OVER 2,000 years ago,silk was the symblol of China;1,000 ago,porcelain was the symblol of China;500 years ago,tea was the symblol of China;today,with human beings’increasing awarness in ecological preservation,the gi...OVER 2,000 years ago,silk was the symblol of China;1,000 ago,porcelain was the symblol of China;500 years ago,tea was the symblol of China;today,with human beings’increasing awarness in ecological preservation,the giant panda has become a symblol of China.In 1869,the French naturalist Armand David discovered the giant panda in Ya’an,and since then,the flagship species of biodiversity conservation has since stepped onto the world stage.展开更多
Calcium (Ca^(2+)) is a key intracellular messenger involved in a variety of cellular functions.Intracellular Ca^(2+)dysregulation drives neuron cell death in multiple degenerative diseases and traumatic conditions.Ret...Calcium (Ca^(2+)) is a key intracellular messenger involved in a variety of cellular functions.Intracellular Ca^(2+)dysregulation drives neuron cell death in multiple degenerative diseases and traumatic conditions.Retinal ganglion cell(RGC) degeneration occurs in blinding diseases such as glaucoma and other optic neuropathies.展开更多
Glucagon is a potent glucose-elevating hormone that is secreted by pancreaticα-cells.While well-controlled glucagon secretion plays an important role in maintaining systemic glucose homeostasis and preventing hypogly...Glucagon is a potent glucose-elevating hormone that is secreted by pancreaticα-cells.While well-controlled glucagon secretion plays an important role in maintaining systemic glucose homeostasis and preventing hypoglycaemia,it is increasingly apparent that defects in the regulation of glucagon secretion contribute to impaired counter-regulation and hyperglycaemia in diabetes.It has therefore been proposed that pharmacological interventions targeting glucagon secretion/signalling can have great potential in improving glycaemic control of patients with diabetes.However,despite decades of research,a consensus on the precise mechanisms of glucose regulation of glucagon secretion is yet to be reached.Second messengers are a group of small intracellular molecules that relay extracellular signals to the intracellular signalling cascade,modulating cellular functions.There is a growing body of evidence that second messengers,such as cAMP and Ca^(2+),play critical roles inα-cell glucose-sensing and glucagon secretion.In this review,we discuss the impact of second messengers onα-cell electrical activity,intracellular Ca^(2+)dynamics and cell exocytosis.We highlight the possibility that the interaction between different second messengers may play a key role in the glucose-regulation of glucagon secretion.展开更多
Infants exhibit diminished susceptibility to external infections,a phenomenon closely linked to the pervasive presence of the bifidobacterial community within their intestinal tract.Nonetheless,a significant knowledge...Infants exhibit diminished susceptibility to external infections,a phenomenon closely linked to the pervasive presence of the bifidobacterial community within their intestinal tract.Nonetheless,a significant knowledge gap remains concerning the distinct species of bifidobacteria initiating anti-infection immune responses during the early developmental stages.In this study,the impact of early intervention with Bifidobacterium bifidum,Bifidobacterium breve,and Bifidobacterium longum on neonatal rats infected with Salmonella enterica serovar Typhimurium SL1344 were compared.The study encompasses various immunity levels,including gut immunity,central immunity(thymus),peripheral immunity(spleen),and brain immunity.Following Salmonella infection,significant alterations in neonatal rats were observed in growth and developmental levels,immune markers,cytokine levels,balance of T lymphocyte subpopulations,intestinal barrier function,and blood-brain barrier integrity.Compared with B.breve and B.longum,B.bifidum demonstrated more pronounced efficacy in regulating these physiological processes.By conducting multi-level analyses of gut microbiota,bifidobacterial community,colonic content metabolomics,and serum metabolomics,the significance of B.bifidum’s role is underscored,and the immune-enhancing function of messenger metabolites is unveiled.Among these metabolites,γ-L-glutamyl-L-glutamic acid and orotic acid were found to be shared by all 3 species,while hippuric acid and 1a,1b-dihomo prostaglandin F2αwere unique to B.bifidum,and DL-arginine was specific to B.longum.Overall,this study has provided novel insights into the intervention and immunomodulation by Bifidobacterium in early-life infections,emphasizing the significant role of B.bifidum.展开更多
Tuberculosis(TB)remains a critical global health challenge,with 10.8 million new cases and over 1.25 million deaths reported annually,disproportionately affecting low-income regions.Despite its use,the Bacillus Calmet...Tuberculosis(TB)remains a critical global health challenge,with 10.8 million new cases and over 1.25 million deaths reported annually,disproportionately affecting low-income regions.Despite its use,the Bacillus Calmette-Guérin(BCG)vaccine provides limited protection against adult pulmonary TB,necessitating novel solutions.The messenger RNA(mRNA)vaccine technology,proven effective in combating coronavirus disease 2019,offers significant promise for TB prevention.These vaccines elicit robust immune responses by encoding antigens that stimulate humoral and cell-mediated immunity,essential for combating mycobacterium TB.Unlike traditional methods,mRNA vaccines are highly adaptable,scalable,and capable of targeting emerging strains.Preclinical studies highlight the enhanced efficacy of mRNA TB vaccines over BCG,demonstrating their ability to reduce bacterial burdens and generate memory T-cell responses critical for long-term protection.However,challenges persist,including mRNA instability,cold-chain storage needs,and mycobacterium’s complex immune evasion strategies.Innovative solutions,such as lipid nanoparticle delivery systems and selfamplifying mRNA platforms,are being developed to address these barriers.The initiation of clinical trials,notably BioNTech’s BNT164,marks a pivotal advancement in TB vaccine development.These trials focus on safety,immuno genicity,and efficacy,particularly in regions with high TB prevalence.While logistical and financial hurdles remain,mRNA vaccines hold transformative potential to bridge critical gaps in TB prevention.Their adaptability extends to tackling co-infections like human immunodeficiency virus,further amplifying their impact on global health.By integrating mRNA vaccines into existing TB control strategies,these advancements could revolutionize prevention efforts,especially in regions where current solutions fall short.Continued innovation and investment are crucial to harnessing the full potential of mRNA vaccines,positioning them as a cornerstone in the fight against TB and its global eradication.展开更多
“A child receiving a single shot containing mRNA vaccines that protect against multiple diseases,all delivered with one lipid nanoparticle”—this is how Professor Drew Weissman,the 2023 Nobel laureate in Physiology ...“A child receiving a single shot containing mRNA vaccines that protect against multiple diseases,all delivered with one lipid nanoparticle”—this is how Professor Drew Weissman,the 2023 Nobel laureate in Physiology or Medicine[1],described the potential of messenger RNA(mRNA)therapy in an interview with Forbes[2].In 2024,the Nobel Prize was again awarded to RNA researchers,this time to Victor Ambros and Gary Ruvkun for the discovery of microRNA and its role in post-transcriptional gene regulation[3],further underscoring the transformative capacity of RNA therapeutics in the 21st century healthcare.展开更多
Since the proposal of the“central dogma,”various types of RNA have been discovered,including messenger RNA(mRNA),ribosomal RNA(rRNA),and transfer RNA(tRNA).These RNAs are further classified into coding and non-codin...Since the proposal of the“central dogma,”various types of RNA have been discovered,including messenger RNA(mRNA),ribosomal RNA(rRNA),and transfer RNA(tRNA).These RNAs are further classified into coding and non-coding RNAs(ncRNAs).The modernization of research on traditional Chinese medicines(TCMs)has led to the increasing availability of whole-genome sequences for medicinal plants and the initiation of RNome(ie,the complete set of all RNA species)projects for TCMs.展开更多
A team of researchers from the Beijing Normal University,the Institute of High Energy Physics(IHEP)under the Chinese Academy of Sciences(CAS),and the National Astronomical Observatories,CAS(NAOC),reported in Nature As...A team of researchers from the Beijing Normal University,the Institute of High Energy Physics(IHEP)under the Chinese Academy of Sciences(CAS),and the National Astronomical Observatories,CAS(NAOC),reported in Nature Astronomy on January 23,2025 their discovery of an X-ray flash about 12.5 billion lightyears away.The signals burst out only 1.2 billion years after the Big Bang,when our 13.8-billion-year-old universe was still in its infancy,and a science satellite swiftly recorded them.展开更多
Dear Editor,Stress granules(SGs)are dynamic membraneless RNAprotein aggregates or organelles that are formed in response to various cellular stresses and disassemble rapidly with the decay of stresses[1].Under stressf...Dear Editor,Stress granules(SGs)are dynamic membraneless RNAprotein aggregates or organelles that are formed in response to various cellular stresses and disassemble rapidly with the decay of stresses[1].Under stressful conditions,protein translation is often inhibited suddenly.The resulting untranslated messenger ribonucleoproteins interact with the so-called"nucleator proteins"(such as G3BP1/2 and TIA1)to form the core structure of SGs,which then grow or merge into mature SGs by sequestering untranslated mRNAs and misfolded proteins[2,3].展开更多
BACKGROUND Esophageal squamous cell carcinoma(ESCC)is a cancer with a poor prognosis,characterized by distinct geographical distribution and family clustering.AIM To investigate if ethnic differences(Han vs Kazakh)cau...BACKGROUND Esophageal squamous cell carcinoma(ESCC)is a cancer with a poor prognosis,characterized by distinct geographical distribution and family clustering.AIM To investigate if ethnic differences(Han vs Kazakh)cause molecular variations in ESCC patients via genomic sequencing 299 samples.METHODS Here,we sequenced samples from 299 ESCC patients collected from Henan Key Laboratory for Esophageal Cancer Research and National Key Laboratory of Metabolic Dysregulation and Esophageal Cancer Prevention and Treatment,The First Affiliated Hospital of Zhengzhou University,including Han and Kazakh ethnic groups,and performed a genomic comparative analysis of these two ethnic cohorts.RESULTS ESCC patients of Kazakh ethnicity present with a later age of onset compared to Han.Kazakh patients exhibit a slightly higher tumor mutation burden compared to their Han counterparts.Three genes GIGYF1,CACNA1D,and ACOT11 exhibited mutation frequencies threefold higher in Kazakh patients than in Han.This enrichment may be associated with Kazakhs’adaptation to cold climates and consumption of high-calorie diets.Among Han patients,the apolipoprotein B messenger RNA-editing enzyme catalytic polypeptide(APOBEC)-associated single base substitutions(SBS)13 mutational signature is more prevalent,whereas SBS6,indicative of DNA mismatch repair deficiency,is more common in Kazakh patients.Additionally,Han Chinese patients with APOBEC-enriched tumors exhibit a significantly higher mutation load than those without.Moreover,patients lacking the APOBEC signature demonstrate superior survival probability compared to the APOBEC-enriched group.CONCLUSION Living environment and diet are major factors in the development of ESCC.Genomic difference may provide guidance for the formulation of clinical treatment plans for ESCC from different ethnics regions.展开更多
Objective: To study the multidrug resistance (MDR) mechanism of lung resistance protein (LRP) gene in hepatocellular carcinoma (HCC), and the relations among the expression of the LRP gene and clinicopathologic featur...Objective: To study the multidrug resistance (MDR) mechanism of lung resistance protein (LRP) gene in hepatocellular carcinoma (HCC), and the relations among the expression of the LRP gene and clinicopathologic features, the influence of α-fetoprotein (AFP), and prognosis of patients who received adjuvant chemotherapy after resection of HCC. Methods: The expression of the LRP gene encoding LRP and mRNA LRP was detected in tissues from 54 untreated patients with HCC, adjacent tissues from 24 patients with HCC and archival paraffin-embedded tissues from 12 patients with posthepatitic cirrhosis. The relationship between the LRP gene expression and the change of AFP level was analyzed in the 24 postoperative HCC patients whose AFP was measured after 2 weeks. All of the HCC patients were followed up. Results: The percentage of positive expression of LRP and mRNA LRP in the 3 tissues was 61.1%, 33.3%, 16.7%, and 75.9%, 37.5%, 33.3% respectively. There was significant difference between the untreated HCC tissue and other tissues (P<0.05). No difference existed between the LRP gene expression and clinicopathologic findings, age, sex, and tumor size (P>0.05), but the expression was related to the degree of differentiation of HCC (P<0.05). The effective rate of AFP in the LRP gene positive expression group or in postoperative chemotherapeutic patients was very lower than that in the negative group (P<0.05). Although the mean survival time of postoperative HCC patients in negative LRP gene expression group was longer than that of positive group, there was no difference between them (P<0.05). Conclusion: LRP gene expression is related to MDR of HCC and initiates the intrinsic MDR. Detection of LRP gene expression is of great guiding significance in accessing chemotherapeutic resistance of HCC. As an index to chemotherapy of HCC, detection of LRP expression provides evidence for making individual chemotherapeutic treatment,and reversing MDR in HCC. Although LRP gene expression correlates with the tumor differential degree (P<0.05), it perhaps does not relate with the prognosis of HCC patients.展开更多
文摘OVER 2,000 years ago,silk was the symblol of China;1,000 ago,porcelain was the symblol of China;500 years ago,tea was the symblol of China;today,with human beings’increasing awarness in ecological preservation,the giant panda has become a symblol of China.In 1869,the French naturalist Armand David discovered the giant panda in Ya’an,and since then,the flagship species of biodiversity conservation has since stepped onto the world stage.
文摘Calcium (Ca^(2+)) is a key intracellular messenger involved in a variety of cellular functions.Intracellular Ca^(2+)dysregulation drives neuron cell death in multiple degenerative diseases and traumatic conditions.Retinal ganglion cell(RGC) degeneration occurs in blinding diseases such as glaucoma and other optic neuropathies.
基金EFSD European Research Programme on New Targets for Type 2 Diabetes(Grant/Award Number:96406)Diabetes UK RD Lawrence Fellowship(Grant/Award Number:14/0005128)。
文摘Glucagon is a potent glucose-elevating hormone that is secreted by pancreaticα-cells.While well-controlled glucagon secretion plays an important role in maintaining systemic glucose homeostasis and preventing hypoglycaemia,it is increasingly apparent that defects in the regulation of glucagon secretion contribute to impaired counter-regulation and hyperglycaemia in diabetes.It has therefore been proposed that pharmacological interventions targeting glucagon secretion/signalling can have great potential in improving glycaemic control of patients with diabetes.However,despite decades of research,a consensus on the precise mechanisms of glucose regulation of glucagon secretion is yet to be reached.Second messengers are a group of small intracellular molecules that relay extracellular signals to the intracellular signalling cascade,modulating cellular functions.There is a growing body of evidence that second messengers,such as cAMP and Ca^(2+),play critical roles inα-cell glucose-sensing and glucagon secretion.In this review,we discuss the impact of second messengers onα-cell electrical activity,intracellular Ca^(2+)dynamics and cell exocytosis.We highlight the possibility that the interaction between different second messengers may play a key role in the glucose-regulation of glucagon secretion.
基金supported by the National Natural Science Foundation of China(32272332,31972052,32021005,31820103010)the Fundamental Research Funds for the Central Universities(JUSRP622020,JUSRP22006,JUSRP51501)the Program of Collaborative Innovation Centre of Food Safety and Quality Control in Jiangsu Province,Postgraduate Research&Practice Innovation Program of Jiangsu Province(KYCX22_2391).
文摘Infants exhibit diminished susceptibility to external infections,a phenomenon closely linked to the pervasive presence of the bifidobacterial community within their intestinal tract.Nonetheless,a significant knowledge gap remains concerning the distinct species of bifidobacteria initiating anti-infection immune responses during the early developmental stages.In this study,the impact of early intervention with Bifidobacterium bifidum,Bifidobacterium breve,and Bifidobacterium longum on neonatal rats infected with Salmonella enterica serovar Typhimurium SL1344 were compared.The study encompasses various immunity levels,including gut immunity,central immunity(thymus),peripheral immunity(spleen),and brain immunity.Following Salmonella infection,significant alterations in neonatal rats were observed in growth and developmental levels,immune markers,cytokine levels,balance of T lymphocyte subpopulations,intestinal barrier function,and blood-brain barrier integrity.Compared with B.breve and B.longum,B.bifidum demonstrated more pronounced efficacy in regulating these physiological processes.By conducting multi-level analyses of gut microbiota,bifidobacterial community,colonic content metabolomics,and serum metabolomics,the significance of B.bifidum’s role is underscored,and the immune-enhancing function of messenger metabolites is unveiled.Among these metabolites,γ-L-glutamyl-L-glutamic acid and orotic acid were found to be shared by all 3 species,while hippuric acid and 1a,1b-dihomo prostaglandin F2αwere unique to B.bifidum,and DL-arginine was specific to B.longum.Overall,this study has provided novel insights into the intervention and immunomodulation by Bifidobacterium in early-life infections,emphasizing the significant role of B.bifidum.
文摘Tuberculosis(TB)remains a critical global health challenge,with 10.8 million new cases and over 1.25 million deaths reported annually,disproportionately affecting low-income regions.Despite its use,the Bacillus Calmette-Guérin(BCG)vaccine provides limited protection against adult pulmonary TB,necessitating novel solutions.The messenger RNA(mRNA)vaccine technology,proven effective in combating coronavirus disease 2019,offers significant promise for TB prevention.These vaccines elicit robust immune responses by encoding antigens that stimulate humoral and cell-mediated immunity,essential for combating mycobacterium TB.Unlike traditional methods,mRNA vaccines are highly adaptable,scalable,and capable of targeting emerging strains.Preclinical studies highlight the enhanced efficacy of mRNA TB vaccines over BCG,demonstrating their ability to reduce bacterial burdens and generate memory T-cell responses critical for long-term protection.However,challenges persist,including mRNA instability,cold-chain storage needs,and mycobacterium’s complex immune evasion strategies.Innovative solutions,such as lipid nanoparticle delivery systems and selfamplifying mRNA platforms,are being developed to address these barriers.The initiation of clinical trials,notably BioNTech’s BNT164,marks a pivotal advancement in TB vaccine development.These trials focus on safety,immuno genicity,and efficacy,particularly in regions with high TB prevalence.While logistical and financial hurdles remain,mRNA vaccines hold transformative potential to bridge critical gaps in TB prevention.Their adaptability extends to tackling co-infections like human immunodeficiency virus,further amplifying their impact on global health.By integrating mRNA vaccines into existing TB control strategies,these advancements could revolutionize prevention efforts,especially in regions where current solutions fall short.Continued innovation and investment are crucial to harnessing the full potential of mRNA vaccines,positioning them as a cornerstone in the fight against TB and its global eradication.
基金supported by the National Key Research and Development Program of China(2022YFB3305900)the Science and Technology Innovation Action Plan Computational Biology Program(24JS2830400)+1 种基金the Fundamental Research Funds for the Central Universities(222202517006)the Programme of Introducing Talents of Discipline to Universities(the 111 Project)(B17017).
文摘“A child receiving a single shot containing mRNA vaccines that protect against multiple diseases,all delivered with one lipid nanoparticle”—this is how Professor Drew Weissman,the 2023 Nobel laureate in Physiology or Medicine[1],described the potential of messenger RNA(mRNA)therapy in an interview with Forbes[2].In 2024,the Nobel Prize was again awarded to RNA researchers,this time to Victor Ambros and Gary Ruvkun for the discovery of microRNA and its role in post-transcriptional gene regulation[3],further underscoring the transformative capacity of RNA therapeutics in the 21st century healthcare.
基金funded by the Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences(2023-I2M-3-009)Key Project at Central Government Level:The Ability Establishment of Sustainable Use for Valuable Chinese Medicine Resources(2060302-2305-02).
文摘Since the proposal of the“central dogma,”various types of RNA have been discovered,including messenger RNA(mRNA),ribosomal RNA(rRNA),and transfer RNA(tRNA).These RNAs are further classified into coding and non-coding RNAs(ncRNAs).The modernization of research on traditional Chinese medicines(TCMs)has led to the increasing availability of whole-genome sequences for medicinal plants and the initiation of RNome(ie,the complete set of all RNA species)projects for TCMs.
文摘A team of researchers from the Beijing Normal University,the Institute of High Energy Physics(IHEP)under the Chinese Academy of Sciences(CAS),and the National Astronomical Observatories,CAS(NAOC),reported in Nature Astronomy on January 23,2025 their discovery of an X-ray flash about 12.5 billion lightyears away.The signals burst out only 1.2 billion years after the Big Bang,when our 13.8-billion-year-old universe was still in its infancy,and a science satellite swiftly recorded them.
基金supported by the National Natural Science Foundation of China(32394032 and 82371402)Postdoctoral Fellowship Program of China(GZC20242295)+1 种基金the Natural Science Foundation of Shaanxi Province(2025SF-YBXM-393)the Military Medical Promoting Project of FMMU(2021JSTS27).
文摘Dear Editor,Stress granules(SGs)are dynamic membraneless RNAprotein aggregates or organelles that are formed in response to various cellular stresses and disassemble rapidly with the decay of stresses[1].Under stressful conditions,protein translation is often inhibited suddenly.The resulting untranslated messenger ribonucleoproteins interact with the so-called"nucleator proteins"(such as G3BP1/2 and TIA1)to form the core structure of SGs,which then grow or merge into mature SGs by sequestering untranslated mRNAs and misfolded proteins[2,3].
基金Supported by the National Natural Science Foundation of China,No.U1301227National Major Science and Technology Projects,No.2024ZD05209060Henan Province Jointly Built Science and Technology Key Projects,No.LHGJ20210337.
文摘BACKGROUND Esophageal squamous cell carcinoma(ESCC)is a cancer with a poor prognosis,characterized by distinct geographical distribution and family clustering.AIM To investigate if ethnic differences(Han vs Kazakh)cause molecular variations in ESCC patients via genomic sequencing 299 samples.METHODS Here,we sequenced samples from 299 ESCC patients collected from Henan Key Laboratory for Esophageal Cancer Research and National Key Laboratory of Metabolic Dysregulation and Esophageal Cancer Prevention and Treatment,The First Affiliated Hospital of Zhengzhou University,including Han and Kazakh ethnic groups,and performed a genomic comparative analysis of these two ethnic cohorts.RESULTS ESCC patients of Kazakh ethnicity present with a later age of onset compared to Han.Kazakh patients exhibit a slightly higher tumor mutation burden compared to their Han counterparts.Three genes GIGYF1,CACNA1D,and ACOT11 exhibited mutation frequencies threefold higher in Kazakh patients than in Han.This enrichment may be associated with Kazakhs’adaptation to cold climates and consumption of high-calorie diets.Among Han patients,the apolipoprotein B messenger RNA-editing enzyme catalytic polypeptide(APOBEC)-associated single base substitutions(SBS)13 mutational signature is more prevalent,whereas SBS6,indicative of DNA mismatch repair deficiency,is more common in Kazakh patients.Additionally,Han Chinese patients with APOBEC-enriched tumors exhibit a significantly higher mutation load than those without.Moreover,patients lacking the APOBEC signature demonstrate superior survival probability compared to the APOBEC-enriched group.CONCLUSION Living environment and diet are major factors in the development of ESCC.Genomic difference may provide guidance for the formulation of clinical treatment plans for ESCC from different ethnics regions.
文摘Objective: To study the multidrug resistance (MDR) mechanism of lung resistance protein (LRP) gene in hepatocellular carcinoma (HCC), and the relations among the expression of the LRP gene and clinicopathologic features, the influence of α-fetoprotein (AFP), and prognosis of patients who received adjuvant chemotherapy after resection of HCC. Methods: The expression of the LRP gene encoding LRP and mRNA LRP was detected in tissues from 54 untreated patients with HCC, adjacent tissues from 24 patients with HCC and archival paraffin-embedded tissues from 12 patients with posthepatitic cirrhosis. The relationship between the LRP gene expression and the change of AFP level was analyzed in the 24 postoperative HCC patients whose AFP was measured after 2 weeks. All of the HCC patients were followed up. Results: The percentage of positive expression of LRP and mRNA LRP in the 3 tissues was 61.1%, 33.3%, 16.7%, and 75.9%, 37.5%, 33.3% respectively. There was significant difference between the untreated HCC tissue and other tissues (P<0.05). No difference existed between the LRP gene expression and clinicopathologic findings, age, sex, and tumor size (P>0.05), but the expression was related to the degree of differentiation of HCC (P<0.05). The effective rate of AFP in the LRP gene positive expression group or in postoperative chemotherapeutic patients was very lower than that in the negative group (P<0.05). Although the mean survival time of postoperative HCC patients in negative LRP gene expression group was longer than that of positive group, there was no difference between them (P<0.05). Conclusion: LRP gene expression is related to MDR of HCC and initiates the intrinsic MDR. Detection of LRP gene expression is of great guiding significance in accessing chemotherapeutic resistance of HCC. As an index to chemotherapy of HCC, detection of LRP expression provides evidence for making individual chemotherapeutic treatment,and reversing MDR in HCC. Although LRP gene expression correlates with the tumor differential degree (P<0.05), it perhaps does not relate with the prognosis of HCC patients.
