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1.
Nano Lett ; 24(18): 5513-5520, 2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38634689

RESUMO

P-type self-doping is known to hamper tin-based perovskites for developing high-performance solar cells by increasing the background current density and carrier recombination processes. In this work, we propose a gradient homojunction structure with germanium doping that generates an internal electric field across the perovskite film to deplete the charge carriers. This structure reduces the dark current density of perovskite by over 2 orders of magnitude and trap density by an order of magnitude. The resultant tin-based perovskite solar cells exhibit a higher power conversion efficiency of 13.3% and excellent stability, maintaining 95% and 85% of their initial efficiencies after 250 min of continuous illumination and 3800 h of storage, respectively. We reveal the homojunction formation mechanism using density functional theory calculations and molecular level characterizations. Our work provides a reliable strategy for controlling the spatial energy levels in tin perovskite films and offers insights into designing intriguing lead-free perovskite optoelectronics.

2.
Angew Chem Int Ed Engl ; 62(39): e202307395, 2023 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-37522562

RESUMO

Stability issues could prevent lead halide perovskite solar cells (PSCs) from commercialization despite it having a comparable power conversion efficiency (PCE) to silicon solar cells. Overcoming drawbacks affecting their long-term stability is gaining incremental importance. Excess lead iodide (PbI2 ) causes perovskite degradation, although it aids in crystal growth and defect passivation. Herein, we synthesized functionalized oxo-graphene nanosheets (Dec-oxoG NSs) to effectively manage the excess PbI2 . Dec-oxoG NSs provide anchoring sites to bind the excess PbI2 and passivate perovskite grain boundaries, thereby reducing charge recombination loss and significantly boosting the extraction of free electrons. The inclusion of Dec-oxoG NSs leads to a PCE of 23.7 % in inverted (p-i-n) PSCs. The devices retain 93.8 % of their initial efficiency after 1,000 hours of tracking at maximum power points under continuous one-sun illumination and exhibit high stability under thermal and ambient conditions.

3.
Small ; 17(50): e2103336, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34708521

RESUMO

The carrier non-radiative recombination and instability of device caused by the inherent defects are main factors limiting development of perovskite solar cells (PSCs). During the fabrication process of a PSC device, perovskite films often produce Pb0 and I0 defects. This paper reports a strategy for synergistic optimization of perovskite films by defects passivation and surface modification. The doping of phthalide (PT) in the Pb-rich (CH(NH2 )2 )1-x (CH3 NH3 )x PbI3 film can passivate lead cation defects, and the modification of 1-iodooctadecane (1-IO) can reduce halogen anion defects and improve stability of PSCs owing to its hydrophobicity. The PT and 1-IO optimized device achieves a power conversion efficiency (PCE) of 22.27%. The optimized PSCs remain 93.2% of the initial PCE when placed in air environment (relative humidity of 10%, 25 °C) more than 70 days. The PT and 1-IO synergistic optimization provides a novel strategy for improving the performance and stability of PSCs.

4.
Nano Lett ; 20(7): 5383-5390, 2020 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-32463679

RESUMO

Single cell manipulation is important in biosensing, biorobotics, and quantitative cell analysis. Although microbeads, droplets, and microrobots have been developed previously, it is still challenging to simultaneously excise, capture, and manipulate single cells in a biocompatible manner. Here, we describe untethered single cell grippers, that can be remotely guided and actuated on-demand to actively capture or excise individual or few cells. We describe a novel molding method to micropattern a thermally responsive wax layer for biocompatible motion actuation. The multifingered grippers derive their energy from the triggered release of residual differential stress in bilayer hinges composed of silicon oxides. A magnetic layer enables remote guidance through narrow conduits and fixed tissue sections ex vivo. Our results provide an important advance in high-throughput single cell scale biopsy tools important to lab-on-a-chip devices, microrobotics, and minimally invasive surgery.


Assuntos
Robótica , Biópsia , Magnetismo , Movimento (Física) , Dióxido de Silício
5.
Small ; 16(47): e2004877, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33136349

RESUMO

High efficiency and good stability are the challenges for perovskite solar cells (PSCs) toward commercialization. However, the intrinsic high defect density and internal nonradiative recombination of perovskite (PVK) limit its development. In this work, a facile additive strategy is devised by introducing bifunctional guanidine sulfamate (GuaSM; CH6 N3 + , Gua+ ; H2 N-SO3 - , SM- ) into PVK. The size of Gua+ ion is suitable with Pb(BrI)2 cavity relatively, so it can participate in the formation of low-dimensional PVK when mixed with Pb(BrI)2 . The O and N atoms of SM- can coordinate with Pb2+ . The synergistic effect of the anions and cations effectively reduces the trap density and the recombination in PVK, so that it can improve the efficiency and stability of PSCs. At an optimal concentration of GuaSM (2 mol%), the PSC presents a champion power conversion efficiency of 21.66% and a remarkably improved stability and hysteresis. The results provide a novel strategy for highly efficient and stable PSCs by bifunctional additive.

6.
Microb Pathog ; 126: 357-362, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30347261

RESUMO

Infection with Salmonella Enteritidis (SE) is one of the main causes for food- and water-borne diseases, and is a major concern to public health for both humans and animals worldwide. Some fimbrial antigens expressed by SE strains have been described and characterized, containing SEF14, SEF17, SEF21, long polar fimbriae and plasmid-encoded fimbriae, they play a role in bacterial survival in the host or external environment. However, their functions remain to be well elucidated, with the initial attachment and binding for fimbriae-mediated SE infections only minimally understood. Meanwhile, host-pathogen interactions provide insights into receptor modulation of the host innate immune system. Therefore, to well understand the pathogenicity of SE bacteria and to comprehend the host response to infection, the host cell-SE interactions need to be characterized. This review describes SE fimbriae receptors with an emphasis on the interaction between the receptor and SE fimbriae.


Assuntos
Proteínas de Fímbrias/metabolismo , Fímbrias Bacterianas/metabolismo , Receptores Imunológicos , Infecções por Salmonella/imunologia , Salmonella enteritidis/metabolismo , Antígenos de Bactérias/genética , Antígenos de Bactérias/metabolismo , Aderência Bacteriana/fisiologia , Proteínas de Fímbrias/genética , Fímbrias Bacterianas/genética , Interações Hospedeiro-Patógeno/imunologia , Imunidade , Imunidade Inata , Família Multigênica , Salmonella enteritidis/genética
7.
Appl Microbiol Biotechnol ; 101(21): 7781-7787, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28918511

RESUMO

Adherent-invasive Escherichia coli (AIEC) has recently attracted more attention because it is closely related to the pathogenicity of human inflammatory bowel disease (IBD). AIEC possesses a multitude of virulence factors. Considering these virulence factors belonging to various virulence groups, including adhesins, invasins, toxins, protectins, and siderophore-mediated iron acquisition, this review summarizes the current knowledge of how the major virulence factors assisting in AIEC survive in, adhere to, and invade host cells. A comprehensive understanding of the interaction of virulence factors with host cells will provide us a new therapeutic strategy for IBD prevention and treatment.


Assuntos
Proteínas de Escherichia coli/metabolismo , Escherichia coli/crescimento & desenvolvimento , Escherichia coli/patogenicidade , Doenças Inflamatórias Intestinais/microbiologia , Doenças Inflamatórias Intestinais/patologia , Fatores de Virulência/metabolismo , Humanos
8.
Microorganisms ; 12(6)2024 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-38930436

RESUMO

Coriolopsis spp. are wood-decaying fungi that inhabit forests. They are mainly distributed in tropical and subtropical areas. Strain Epi910 was isolated from the asymbiotically germinated protocorm of Epidendrum sp. and identified as Coriolopsis strumosa. Symbiotic germination and high-throughput sequencing of the endophytic fungal communities of different parts were performed to characterize the function and spatial distribution of the Epi910 isolate. Under symbiotic germination, Epi910 promoted seed germination and seedling formation as an endophytic native fungus of Epidendrum sp. Endophytic fungal communities from seven different parts of Epidendrum sp. were characterized. In total, 645 OTUs were identified; 30 OTUs were shared among all seven parts. The internal transcribed spacer sequence of Epi910 was identical to that of a dominant shared OTU (OTU6). The relative abundance of OTU6 in the seven parts was identified as follows: capsule pericarp > seed > root > asymbiotically germinated protocorm > epiphytic root > ovary > rachis. Our results suggest that the isolate belonging to Coriolopsis strumosa could promote the germination of Epidendrum sp. There may, therefore, be endophytic fungi other than common orchid mycorrhizal fungi with the ability to enhance germination in orchids.

9.
Diabetes ; 2024 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-39058664

RESUMO

Maturation of postnatal ß cells is regulated in a cell-autonomous manner, and metabolically stressed ß cells regress to an immature state, ensuring defective ß-cell function and the onset of type 2 diabetes. The molecular mechanisms connecting the nutritional transition to ß-cell maturation remain largely unknown. Here, we report a miR-203/ZBTB20/MAFA regulatory axis that mediates the ß-cell maturation process. We show that miR-203 level in ß cells changes during the nutritional transition and that miR-203 inhibits ß-cell maturation at the neonatal stage and under high-fat diet (HFD) conditions. Using single-cell RNA sequencing, we demonstrated that miR-203 elevation promoted the transition of immature ß cells into CgBHi endocrine cells, while suppressing gene expressions associated with ß-cell maturation in a ZBTB20/MAFA-dependent manner. ZBTB20 is an authentic target of miR-203 and transcriptionally upregulates MAFA expression. Manipulating the miR-203/ZBTB20/MAFA axis may therefore offer a novel strategy for boosting functional ß-cell numbers to alleviate diabetes.

10.
J Tissue Eng ; 15: 20417314241237052, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38481708

RESUMO

The incidence of ischemic stroke (IS) is rising in tandem with the global aging population. There is an urgent need to delve deeper into the pathological mechanisms and develop new neuroprotective strategies. In the present review, we discuss the latest advancements and research on various nanodrug delivery systems (NDDSs) for targeting microglial polarization in IS treatment. Furthermore, we critically discuss the different strategies. NDDSs have demonstrated exceptional qualities to effectively permeate the blood-brain barrier, aggregate at the site of ischemic injury, and target specific cell types within the brain when appropriately modified. Consequently, NDDSs have considerable potential for reshaping the polarization phenotype of microglia and could be a prospective therapeutic strategy for IS. The treatment of IS remains a challenge. However, this review provides a new perspective on neuro-nanomedicine for IS therapies centered on microglial polarization, thereby inspiring new research ideas and directions.

11.
Adv Mater ; 36(7): e2310800, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38019266

RESUMO

The best research-cell efficiency of perovskite solar cells (PSCs) is comparable with that of mature silicon solar cells (SSCs); However, the industrial development of PSCs lags far behind SSCs. PSC is a multiphase and multicomponent system, whose consequent interfacial energy loss and carrier loss seriously affect the performance and stability of devices. Here, by using spinodal decomposition, a spontaneous solid phase segregation process, in situ introduces a poly(3-hexylthiophene)/perovskite (P3HT/PVK) heterointerface with interpenetrating structure in PSCs. The P3HT/PVK heterointerface tunes the energy alignment, thereby reducing the energy loss at the interface; The P3HT/PVK interpenetrating structure bridges a transport channel, thus decreasing the carrier loss at the interface. The simultaneous mitigation of energy and carrier losses by P3HT/PVK heterointerface enables n-i-p geometry device a power conversion efficiency of 24.53% (certified 23.94%) and excellent stability. These findings demonstrate an ingenious strategy to optimize the performance of PSCs by heterointerface via Spinodal decomposition.

12.
Adv Mater ; 36(21): e2311145, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38334458

RESUMO

High-quality perovskite films are essential for achieving high performance of optoelectronic devices; However, solution-processed perovskite films are known to suffer from compositional and structural inhomogeneity due to lack of systematic control over the kinetics during the formation. Here, the microscopic homogeneity of perovskite films is successfully enhanced by modulating the conversion reaction kinetics using a catalyst-like system generated by a foaming agent. The chemical and structural evolution during this catalytic conversion is revealed by a multimodal synchrotron toolkit with spatial resolutions spanning many length scales. Combining these insights with computational investigations, a cyclic conversion pathway model is developed that yields exceptional perovskite homogeneity due to enhanced conversion, having a power conversion efficiency of 24.51% for photovoltaic devices. This work establishes a systematic link between processing of precursor and homogeneity of the perovskite films.

13.
Micromachines (Basel) ; 14(2)2023 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-36838088

RESUMO

Microneedles have been used in various applications in biomedical engineering, including drug delivery, biosensing, and vaccine delivery. In this study, we develop a novel protocol to fabricate silk fibroin/off-stoichiometry thiol-ene (OSTE) hybrid microneedle array patches. Silk fibroin, as a natural biomaterial, has been proven to be suitable as a drug carrier. Firstly, drug (we use insulin in this experiment) dissolved in silk fibroin solution is deposited on a microneedle mold and dried thoroughly. After that, silk fibroin needle tips are formed on the OSTE base by replica molding. We investigated the influence of the silk fibroin concentration on the length of silk needle tips and found that the silk concentration had a small influence on the tip length. We also tested the mechanical strength of the microneedles by inserting them into gelatin gel for dummy drug delivery tests. Such composite structures have the potential to increase the delivery efficiency by delivering the whole silk tip into the dermis.

14.
Cortex ; 166: 154-171, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37385005

RESUMO

Psychological refractory period (PRP) effect refers to the delay in responding to the second of two tasks occurring in rapid succession. While all the major models of PRP highlight the importance of the frontoparietal control network (FPCN) in prioritizing the neural processing of the first task, the fate of the second task remains poorly understood. Here, we provide novel neural evidence on how the functional connectivity between sensory systems and the default-mode network (DMN) suspends the neural processing of the second task to ensure the efficient completion of the first task in dual-task situation. In a cross-modal PRP paradigm, a visual task could either precede or follow an auditory task. The DMN was generally deactivated during task performance and selectively coupled with the sensory system underlying the second task subjected to the PRP effect. Specifically, the DMN showed neural coupling with the auditory system when the auditory task came after the visual task, and with the visual system vice versa. More critically, the strength of the DMN-Sensory coupling correlated negatively with the size of the PRP effect: the stronger the coupling, the shorter the PRP. Therefore, rather than being detrimental to the dual-task performance, temporary suspension of the second task, via the DMN-Sensory coupling, surprisingly guaranteed the efficient completion of the first task by reducing the interference from the second task. Accordingly, the entry and processing of the second stimuli in the central executive system were speeded up as well.


Assuntos
Rede de Modo Padrão , Análise e Desempenho de Tarefas , Humanos , Órgãos dos Sentidos , Imageamento por Ressonância Magnética , Mapeamento Encefálico , Encéfalo , Vias Neurais , Rede Nervosa
15.
Nat Prod Res ; 37(20): 3478-3483, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-35687836

RESUMO

Toxicodendron vernicifluum (Stokes) F.A. Barkley, also called 'Qishu', is a shrub belonging to the Anacardiaceae family and producing lacquer. In this work, a new flavonoid glycoside (1), was isolated from the heartwood of T. vernicifluum, together with four known compounds (2-5). The structure of the new compound was determined as 4',7-dihydroxy-3'-methoxy-3-O-ß-D-glucopyranosyl-flavonoid (1), on the basis of acidic hydrolysis, and spectroscopic analyses. Compound 1 showed significantly cytotoxic against A549 cell lines with the values of IC50 at 1.5 µM.

16.
Front Pediatr ; 11: 1237747, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37744439

RESUMO

Background: Neonatal resuscitation is an important skillset for clinicians attending deliveries. Accredited neonatal resuscitation training is not obligatory in most training centers of standardized medical residency programs before 2022 in China. We investigated the feasibility and effectiveness of neonatal resuscitation simulation training (neo-RST) in residents in Shenzhen, China. Methods: Four two-day neo-RST workshops were conducted in the University of Hong Kong-Shenzhen Hospital and Shenzhen Health Capacity Building and Continuing Education Center in 2020-2021. The workshops had Neonatal Resuscitation Program (NRP)® update, skill stations and simulation practice with debriefing. Each participant had the integrated skill station assessment (ISSA) at the end of workshop. Participants of workshops included residents of different disciplines and health care providers (HCPs) of neonatal and obstetrical departments. We compared demographic characteristics, neonatal resuscitation knowledge before training, ISSA overall and categorical scores on skill sets between residents and HCPs. Results: In 2020-2021, 4 neo-RST workshops were conducted with 48 residents and 48 HCPs. The residents group had less working experience, less prior experience in neo-RST and lower neonatal resuscitation knowledge scores than those of HCPs group. After the workshop, residents had higher overall ISSA score than that of HCPs group (90.2 ± 5.9 vs. 86.3 ± 6.6%, P = 0.003, respectively). There was no significant difference in the numbers of participants scored <80% in residents and HCPs group (3 [6.3%] vs. 7 [14.6%], respectively). Regarding the categorical scores, residents scored significantly higher in preparation, ventilation, crisis resource management and behavioral skills but lower in appropriate oxygen use, when compared with the HCPs. Conclusion: Neo-RST for residents is feasible with promising short-term educational outcomes. Neo-RST could be implemented in standardized medical residency programs in China.

17.
J Pharm Pharmacol ; 74(3): 337-350, 2022 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-34923582

RESUMO

OBJECTIVES: Plant-derived flavonolignans had been demonstrated to have various biological functions. They are an important class of natural products combined by a flavonoid unit and a phenylpropanoid unit. KEY FINDINGS: From the literature survey, 88 constituents from natural resources were identified. Different derivatives of flavonolignans were listed, fused phenylpropanoid unit with dioxane ring, or cyclic ether, or simple ether side chain, or lactone, and so on. Besides, the pharmacological effects of flavonolignans were summarized as well. It has a wide range of anti-tumour, antioxidant, anti-microorganic and anti-inflammatory effects. SUMMARY: This review had provided a full-scale profile of flavonolignans on its plant sources, phytochemistry and pharmacology, and also proposed some issues and perspectives which may be of concern in the future. It was greatly anticipated that the commercialization of the flavonolignans would lead to uplift the financial abilities of communities attending the growing of the flavonolignans and the relevant and potential production becoming an international herbal and pharmaceutical commodity.


Assuntos
Flavonolignanos/farmacologia , Extratos Vegetais/farmacologia , Plantas Medicinais/química , Animais , Flavonolignanos/isolamento & purificação , Humanos , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia
18.
Endocrine ; 76(3): 526-535, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35194770

RESUMO

PURPOSE: Pancreatic ß-cell failure is a central hallmark of the pathogenesis of diabetes mellitus; however, the molecular basis underlying chronic inflammation-caused ß-cell failure remains unclear. This study reported here specifically assessed the association between miR-25/miR-92b family and ß-cell failure in diabetes. METHODS: IL-1ß and two additional ER stress activators, palmitate and tunicamycin were applied to evaluate the expression level miR-25 by Taqman® RT-PCR. Glucose- and potassium-stimulated insulin secretion assays were performed to assess ß-cell function. Dual-luciferase activity, and western blotting assays were utilized for miR-25 target gene verification. CCK-8 and TUNEL staining were used to evaluate ß-cell viability and apoptosis. RESULTS: miRNA ChIP identified the increased level of miR-25 in INS-1 cells by IL-1ß treatment. Expression levels of miR-25 were significantly upregulated with the treatment of IL-1ß, palmitate or tunicamycin in both INS-1 cells and human islets. Ectopic elevation of miR-25 recapitulated most featured ß-cell defects caused by IL-1ß, including inhibition of insulin biosynthesis and increased ß-cell apoptosis. These detrimental effects of miR-25 relied on its seed sequence recognition and repressed expression of its target genes Neurod1 and Mcl1. The miR-25/NEUROD1 axis reduced insulin biosynthesis via transcriptional regulation of ß-cell specific genes. The miR-25/MCL1 axis caused ß-cell apoptosis in a CASPASE-3/PARP1-dependent manner. Comparable impairments were generated by miR-92b and miR-25, emphasizing the redundant biological roles of miRNA family members with the same seed sequence. CONCLUSION: MiR-25/miR-92b family plays a major role in ß-cell failure occurring under inflammation and diabetes states.


Assuntos
Células Secretoras de Insulina , MicroRNAs , Apoptose/genética , Humanos , Inflamação/metabolismo , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Palmitatos/metabolismo , Palmitatos/farmacologia , Tunicamicina/farmacologia
19.
Bioact Mater ; 15: 288-304, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35356817

RESUMO

While most studies of mechanical stimulation of cells are focused on two-dimensional (2D) and three-dimensional (3D) systems, it is rare to study the effects of cyclic stretching on cells under a quasi-3D microenvironment as a linkage between 2D and 3D. Herein, we report a new method to prepare an elastic membrane with topographic microstructures and integrate the membrane into a microfluidic chip. The fabrication difficulty lay not only in the preparation of microstructures but also in the alignment and bonding of the patterned membrane to other layers. To resolve the problem, we designed and assembled a fast aligner that is cost-effective and convenient to operate. To enable quasi-3D microenvironment of cells, we fabricated polydimethylsiloxane (PDMS) microwell arrays (formed by micropillars of a few microns in diameter) with the microwell diameters close to the cell sizes. An appropriate plasma treatment was found to afford a coating-free approach to enable cell adhesion on PDMS. We examined three types of cells in 2D, quasi-3D, and 3D microenvironments; the cell adhesion results showed that quasi-3D cells behaved between 2D and 3D cells. We also constructed transgenic human mesenchymal stem cells (hMSCs); under cyclic stretching, the visualizable live hMSCs in microwells were found to orientate differently from in a 3D Matrigel matrix and migrate differently from on a 2D flat plate. This study not only provides valuable tools for microfabrication of a microfluidic device for cell studies, but also inspires further studies of the topological effects of biomaterials on cells.

20.
Front Med (Lausanne) ; 9: 1111830, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36733933

RESUMO

Background: Brucellosis is a zoonotic disease that threatens public health and creates an economic burden. Unfortunately, it is often overlooked in developing countries, with misdiagnosis causing negative impacts on those with low income. Although the symptoms of brucellosis are commonly reported as fever and fatigue, rare pulmonary, and psychiatric involvements should also be considered. We present the first brucellosis patient in China with multiple pulmonary nodules and depression. Furthermore, this report highlights the importance of collecting patient history in epidemic areas of brucellosis. Case presentation: We report the case of a 40-year-old woman with intermittent fever for 2 months and gradually accompanied by chills, dry cough, arthralgia, and fatigue. The patient was also diagnosed with depression after fever. She received symptomatic treatment at a regional hospital; however, there was no significant symptom relief. She suddenly developed hemoptysis 1 day prior to arrival at our hospital, where we discovered that her liver, spleen, neck, and axillary lymph nodes were enlarged, and there were multiple nodules in both lungs. The patient was eventually diagnosed with brucellosis after the serum agglutination test and received antibiotic therapy, which provided symptom relief. Conclusion: This report describes a case of brucellosis with uncommon multipulmonary nodules and depression in China. This study has widened the evidence of respiratory involvement due to brucellosis. Second, it demonstrates the importance of collecting a comprehensive medical history, especially in epidemic areas. In conclusion, for febrile patients with pulmonary nodules and depression, especially in endemic areas, brucellosis should be considered.

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