020) to compare people with IBD to matched controls (1:10 by sex and birth year) on trends in age-sex standardized cancer incidence and risk ratios of incident cancers and cancer-related deaths. Among 110,919 people with IBD and 1,109,190 controls, colorectal cancer incidence (per 100,000 person-years) declined similarly in people with ulcerative colitis (average annual percentage change [AAPC] -1.81; 95% confidence interval [CI] -2.48 to -1.156) and controls (AAPC -2.79; 95% CI -3.44 to -2.14), while small bowel cancer incidence rose faster in those with Crohn's disease (AAPC 9.68; 95% CI 2.51-17.3) than controls (AAPC 3.64; 95% CI 1.52-5.80). Extraintestinal digestive cancer incidence rose faster in people with IBD (AAPC 3.27; 95% CI 1.83-4.73) than controls (AAPC -1.87; 95% CI -2.33 to -1.42), particularly for liver (IBD AAPC 8.48; 95% CI 4.11-13.1) and bile duct (IBD AAPC 7.22; 95% CI 3.74-10.8) cancers. Beyond 2010, the incidences (and respective mortality rates) of colorectal (1.60; 95% CI 1.46-1.75), small bowel (4.10; 95% CI 3.37-4.99), bile duct (2.33; 95% CI 1.96-2.77), and pancreatic (1.19; 95% CI 1.00-1.40) cancers were higher in people with IBD. Cancer incidence is declining for colorectal cancer and rising for other digestive cancers in people with IBD. Incidence and mortality remain higher in people with IBD than controls for colorectal, small bowel, bile duct, and pancreatic cancers.

Influence of familial forms of inflammatory bowel disease on the use of immunosuppressants, biological agents, and surgery in the era of biological therapies. Results from the ENEIDA project.

Familial inflammatory bowel disease (IBD) history is a controversial prognostic factor in IBD. We aimed to evaluate the impact of a familial history of IBD on the use of medical and surgical treatments in the biological era. Patients included in the prospectively maintained ENEIDA database and diagnosed with IBD after 2005 were included. Familial forms were defined as those cases with at least one first-degree relative diagnosed with IBD. Disease phenotype, the use of biological agents, or surgical treatments were the main outcomes. A total of 5263 patients [2627 Crohn's disease (CD); 2636 ulcerative colitis (UC)] were included, with a median follow-up of 31months. Of these, 507 (10%) corresponded to familial forms. No clinical differences were observed between familial and sporadic IBD forms except a lower age at IBD diagnosis and a higher rate of males in familial forms of UC. In CD, the proportions of patients treated with thiopurines (54.4% vs 46.7%; P = .015) and survival time free of thiopurines (P = .009) were lower in familial forms. No differences were found regarding the use of biological agents. Concerning surgery, a higher rate of intestinal resections was observed in sporadic CD (14.8% vs 9.9%, P = .027). No differences were observed in UC. In the era of biological therapies, familial and sporadic forms of IBD show similar phenotypes and are managed medically in a similar way; whether these is due to lack of phenotypical differences or an effect of biological therapies is uncertain. What is already known on this topic: IBD's etiopathogenesis points to an interaction between environmental and genetic factors, being familial history a controversial prognostic factor. Biological agents use and need for surgery regarding familial or sporadic forms of IBDs present conflicting results. What this study adds: Familial and sporadic forms of IBD have similar phenotypes and are managed medically and surgically in a similar way. How this study might affect research, practice or policy: Familial aggregation should not be considered a factor associated with more aggressive disease.

Revolutionizing Lung Cancer Treatment: Innovative CRISPR-Cas9 Delivery Strategies.

Lung carcinoma, including both non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), remains a significant global health challenge due to its high morbidity and mortality rates. The objsective of this review is to meticulously examine the current advancements and strategies in the delivery of CRISPR-Cas9 gene-editing technology for the treatment of lung carcinoma. This technology heralds a new era in molecular biology, offering unprecedented precision in genomic modifications. However, its therapeutic potential is contingent upon the development of effective delivery mechanisms that ensure the efficient and specific transport of gene-editing tools to tumor cells. We explore a variety of delivery approaches, such as viral vectors, lipid-based nanoparticles, and physical methods, highlighting their respective advantages, limitations, and recent breakthroughs. This review also delves into the translational and clinical significance of these strategies, discussing preclinical and clinical studies that investigate the feasibility, efficacy, and safety of CRISPR-Cas9 delivery for lung carcinoma. By scrutinizing the landscape of ongoing clinical trials and offering translational perspectives, we aim to elucidate the current state and future directions of this rapidly evolving field. The review is structured to first introduce the problem and significance of lung carcinoma, followed by an overview of CRISPR-Cas9 technology, a detailed examination of delivery strategies, and an analysis of clinical applications and regulatory considerations. Our discussion concludes with future perspectives and challenges, such as optimizing delivery strategies, enhancing specificity, mitigating immunogenicity concerns, and addressing regulatory issues. This comprehensive overview seeks to provide insights into the potential of CRISPR-Cas9 as a revolutionary approach for targeted therapies and personalized medicine in lung carcinoma, emphasizing the importance of delivery strategy development in realizing the full potential of this groundbreaking technology.

Perioperative Nutritional Considerations In Patients With Inflammatory Bowel Disease

Despite significant advances in medical therapy for inflammatory bowel disease (IBD) in recent decades, surgical management remains common in the setting of both Crohn’s disease (CD) and ulcerative colitis (UC). While the risk of colectomy for UC has declined in the biologic era, most patients with CD will undergo at least one intestinal resection in their lifetime. Preoperative nutritional status is a wellestablished determinant of surgical morbidity. Surgery elicits a metabolic stress response that is proportional to the extent of surgical injury. Adequate lean body and micronutrient stores are needed for healing of surgical incisions, and the individual must be metabolically capable of anabolism for tissue repair. Deficits at any point in this process may lead to complications including anastomotic failure, surgical site infections, delayed return of gastrointestinal (GI) function, and postoperative physical disability with prolonged length of hospital stay.

When the diagnosis is in the patient's hand and in the neurologist's eye.

The objective of this study was to encompass current knowledge about pathophysiological mechanisms of those specific hand postures or deformities caused by central nervous system disorders. In the era of high-resolution neuroimaging and molecular biology, clinicians are progressively losing confidence with neurological examination. Careful hand observation is of key importance in order to differentiate neurological from non-neurological conditions, central from peripheral aetiologies, and organic from functional disorders. Localizing the potential anatomical site is essential to properly conduct subsequent exams. We provided a practical guide for clinicians to recognize hand patterns caused by central nervous system disorders, avoiding mimicking conditions, thus optimizing and prompting the diagnostic pathway.

Increasing Rates of Bowel Resection Surgery for Stricturing Crohn's Disease in the Biologic Era.

The era of biologics is associated with declining rates of surgery for Crohn's disease (CD), but the impact on surgery for stricturing CD is unknown. Our study aimed to assess nationwide trends in bowel resection surgery for obstruction in CD since the introduction of infliximab for CD in 1998. Using the Nationwide Inpatient Sample, we performed a nationwide analysis, identifying patients hospitalized for CD who underwent bowel resection for an indication of obstruction between 1998 and 2020 (era of biologics). Longitudinal trends in all CD-related resections and resection for obstruction were evaluated. Multivariable logistic regression identified patient and hospital characteristics associated with bowel resection surgery for obstruction. Hospitalizations for all CD-related resections decreased from 12.0% of all hospitalizations in 1998 to 6.9% in 2020, while hospitalizations for CD-related resection for obstructive indication increased from 1.3% to 2.0%. The proportion of resections for obstructive indication amongst all CD-related bowel resections increased from 10.8% in 1998 to 29.1% in 2020. In the multivariable models stratified by elective admission, the increasing year was associated with risk of resection for obstructive indication regardless of urgency (nonelective model: odds ratio, 1.01; 95% CI, 1.00-1.02; elective model: odds ratio, 1.06; 95% CI, 1.04-1.08). In the era of biologics, our findings demonstrate a decreasing annual rate of CD-related bowel resections but an increase in resection for obstructive indication. Our findings highlight the effect of medical therapy on surgical rates overall but suggest limited impact of current medical therapy on need of resection for stricturing disease.