Characterization and application of Bacillus velezensis D6 co-producing α-amylase and protease.

BACKGROUND: Research on the co-production of multiple enzymes by Bacillus velezensis as a novel species is still a topic that needs to be studied. This study aimed to investigate the fermentation characteristics of B. velezensis D6 co-producing α-amylase and protease and to explore their enzymatic properties and applications in fermentation. RESULTS: The maximum co-production of α-amylase and protease reached 13.13 ± 0.72 and 2106.63 ± 64.42 U mL-1, respectively, under the optimal fermented conditions (nutrients: 20.0 g L-1 urea, 20.0 g L-1 glucose, 0.7 g L-1 MnCl2; incubation conditions: initial pH 7.0, temperature 41 °C, 8% inoculation size and 30% working volume). Moreover, the genetic co-expression of α-amylase and protease increased from 0 to 24 h and then decreased after 36 h at the transcriptional level, which coincided with the growth trend of B. velezensis D6. The optimal reaction temperature of α-amylase was 55-60 °C, while that of protease was 35-40 °C. The activities of α-amylase and protease were retained by over 80% after thermal treatment (90 °C, 1 h), which indicated that two enzymes co-produced by B. velezensis D6 demonstrated excellent thermal stability. Moreover, the two enzymes were stable over a wide pH range (pH 4.0-8.0 for α-amylase; pH 4.0-9.0 for protease). Finally, the degrees of hydrolysis of corn, rice, sorghum and soybeans by α-amylase from B. velezensis D6 reached 44.95 ± 2.95%, 57.16 ± 2.75%, 52.53 ± 4.01% and 20.53 ± 2.42%, respectively, suggesting an excellent hydrolysis effect on starchy raw materials. The hydrolysis degrees of mackerel heads and soybeans by protease were 43.93 ± 2.19% and 26.38 ± 1.72%, respectively, which suggested that the protease from B. velezensis D6 preferentially hydrolyzed animal-based protein. CONCLUSION: This is a systematic study on the co-production of α-amylase and protease by B. velezensis D6, which is crucial in widening the understanding of this species co-producing multi-enzymes and in exploring its potential application. © 2024 Society of Chemical Industry.

Male autism spectrum disorder is linked to brain aromatase disruption by prenatal BPA in multimodal investigations and 10HDA ameliorates the related mouse phenotype.

Male sex, early life chemical exposure and the brain aromatase enzyme have been implicated in autism spectrum disorder (ASD). In the Barwon Infant Study birth cohort (n = 1074), higher prenatal maternal bisphenol A (BPA) levels are associated with higher ASD symptoms at age 2 and diagnosis at age 9 only in males with low aromatase genetic pathway activity scores. Higher prenatal BPA levels are predictive of higher cord blood methylation across the CYP19A1 brain promoter I.f region (P = 0.009) and aromatase gene methylation mediates (P = 0.01) the link between higher prenatal BPA and brain-derived neurotrophic factor methylation, with independent cohort replication. BPA suppressed aromatase expression in vitro and in vivo. Male mice exposed to mid-gestation BPA or with aromatase knockout have ASD-like behaviors with structural and functional brain changes. 10-hydroxy-2-decenoic acid (10HDA), an estrogenic fatty acid alleviated these features and reversed detrimental neurodevelopmental gene expression. Here we demonstrate that prenatal BPA exposure is associated with impaired brain aromatase function and ASD-related behaviors and brain abnormalities in males that may be reversible through postnatal 10HDA intervention.

Structural insights into transcription activation of the Streptomyces antibiotic regulatory protein, AfsR.

The Streptomyces antibiotic regulatory proteins (SARPs) are ubiquitously distributed transcription activators in Streptomyces and control antibiotics biosynthesis and morphological differentiation. However, the molecular mechanism behind SARP-dependent transcription initiation remains elusive. We here solve the cryo-EM structure of an AfsR-loading RNA polymerase (RNAP)-promoter intermediate complex (AfsR-RPi) including the Streptomyces coelicolor RNAP, a large SARP member AfsR, and its target promoter DNA that retains the upstream portion straight. The structure reveals that one dimeric N-terminal AfsR-SARP domain (AfsR-SARP) specifically engages with the same face of the AfsR-binding sites by the conserved DNA-binding domains (DBDs), replacing σHrdBR4 to bind the suboptimal -35 element, and shortens the spacer between the -10 and -35 elements. Notably, the AfsR-SARPs also recruit RNAP through extensively interacting with its conserved domains (ß flap, σHrdBR4, and αCTD). Thus, these macromolecular snapshots support a general model and provide valuable clues for SARP-dependent transcription activation in Streptomyces.

Studying on the in vivo pathological evolution of spinal cord injury with the rat model by the method of integrated multispectral imaging and Raman spectroscopy.

Spinal cord injury (SCI) is a debilitating neurological and pathological condition that results in significant impairments in motor, sensory, and autonomic functions. By integrating multispectral imaging (MSI) with Raman spectroscopy, a label-free optical methodology was developed for achieving a non-invasive in vivo understanding on the pathological features of SCI evolution. Under the guidance of captured the spectral imaging data cube with a rigid endoscope based MSI system, a special designed fiber probe passed through the instrumental channel for acquiring the finger-print spectral information from compression rat SCI models. After identifying the main visual features of injured spinal cord tissue in all Sham, 0-, 3- and 7-days post injury (0 DPI, 3 DPI, and 7 DPI) groups, the blood volume and oxygen content were visualized to describe hemorrhage, hypoxia and inflammatory state after acute injury. The averaged reflectance spectra, which were deduced from MSI data cubes, were utilized for describing oxygen saturation and hemoglobin concentration in living tissue. The results of Raman spectroscopy addressed complex compositional and conformational phenomena during SCI progression, correlated with the well-known event like neuronal apoptosis, hemorrhage, demyelination, and even the upregulation of chondroitin sulfate proteoglycans (CSPGs). A principal component analysis and linear discriminate algorithm (PCA-LDA) based discriminate model was introduced for categorizing spectral features in different injury stages, which was applicable for intraoperative interpretations on the complex pathological courses of SCI and therapeutic outcomes.

Mitochondrial Genomes of Streptopelia decaocto: Insights into Columbidae Phylogeny.

In this research, the mitochondrial genome of the Streptopelia decaocto was sequenced and examined for the first time to enhance the comprehension of the phylogenetic relationships within the Columbidae. The complete mitochondrial genome of Streptopelia decaocto (17,160 bp) was structurally similar to the recognized members of the Columbidae family, but with minor differences in gene size and arrangement. The structural AT content was 54.12%. Additionally, 150 mitochondrial datasets, representing valid species, were amassed in this investigation. Maximum likelihood (ML) and Bayesian inference (BI) phylogenetic trees and evolutionary time relationships of species were reconstructed based on cytb gene sequences. The findings from the phylogenetic evaluations suggest that the S. decaocto was classified under the Columbinae subfamily, diverging from the Miocene approximately 8.1 million years ago, indicating intricate evolutionary connections with its close relatives, implying a history of species divergence and geographic isolation. The diversification of the Columbidae commenced during the Late Oligocene and extended into the Miocene. This exploration offers crucial molecular data for the S. decaocto, facilitating the systematic taxonomic examination of the Columbidae and Columbiformes, and establishing a scientific foundation for species preservation and genetic resource management.

Mullite-Fibers-Reinforced Bagasse Cellulose Aerogels with Excellent Mechanical, Flame Retardant, and Thermal Insulation Properties.

Cellulose aerogels are considered as ideal thermal insulation materials owing to their excellent properties such as a low density, high porosity, and low thermal conductivity. However, they still suffer from poor mechanical properties and low flame retardancy. In this study, mullite-fibers-reinforced bagasse cellulose (Mubce) aerogels are designed using bagasse cellulose as the raw material, mullite fibers as the reinforcing agent, glutaraldehyde as the cross-linking agent, and chitosan as the additive. The resulted Mubce aerogels exhibit a low density of 0.085 g/cm3, a high porosity of 93.2%, a low thermal conductivity of 0.0276 W/(m∙K), superior mechanical performances, and an enhanced flame retardancy. The present work offers a novel and straightforward strategy for creating high-performance aerogels, aiming to broaden the application of cellulose aerogels in thermal insulation.

Melanin-Like Nanomedicine Functions as a Novel RPE Ferroptosis Inhibitor to Ameliorate Retinal Degeneration and Visual Impairment in Dry Age-Related Macular Degeneration.

Ferrous ion accumulation and lethal oxidative stress mediate irreversible retinal pigment epithelial (RPE) cell ferroptosis and subsequent photoreceptor degeneration, a potential key pathogenic factor in the onset of dry age-related macular degeneration (dAMD), causing irreversible vision loss in the global elderly population. However, currently, no effective interventional treatment strategy exists in clinical practice. Herein, lesion site-targeted melanin-like nanoparticles, named ConA-MelNPs, are designed as a novel ferroptosis inhibitor for retinal degenerative diseases. ConA-MelNPs possessed chelating iron ion characteristics, alleviating severe mitochondrial damage caused by oxidative stress and protecting RPE cells from ferroptosis induced by sodium iodate (NaIO3). In a preclinical dAMD mouse model, a single intravitreal injection of ConA-MelNPs yielded significant responses in electroretinograms and visually-driven optomotor responses in visually impaired mice, resisting the challenge posed by secondary NaIO3-induced injuries, with the long-term sustainability of its therapeutic effect. Mechanistically, ConA-MelNPs achieve a therapeutic effect by interrupting the detrimental cascade involving "RPE cell ferroptosis, lethal oxidative stress, and microglial proinflammatory activation," affording the restoration of retinal homeostasis. The synthesized ConA-MelNPs demonstrated good biosafety, with no detected ophthalmic or systemic side effects. Collectively, ConA-MelNPs are proposed as a promising therapeutic option for atrophic retinal diseases such as dAMD.

Ultrahigh Stretchable, Highly Transparent, Self-Adhesive, and Environment-Tolerant Chitin Nanocrystals Engineered Eutectogels toward Multisignal Sensors.

Addressing the conflict between achieving elevated mechanical stretchability and environmental adaptability is significant to a breakthrough in the practical application of flexible wearable materials. Therefore, inspired by the perceptive and protective properties of human skin, flexible wearable electronic skins (E-skins) based on deep eutectic solvent (DES) liquid and multiresponse eutectogel have been widely considered to be a promising platform for building a flexible wearable management system to achieve the purpose of "one stone, two birds". In this work, a multifunctional E-skin was designed based on an ultrastretchable, transparent, self-adhesive, and environmentally tolerant eutectogel by first incorporating cationized modified chitin nanocrystals into a covalently cross-linked polymer network comprised of the skeleton formed by a PAA polymerization network structure serving as a stretchable matrix and filled with DESs (ChCl:EG). The obtained eutectogel exhibits superhigh stretchability (up to 6707%), high toughness (17.7 MJ/m3), mechanical strength (0.48 MPa), self-adhesive, and high transparency (91.2%). Simultaneously, the multisignal sensor based on the above comprehensive properties and thermosensitive capacity exhibits a wide monitoring range, high strain/compression/temperature sensitivity, and good reproducibility. Remarkably, the sensor could be attached to rat hearts without glue or stickers for long-term monitoring of high-quality in vivo heartbeat signals. In this way, it is believed that the designed E-skin system based on eutectogel has great potential to serve as a promising platform for the next generation of flexible multisignal monitoring integrated wearable management systems.

The Effects of Different Developmental Stages on Bone Regeneration of Periodontal Ligament Stem Cells and Periodontal Ligament Cell Sheets In Vitro and Vivo.

Periodontal ligament stem cells (PDLSCs) have broad applications in tissue engineering and regeneration. However, the function of PDLSCs changes in different microenvironments. This study aimed to explore the effects of different developmental stages on the biological characteristics of PDLSCs. Here, PDLSCs were successfully cultured from the periodontal tissues of various groups, including a group with immature roots, a young group with mature roots, and an aging group with mature roots. By comparing the results of the three experimental groups, we found that the donors with immature roots exhibited the best proliferative ability and osteogenic differentiation, while the aging group demonstrated the worst proliferation. The trend for adipogenic differentiation was the opposite to that for osteogenic differentiation. The cell sheet and in vivo experiments revealed that in the immature root group, the cells produced more extracellular matrix (ECM) and new bone and better absorbed the implant materials. These results indicate that PDLSCs perform various functions at different stages of development. In clinical applications of PDLSCs for periodontal regeneration, donors with incompletely developed roots have stronger biological characteristics.

GBF1 deficiency causes cataracts in human and mouse.

Any opacification of the lens can be defined as cataracts, and lens epithelium cells play a crucial role in guaranteeing lens transparency by maintaining its homeostasis. Although several causative genes of congenital cataracts have been reported, the mechanisms underlying lens opacity remain unclear. In this study, a large family with congenital cataracts was collected and genetic analysis revealed a pathological mutation (c.3857 C > T, p.T1287I) in the GBF1 gene; all affected individuals in the family carried this heterozygous mutation, while unaffected family members did not. Functional studies in human lens epithelium cell line revealed that this mutation led to a reduction in GBF1 protein levels. Knockdown of endogenous GBF1 activated XBP1s in the unfolded protein response signal pathway, and enhances autophagy in an mTOR-independent manner. Heterozygous Gbf1 knockout mice also displayed typic cataract phenotype. Together, our study identified GBF1 as a novel causative gene for congenital cataracts. Additionally, we found that GBF1 deficiency activates the unfolded protein response and leads to enhanced autophagy, which may contribute to lens opacity.

Intestinal Akkermansia muciniphila is Beneficial to Functional Recovery Following Ischemic Stroke.

Recent studies have demonstrated the interaction between gut microbiota and brain on ischemic stroke, but the roles of gut microbiota in the pathophysiology of ischemic stroke remain largely unclear. In this study, we detected a significant increase of intestinal Akkermansia muciniphila (AKK) following ischemic stroke by a rose bengal photothrombosis model. To investigate the function and mechanism of AKK on ischemic stroke, we performed the AKK administration prior to stroke surgery. The results showed that mice treated with AKK gained significantly higher body weight and behaved better than those in PBS group at 3 days after ischemic stroke. Consistently, AKK administration remarkably decreased the infarct volumes as well as the density of degenerating neurons and apoptotic cells after ischemic stroke. Notably, AKK is a potential therapeutic target in immune-related disorders connected to the microbiota, and inflammation is crucially involved in the pathophysiological process of ischemic stroke. For the determination of underlying mechanisms of this protective effect, we investigated whether there are associations between AKK and neuroinflammation following ischemic stroke. The results suggested that AKK administration significantly reduced the activation of astrocytes and microglia but up-regulated multiple anti-inflammatory factors following ischemic stroke. Therefore, our study highlighted the beneficial roles of intestinal AKK on ischemic stroke and provided a new perspective for the treatment of ischemic stroke.

Dioscin exerts nephroprotective effects by attenuating oxidative stress and necroptosis-induced inflammation.

Acute kidney injury (AKI) is a syndrome characterized by the rapid loss of the renal function and has high morbidity and mortality worldwide, yet there is no satisfactory means of prevention and treatment at present. Dioscin, a natural steroidal saponin, has been found to have antioxidant, anti-inflammatory and anti-apoptotic effects. In this experiment, we pretreated cisplatin-induced AKI rats with dioscin and found that dioscin significantly enhanced renal function and reduced renal pathological injury in AKI rats. We also found that dioscin improved renal antioxidant capacity by suppressing the accumulation of oxides such as ROS, MDA and H2O2, and increasing the levels of antioxidant enzymes SOD and CAT. In addition, dioscin down-regulated the expression of inflammation-related proteins (IL-1ß, TNF-α, NF-κB) and necroptosis-critical proteins RIP1/RIP3, whereas up-regulated Caspase-8 protein levels in the kidney of AKI rats. Mechanistically, dioscin promoted the nuclear transcription of Nrf2 and activated Nrf2/HO-1 signaling axis to play a positive role in the kidney of AKI rats, while the reno-protective effect of dioscin was significantly attenuated after inhibiting Nrf2. In conclusion, our data indicate that dioscin decreases cisplatin-induced renal oxidative stress and thwarts necroptosis induced inflammation via regulating the Nrf2/HO-1pathway. Our study provides more data and theoretical support for the study of natural drugs to improve AKI.

Origin of Manipulating Selectivity in Prins Cyclization by [Ga4L6]12- Supramolecular Catalysis through Host-Guest Interactions.

The host effect of the supramolecular [Ga4L6]12- tetrahedral metallocage on Prins cyclization reaction of the substrate by encapsulated citronellal has been investigated by means of molecular dynamics and quantum mechanics. The encapsulation process of the substrate into the [Ga4L6]12- cavity was simulated via attach-pull-release (APR) methods. Thermodynamic calculations and classical molecular dynamics simulations assessed the substrate's microenvironment inside the cavity, guiding DFT-level modeling of the reaction. DFT calculations show diol product predominance in acidic solution but high enol selectivity inside [Ga4L6]12-, consistent with experimental findings. [Ga4L6]12- alters the selectivity of the Prins cyclization reaction by inhibiting diol formation. The activation strain model-based decomposition analysis (ASM-DA) of the barrier difference among distortion and interaction terms indicates that the more positive interaction between a host and guest in the diol transition state than enol determines the product selectivity, particularly the fewer C-H···O and O-H···O hydrogen-bonding interactions. These theoretical insights could contribute to a deeper understanding of the nature of supramolecular catalysis and to further develop new supramolecular catalysts.

Exploring the Relationship Between Subcutaneous Fat Index and Neck Pain in Patients with Spinal Cervical Spondylosis: A Retrospective Cohort Study.

STUDY DESIGN: Retrospective Cohort Study. OBJECTIVES: This study measures the subcutaneous fat index (SFI) of the cervical spine in patients with spinal cervical spondylosis using cervical magnetic resonance imaging and explores its relationship with neck pain in patients with spinal cervical spondylosis. METHODS: In this single-center retrospective study, 298 patients hospitalized for spinal cervical spondylosis between January and June 2021 were initially considered. After applying inclusion and exclusion criteria, 93 patients were enrolled. The cervical magnetic resonance imaging data for these patients were analyzed using A-Site software. The SFI was measured at the median sagittal plane on T2-weighted images. Patients were categorized into 2 groups based on their admission complaints: those with cervical pain and those without it. Differences between these groups were then statistically analyzed. RESULTS: The mean SFIs with standard deviations for the neck and non-neck pain groups were 36.4% ± 7.7% and 27.0% ± 7.9%, respectively, with a significant difference (P < 0.0001). The SFI was consistently higher across all neck segments in the neck pain group compared to the nonneck pain group (P < 0.05). The 2 groups had no statistically significant difference in the body mass index. CONCLUSIONS: The SFI provides a more precise assessment of muscle and fat distribution in the posterior cervical region than body mass index and is generally higher in patients with spinal cervical spondylosis who experience neck pain. These findings suggest the importance of early functional exercises postsurgery for potentially improving surgical outcomes in this patient population.

NRIMD, a Web Server for Analyzing Protein Allosteric Interactions Based on Molecular Dynamics Simulation.

Long-range allosteric communication between distant sites and active sites in proteins is central to biological regulation but still poorly characterized, limiting the development of protein engineering and drug design. Addressing this gap, NRIMD is an open-access web server for analyzing long-range interactions in proteins from molecular dynamics (MD) simulations, such as the effect of mutations at distal sites or allosteric ligand binding at allosteric sites on the active center. Based on our recent works on neural relational inference using graph neural networks, this cloud-based web server accepts MD simulation data on any length of residues in the alpha-carbon skeleton format from mainstream MD software. The input trajectory data are validated at the frontend deployed on the cloud and then processed on the backend deployed on a high-performance computer system with a collection of complementary tools. The web server provides a one-stop-shop MD analysis platform to predict long-range interactions and their paths between distant sites and active sites. It provides a user-friendly interface for detailed analysis and visualization. To the best of our knowledge, NRIMD is the first-of-its-kind online service to provide comprehensive long-range interaction analysis on MD simulations, which significantly lowers the barrier of predictions on protein long-range interactions using deep learning. The NRIMD web server is publicly available at https://nrimd.luddy.indianapolis.iu.edu/.

Asymmetric Intramolecular Amination Catalyzed with Cp*Ir-SPDO via Nitrene Transfer for Synthesis of Spiro-Quaternary Indolinone.

An asymmetric intramolecular spiro-amination to high steric hindering α-C-H bond of 1,3-dicarbonyl via nitrene transfer using inactive aryl azides has been carried out by developing a novel Cp*Ir(III)-SPDO (spiro-pyrrolidine oxazoline) catalyst, thereby enabling the first successful construction of structurally rigid spiro-quaternary indolinone cores with moderate to high yields and excellent enantioselectivities. DFT computations support the presence of double bridging H-F bonds between [SbF6]- and both the ligand and substrate, which favors the plane-differentiation of the enol π-bond for nitrenoid attacking. These findings open up numerous opportunities for the development of new asymmetric nitrene transfer systems.

PagbHLH35 Enhances Salt Tolerance through Improving ROS Scavenging in Transgenic Poplar.

The bHLH transcription factor family plays crucial roles in plant growth and development and their responses to adversity. In this study, a highly salt-induced bHLH gene, PagbHLH35 (Potri.018G141600), was identified from Populus alba × P. glandullosa (84K poplar). PagbHLH35 contains a highly conserved bHLH domain within the region of 52-114 amino acids. A subcellular localization result confirmed its nuclear localization. A yeast two-hybrid assay indicated PagbHLH35 lacks transcriptional activation activity, while a yeast one-hybrid assay indicated it could specifically bind to G-box and E-box elements. The expression of PagbHLH35 reached its peak at 12 h and 36 h time points under salt stress in the leaves and roots, respectively. A total of three positive transgenic poplar lines overexpressing PagbHLH35 were generated via Agrobacterium-mediated leaf disk transformation. Under NaCl stress, the transgenic poplars exhibited significantly enhanced morphological and physiological advantages such as higher POD activity, SOD activity, chlorophyll content, and proline content, and lower dehydration rate, MDA content and hydrogen peroxide (H2O2) content, compared to wild-type (WT) plants. In addition, histological staining showed that there was lower ROS accumulation in the transgenic poplars under salt stress. Moreover, the relative expression levels of several antioxidant genes in the transgenic poplars were significantly higher than those in the WT. All the results indicate that PagbHLH35 can improve salt tolerance by enhancing ROS scavenging in transgenic poplars.

PPARγ/NF-κB axis contributes to cold-induced resolution of experimental colitis and preservation of intestinal barrier.

BACKGROUND: Environmental stress is a significant contributor to the development of inflammatory bowel disease (IBD). The involvement of temperature stimulation in the development of IBD remains uncertain. Our preliminary statistical data suggest that the prevalence of IBD is slightly lower in colder regions compared to non-cold regions. The observation indicates that temperature changes may play a key role in the occurrence and progression of IBD. Here, we hypothesized that cold stress has a protective effect on IBD. METHODS: The cold exposure model for mice was placed in a constant temperature and humidity chamber, maintained at a temperature of 4 °C. Colitis models were induced in the mice using TNBS or DSS. To promote the detection methods more clinically, fluorescence confocal endoscopy was used to observe the mucosal microcirculation status of the colon in the live model. Changes in the colonic wall of the mice were detected using 9.4 T Magnetic Resonance Imaging (MRI) imaging and in vivo fluorescence imaging. Hematoxylin and eosin (H&E) and Immunofluorescence (IF) staining confirmed the pathological alterations in the colons of sacrificed mice. Molecular changes at the protein level were assessed through Western blotting and Enzyme-Linked Immunosorbent Assay (ELISA) assays. RNA sequencing (RNA-seq) and metabolomics (n = 18) were jointly analyzed to investigate the biological changes in the colon of mice treated by cold exposure. RESULTS: Cold exposure decreased the pathologic and disease activity index scores in a mouse model. Endomicroscopy revealed that cold exposure preserved colonic mucosal microcirculation, and 9.4 T MRI imaging revealed alleviation of intestinal wall thickness. In addition, the expression of the TLR4 and PP65 proteins was downregulated and epithelial cell junctions were strengthened after cold exposure. Intriguingly, we found that cold exposure reversed the decrease in ZO-1 and occludin protein levels in dextran sulfate sodium (DSS)- and trinitrobenzenesulfonic acid-induced colitis mouse models. Multi-omics analysis revealed the biological landscape of DSS-induced colitis under cold exposure and identified that the peroxisome proliferator-activated receptor (PPAR) signaling pathway mediates the effects of cold on colitis. Subsequent administration of rosiglitazone (PPAR agonist) enhanced the protective effect of cold exposure on colitis, whereas GW9662 (PPAR antagonist) administration mitigated these protective effects. Overall, cold exposure ameliorated the progression of mouse colitis through the PPARγ/NF-κB signaling axis and preserved the intestinal mucosal barrier. CONCLUSION: Our study provides a mechanistic link between intestinal inflammation and cold exposure, providing a theoretical framework for understanding the differences in the prevalence of IBD between the colder regions and non-cold regions, and offering new insights into IBD therapy.