Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 710
Filtrar
1.
Methods Mol Biol ; 2383: 293-306, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34766298

RESUMO

The mature spermatozoon, a highly differentiated cell equipped for the sole purpose of fertilization, lacks the protein machinery required for conventional endocytotic mechanisms. Perhaps contrary to expectation, cell-penetrating peptides (CPPs) rapidly translocate across the unique sperm plasma membrane to accrete within distinct intracellular compartments. Confocal microscopy, employing red-fluorescent CPPs and bioportides, is a convenient platform to study this membrane translocation process. In the virtual absence of genetic expression, rapid physiological responses of human sperm are dependent upon protein-protein interactions that may be regulated by posttranslational modifications including phosphorylation. This chapter provides an outline of the design of bioactive CPPs, or bioportides, which include protein-mimetic sequences from the interaction domains of sperm proteins. Protocols are included which enable the biological assessment of the impact of bioportides upon the viability and motility of spermatozoa.

2.
Lancet Microbe ; 2021 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-34778853

RESUMO

Background: Previous infection with SARS-CoV-2 affects the immune response to the first dose of the SARS-CoV-2 vaccine. We aimed to compare SARS-CoV-2-specific T-cell and antibody responses in health-care workers with and without previous SARS-CoV-2 infection following a single dose of the BNT162b2 (tozinameran; Pfizer-BioNTech) mRNA vaccine. Methods: We sampled health-care workers enrolled in the PITCH study across four hospital sites in the UK (Oxford, Liverpool, Newcastle, and Sheffield). All health-care workers aged 18 years or older consenting to participate in this prospective cohort study were included, with no exclusion criteria applied. Blood samples were collected where possible before vaccination and 28 (±7) days following one or two doses (given 3-4 weeks apart) of the BNT162b2 vaccine. Previous infection was determined by a documented SARS-CoV-2-positive RT-PCR result or the presence of positive anti-SARS-CoV-2 nucleocapsid antibodies. We measured spike-specific IgG antibodies and quantified T-cell responses by interferon-γ enzyme-linked immunospot assay in all participants where samples were available at the time of analysis, comparing SARS-CoV-2-naive individuals to those with previous infection. Findings: Between Dec 9, 2020, and Feb 9, 2021, 119 SARS-CoV-2-naive and 145 previously infected health-care workers received one dose, and 25 SARS-CoV-2-naive health-care workers received two doses, of the BNT162b2 vaccine. In previously infected health-care workers, the median time from previous infection to vaccination was 268 days (IQR 232-285). At 28 days (IQR 27-33) after a single dose, the spike-specific T-cell response measured in fresh peripheral blood mononuclear cells (PBMCs) was higher in previously infected (n=76) than in infection-naive (n=45) health-care workers (median 284 [IQR 150-461] vs 55 [IQR 24-132] spot-forming units [SFUs] per 106 PBMCs; p<0·0001). With cryopreserved PBMCs, the T-cell response in previously infected individuals (n=52) after one vaccine dose was equivalent to that of infection-naive individuals (n=19) after receiving two vaccine doses (median 152 [IQR 119-275] vs 162 [104-258] SFUs/106 PBMCs; p=1·00). Anti-spike IgG antibody responses following a single dose in 142 previously infected health-care workers (median 270 373 [IQR 203 461-535 188] antibody units [AU] per mL) were higher than in 111 infection-naive health-care workers following one dose (35 001 [17 099-55 341] AU/mL; p<0·0001) and higher than in 25 infection-naive individuals given two doses (180 904 [108 221-242 467] AU/mL; p<0·0001). Interpretation: A single dose of the BNT162b2 vaccine is likely to provide greater protection against SARS-CoV-2 infection in individuals with previous SARS-CoV-2 infection, than in SARS-CoV-2-naive individuals, including against variants of concern. Future studies should determine the additional benefit of a second dose on the magnitude and durability of immune responses in individuals vaccinated following infection, alongside evaluation of the impact of extending the interval between vaccine doses. Funding: UK Department of Health and Social Care, and UK Coronavirus Immunology Consortium.

3.
Cell ; 184(23): 5699-5714.e11, 2021 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-34735795

RESUMO

Extension of the interval between vaccine doses for the BNT162b2 mRNA vaccine was introduced in the United Kingdom to accelerate population coverage with a single dose. At this time, trial data were lacking, and we addressed this in a study of United Kingdom healthcare workers. The first vaccine dose induced protection from infection from the circulating alpha (B.1.1.7) variant over several weeks. In a substudy of 589 individuals, we show that this single dose induces severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing antibody (NAb) responses and a sustained B and T cell response to the spike protein. NAb levels were higher after the extended dosing interval (6-14 weeks) compared with the conventional 3- to 4-week regimen, accompanied by enrichment of CD4+ T cells expressing interleukin-2 (IL-2). Prior SARS-CoV-2 infection amplified and accelerated the response. These data on dynamic cellular and humoral responses indicate that extension of the dosing interval is an effective immunogenic protocol.


Assuntos
Vacinas contra COVID-19/imunologia , Vacinas Sintéticas/imunologia , Adulto , Idoso , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , COVID-19/sangue , COVID-19/imunologia , COVID-19/virologia , Apresentação Cruzada/imunologia , Relação Dose-Resposta Imunológica , Grupos Étnicos , Feminino , Humanos , Imunidade , Imunoglobulina G/imunologia , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Padrões de Referência , SARS-CoV-2/imunologia , Linfócitos T/imunologia , Resultado do Tratamento , Adulto Jovem
4.
Artigo em Inglês | MEDLINE | ID: mdl-34799259

RESUMO

BACKGROUND: For a vaccine to be successful, communities must perceive it as important, safe, effective, and necessary. However, there are many barriers and hesitancies to vaccination. Underserved patient populations may face additional challenges related to access and cost. Because community pharmacists improve vaccine access and increase vaccination rates, it is beneficial for pharmacists to understand perceptions and barriers to vaccinations in their community to increase vaccine confidence. OBJECTIVES: This study aims to assess and compare barriers and perceptions of the annual influenza to the coronavirus disease 2019 (COVID-19) vaccine for underserved patients of a charitable pharmacy. METHODS: Patients who qualified to receive medications from an outpatient charitable pharmacy took an electronic survey when receiving medications. The survey incorporated questions developed by the World Health Organization's Strategic Advisory Group of Experts on Vaccine Hesitancy on a 5-point Likert scale. Questions about the influenza and COVID-19 vaccines mirrored one another. Demographic data such as age, race, sex, and education level were also collected. RESULTS: Of the 189 patients surveyed at the charitable pharmacy, 71.7% were 55 years old and older and 58.9% were female. Of note, 78% and 77% of participants agreed or strongly agreed that the influenza and COVID-19 vaccines, respectively, were important for the health of others in their community. Adverse effects and the cost of the COVID-19 vaccine were noted to be statistically significantly more of a concern with the COVID-19 vaccine than that of the influenza vaccine (P < 0.001). CONCLUSION: Ensuring equitable vaccine access, promoting the COVID-19 vaccine as free, and eliciting and addressing individual persons' concerns related to vaccine safety and adverse effects are all important ways pharmacists and other health care providers and community stakeholders can help promote vaccine confidence within the populations they serve.

5.
Adv Drug Deliv Rev ; 180: 114044, 2021 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-34774552

RESUMO

Extensive research has been undertaken in the pursuit of anticancer therapeutics. Many anticancer drugs require specificity of delivery to cancer cells, whilst sparing healthy tissue. Cell-penetrating peptides (CPPs), now well established as facilitators of intracellular delivery, have in recent years advanced to incorporate target specificity and thus possess great potential for the targeted delivery of anticancer cargoes. Though none have yet been approved for clinical use, this novel technology has already entered clinical trials. In this review we present CPPs, discuss their classification, mechanisms of cargo internalization and highlight strategies for conjugation to anticancer moieties including their incorporation into therapeutic proteins. As the mainstay of this review, strategies to build specificity into tumor targeting CPP constructs through exploitation of the tumor microenvironment and the use of tumor homing peptides are discussed, whilst acknowledging the extensive contribution made by CPP constructs to target specific protein-protein interactions integral to intracellular signaling pathways associated with tumor cell survival and progression. Finally, antibody/antigen CPP conjugates and their potential roles in cancer immunotherapy and diagnostics are considered. In summary, this review aims to harness the potential of CPP-aided drug delivery for future cancer therapies and diagnostics whilst highlighting some of the most recent achievements in selective delivery of anticancer drugs, including cytostatic drugs, to a range of tumor cells both in vitro and in vivo.

6.
iScience ; 24(11): 103353, 2021 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-34729465

RESUMO

We identify amino acid variants within dominant SARS-CoV-2 T cell epitopes by interrogating global sequence data. Several variants within nucleocapsid and ORF3a epitopes have arisen independently in multiple lineages and result in loss of recognition by epitope-specific T cells assessed by IFN-γ and cytotoxic killing assays. Complete loss of T cell responsiveness was seen due to Q213K in the A∗01:01-restricted CD8+ ORF3a epitope FTSDYYQLY207-215; due to P13L, P13S, and P13T in the B∗27:05-restricted CD8+ nucleocapsid epitope QRNAPRITF9-17; and due to T362I and P365S in the A∗03:01/A∗11:01-restricted CD8+ nucleocapsid epitope KTFPPTEPK361-369. CD8+ T cell lines unable to recognize variant epitopes have diverse T cell receptor repertoires. These data demonstrate the potential for T cell evasion and highlight the need for ongoing surveillance for variants capable of escaping T cell as well as humoral immunity.

7.
Sci Rep ; 11(1): 19796, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34611283

RESUMO

We previously reported that growth promoter-induced skeletal muscle hypertrophy co-ordinately upregulated expression of genes associated with an integrated stress response (ISR), as well as potential ISR regulators. We therefore used Adeno-Associated Virus (AAV)-mediated overexpression of these genes, individually or in combination, in mouse skeletal muscle to test whether they induced muscle hypertrophy. AAV of each target gene was injected into mouse Tibialis anterior (TA) and effects on skeletal muscle growth determined 28 days later. Individually, AAV constructs for Arginase-2 (Arg2) and Activating transcription factor-5 (Atf5) reduced hindlimb muscle weights and upregulated expression of genes associated with an ISR. AAV-Atf5 also decreased Myosin heavy chain (MyHC)-IIB mRNA, but increased MyHC-IIA and isocitrate dehydrogenase-2 (Idh2) mRNA, suggesting ATF5 is a novel transcriptional regulator of Idh2. AAV-Atf5 reduced the size of both TA oxidative and glycolytic fibres, without affecting fibre-type proportions, whereas Atf5 combined with Cebpg (CCAAT enhancer binding protein-gamma) only reduced the size of glycolytic fibres and tended to increase the proportion of oxidative fibres. It is likely that persistent Atf5 overexpression maintains activation of the ISR, thereby reducing protein synthesis and/or increasing protein degradation and possibly apoptosis, resulting in inhibition of muscle growth, with overexpression of Arg2 having a similar effect.

8.
Nat Commun ; 12(1): 5839, 2021 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-34611163

RESUMO

There is an urgent need to understand the nature of immune responses against SARS-CoV-2, to inform risk-mitigation strategies for people living with HIV (PLWH). Here we show that the majority of PLWH with ART suppressed HIV viral load, mount a detectable adaptive immune response to SARS-CoV-2. Humoral and SARS-CoV-2-specific T cell responses are comparable between HIV-positive and negative subjects and persist 5-7 months following predominately mild COVID-19 disease. T cell responses against Spike, Membrane and Nucleoprotein are the most prominent, with SARS-CoV-2-specific CD4 T cells outnumbering CD8 T cells. We further show that the overall magnitude of SARS-CoV-2-specific T cell responses relates to the size of the naive CD4 T cell pool and the CD4:CD8 ratio in PLWH. These findings suggest that inadequate immune reconstitution on ART, could hinder immune responses to SARS-CoV-2 with implications for the individual management and vaccine effectiveness in PLWH.


Assuntos
Infecções por HIV/imunologia , Infecções por HIV/virologia , Imunidade Humoral , SARS-CoV-2/fisiologia , Linfócitos T/imunologia , Adulto , Idoso , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Formação de Anticorpos/imunologia , Antígenos Virais/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , COVID-19/sangue , COVID-19/imunologia , COVID-19/virologia , Estudos de Coortes , Feminino , Genoma Humano , Infecções por HIV/sangue , Humanos , Interferon gama/metabolismo , Masculino , Pessoa de Meia-Idade , Fenótipo , Especificidade da Espécie , Doadores de Tecidos
9.
Cancer Chemother Pharmacol ; 88(6): 1033-1048, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34618197

RESUMO

PURPOSE: To evaluate the pharmacodynamics (PD), pharmacokinetics (PK), and safety of single and multiple doses of PF-06881894 (pegfilgrastim-apgf; Nyvepria™), a biosimilar to reference pegfilgrastim (Neulasta®), in women with non-distantly metastatic breast cancer. METHODS: In Phase I (Cycle 0) of this Phase I/II study, the PD response (absolute neutrophil count [ANC]; CD34 + count), PK profile, and safety of a single 3- or 6-mg subcutaneous dose of PF-06881894 were assessed in chemotherapy-naïve patients before definitive breast surgery. In Phase II (Cycles 1-4), the PD response (duration of severe neutropenia [DSN, Cycle 1], ANC [Cycles 1 and 4]) and PK profile (Cycles 1 and 4) of single and multiple 6-mg doses of PF-06881894 concomitant with chemotherapy and after definitive breast surgery were assessed. RESULTS: Twenty-five patients (mean age 59 years) were enrolled (Cycle 0, n = 12; Cycles 1-4, n = 13). In Cycle 0, PD responses and PK values were lower with 3-mg versus 6-mg PF-06881894. In Cycles 1 and 4, mean DSN was 0.667 days after single or multiple 6-mg doses of PF-06881894, respectively. In Cycle 4 versus Cycle 1, PD responses were more robust; PK values (mean area under the curve, maximum concentration) were lower; and clearance values were higher. The safety profile of PF-06881894 was similar to that for reference pegfilgrastim. CONCLUSION: PF-06881894 as a single 3- or 6-mg dose prior to definitive surgery, or multiple 6-mg/cycle doses postoperatively, with/without myelosuppressive chemotherapy, was consistent with the clinical pharmacology and safety profile of reference pegfilgrastim. TRIAL REGISTRATION: October 2017. ClinicalTrials.gov Identifier: NCT02650193. EudraCT Number: 2015-002057-35.

11.
BMJ Case Rep ; 14(10)2021 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-34706912

RESUMO

Hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC) is a rare autosomal recessive condition characterised by early-onset severe progressive neuropathy, variable degrees of ACC and cognitive impairment. Mutations in SLC12A6 (solute carrier family 12, member 6) encoding the K+-Cl- transporter KCC3 have been identified as the genetic cause of HMSN/ACC. We describe fraternal twins with compound heterozygous mutations in SLC12A6 and much milder phenotype than usually described. Neither of our patients requires assistance to walk. The female twin is still running and has a normal intellect. Charcot-Marie-Tooth Examination Score 2 was 8/28 in the brother and 5/28 in the sister. Neurophysiology demonstrated a length-dependent sensorimotor neuropathy. MRI brain showed normal corpus callosum. Genetic analysis revealed compound heterozygous mutations in SLC12A6, including a whole gene deletion. These cases expand the clinical and genetic phenotype of this rare condition and highlight the importance of careful clinical phenotyping.


Assuntos
Doença de Charcot-Marie-Tooth , Simportadores , Adulto , Agenesia do Corpo Caloso , Feminino , Humanos , Masculino , Mutação , Fenótipo , Simportadores/genética , Gêmeos
12.
Autism Res Treat ; 2021: 9974791, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34552768

RESUMO

Adult referrals to specialist autism spectrum disorder diagnostic services have increased in recent years, placing strain on existing services. It was proposed that the Ritvo Autism Asperger's Diagnostic Scale could be used as a screening tool, in order to identify and prioritise patients most likely to receive an ASD diagnosis. This study evaluates the validity of the RAADS-R as a screening tool for ASD in an adult population. Retrospective case note analysis was used to evaluate the efficacy of the RAADS-R as a screening tool to predict ASD diagnostic outcomes in 50 service users of a NHS specialist autism service. Results indicate no association between RAADS-R scores and clinical diagnostic outcome, suggesting the RAADS-R is not an effective screening tool for identifying service users most likely to receive an ASD diagnosis. In conclusion, used as a self-report measure pre-full diagnostic assessment, the RAADS-R lacks predictive validity and is not a suitable screening tool for adults awaiting autism assessments. Future research should aim to identify reliable screening tools for this purpose.

13.
J Clin Med ; 10(18)2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34575196

RESUMO

Given the differing mechanisms thought to underlie therapeutic sub- and supra-perception-based neurostimulative modalities, Spinal Cord Stimulation (SCS) systems designed for combined delivery of these approaches may help improve analgesic outcomes and quality of life, and reduce treatment failures. This multicenter, observational case-series evaluated 188 patients with chronic back and/or leg pain implanted with an SCS device capable of sequential or simultaneous delivery of sub-perception and supra-perception stimulation programming (i.e., combination therapy) at 16 in Europe. Following implantation, patients were provided with an array of advanced supra-perception programs (e.g., paresthesia-based SCS using multiple independent current sources), and a custom set of sub-perception programs optimized with specific waveforms and/or field shapes. A mean overall pain score of 7.9 ± 1.7 (Standard Deviation (SD)) was reported pre-trial (Baseline). Overall pain was reduced by 4.4 ± 2.8 points (NRS) at 3-months (n = 117) and at 12 months post-implant (n = 90), respectively (p < 0.0001). Substantial quality-of-life (EQ-5D-5L) improvement as assessed at last follow-up was also observed (n = 60). These results suggest that an implanted SCS device capable of combination therapy, while also enabled with patient-specific waveform optimization and stimulation field targeting capabilities, can enable highly effective pain relief and improve quality of life in patients suffering with chronic pain.

15.
Pathog Immun ; 6(2): 27-49, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34541432

RESUMO

Background: Genetic variations across the SARS-CoV-2 genome may influence transmissibility of the virus and the host's anti-viral immune response, in turn affecting the frequency of variants over time. In this study, we examined the adjacent amino acid polymorphisms in the nucleocapsid (R203K/G204R) of SARS-CoV-2 that arose on the background of the spike D614G change and describe how strains harboring these changes became dominant circulating strains globally. Methods: Deep-sequencing data of SARS-CoV-2 from public databases and from clinical samples were analyzed to identify and map genetic variants and sub-genomic RNA transcripts across the genome. Results: Sequence analysis suggests that the 3 adjacent nucleotide changes that result in the K203/R204 variant have arisen by homologous recombination from the core sequence of the leader transcription-regulating sequence (TRS) rather than by stepwise mutation. The resulting sequence changes generate a novel sub-genomic RNA transcript for the C-terminal dimerization domain of nucleocapsid. Deep-sequencing data from 981 clinical samples confirmed the presence of the novel TRS-CS-dimerization domain RNA in individuals with the K203/R204 variant. Quantification of sub-genomic RNA indicates that viruses with the K203/R204 variant may also have increased expression of sub-genomic RNA from other open reading frames. Conclusions: The finding that homologous recombination from the TRS may have occurred since the introduction of SARS-CoV-2 in humans, resulting in both coding changes and novel sub-genomic RNA transcripts, suggests this as a mechanism for diversification and adaptation within its new host.

16.
Pain Ther ; 10(2): 1451-1465, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34478115

RESUMO

INTRODUCTION: Low back pain impacts most people throughout the course of their lives and contributes significantly to the global burden of disease. In some patients, symptoms resolve with little intervention, while others are amenable to surgical intervention, some cases are intractable to current care paradigms. Restorative neurostimulation is an emerging therapy for chronic mechanical low back pain. METHODS: We conducted a prospective post-market follow-up of 42 patients treated for longstanding chronic mechanical low back pain with restorative neurostimulation. Patients were followed up at 45, 90, and 180 days and 1 and 2 years following activation of the device. Pain, disability, and health-related quality of life were recorded. RESULTS: Among the 37 patients completing 2-year follow-up, numerical rating scale (NRS) pain scores improved from 7.0 ± 0.2 to 3.5 ± 0.3 (p < 0.001), Oswestry Disability Index (ODI) scores improved from 46.2 ± 2.2 to 29.2 ± 3.1 (p < 0.001), and health-related quality of life (measured by the EuroQol 5-Dimension 5-Level questionnaire-EQ-5D-5L) improved from 0.426 ± 0.035 to 0.675 ± 0.030 (p < 0.001). Additionally, 57% of patients experienced a greater than 50% reduction in pain, and 51% of patients benefited by a greater than 15-point reduction in ODI, both substantial improvements. CONCLUSION: This real-world sample of patients shows that restorative neurostimulation can provide substantial and durable benefit to a cohort of patients that have traditionally had few reliable treatment options. Our findings support the continued used of this therapy in well-selected patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01985230.

17.
Pediatr Allergy Immunol Pulmonol ; 34(3): 106-108, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34495747

RESUMO

Introduction: Echinocandin antifungal medications including micafungin are being used more commonly in the treatment of invasive fungal infections in both pediatric and adult patients. Micafungin is also a first-line therapeutic option for candidemia and antifungal prophylaxis in a variety of clinical settings. Hypersensitivity reactions have not been well described; however, isolated cases have been reported. No cases of desensitization to echinocandins have been previously described. Case Presentation: In this report, we described a 14-year-old female with high-risk pre-B cell acute lymphoblastic leukemia diagnosed with pulmonary aspergillosis. She developed a hypersensitivity reaction to micafungin, which was deemed first-line therapy for the infection. A rapid intravenous desensitization protocol was successfully completed without reactions. The patient completed the remaining 2 months of therapy without reactions. Conclusion: This report outlines the first report of a successful desensitization to micafungin or any echinocandin. This is a safe method of completing antifungal therapy in a patient with echinocandin hypersensitivity and may be considered for other patients with micafungin hypersensitivities.

18.
J Virol ; 95(23): e0125921, 2021 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-34523962

RESUMO

Although mutant-specific T cells are elicited in some individuals infected with HIV-1 mutant viruses, the detailed characteristics of these T cells remain unknown. A recent study showed that the accumulation of strains expressing Nef135F, which were selected by HLA-A*24:02-restricted T cells, was associated with poor outcomes in individuals with the detrimental HLA-B*35:01 allele and that HLA-B*35:01-restricted NefYF9 (Nef135-143)-specific T cells failed to recognize target cells infected with Nef135F mutant viruses. Here, we investigated HLA-B*35:01-restricted T cells specific for the NefFF9 epitope incorporating the Nef135F mutation. Longitudinal T-cell receptor (TCR) clonotype analysis demonstrated that 3 types of HLA-B*35:01-restricted T cells (wild-type [WT] specific, mutant specific, and cross-reactive) with different T cell repertoires were elicited during the clinical course. HLA-B*35:01+ individuals possessing wild-type-specific T cells had a significantly lower plasma viral load (pVL) than those with mutant-specific and/or cross-reactive T cells, even though the latter T cells effectively recognized the mutant virus-infected cells. These results suggest that mutant-specific and cross-reactive T cells could only partially suppress HIV-1 replication in vivo. An ex vivo analysis of the T cells showed higher expression of PD-1 on cross-reactive T cells and lower expression of CD160/2B4 on the mutant-specific T cells than other T cells, implying that these inhibitory and stimulatory molecules are key to the reduced function of these T cells. In the present study, we demonstrate that mutant-specific and cross-reactive T cells do not contribute to the suppression of HIV-1 replication in HIV-1-infected individuals, even though they have the capacity to recognize mutant virus-infected cells. Thus, the collaboration of HLA-A*24:02 with the detrimental allele HLA-B*35:01 resulted in the coevolution of HIV-1 alongside virus-specific T cells, leading to poorer clinical outcomes. IMPORTANCE HIV-1 escape mutations are selected under pressure from HIV-1-specific CD8+ T cells. Accumulation of these mutations in circulating viruses impairs the control of HIV-1 by HIV-1-specific T cells. Although it is known that HIV-1-specific T cells recognizing mutant virus were elicited in some individuals infected with a mutant virus, the role of these T cells remains unclear. Accumulation of phenylalanine at HIV-1 Nef135 (Nef135F), which is selected by HLA-A*24:02-restricted T cells, led to poor clinical outcome in individuals carrying the detrimental HLA-B*35:01 allele. In the present study, we found that HLA-B*35:01-restricted mutant-specific and cross-reactive T cells were elicited in HLA-B*35:01+ individuals infected with the Nef135F mutant virus. These T cells could not effectively suppress HIV-1 replication in vivo even though they could recognize mutant virus-infected cells in vitro. Mutant-specific and cross-reactive T cells expressed lower levels of stimulatory molecules and higher levels of inhibitory molecules, respectively, suggesting a potential mechanism whereby these T cells fail to suppress HIV-1 replication in HIV-1-infected individuals.

19.
Sci Data ; 8(1): 212, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34376684

RESUMO

With the Convention on Biological Diversity conference (COP15), United Nations Climate Change Conference (COP26), and United Nations Food Systems Summit, 2021 is a pivotal year for transitioning towards sustainable food systems. Diversified farming systems are key to more sustainable food production. Here we present a global dataset documenting outcomes of diversified farming practices for biodiversity and yields compiled following best standards for systematic review of primary studies and specifically designed for use in meta-analysis. The dataset includes 4076 comparisons of biodiversity outcomes and 1214 of yield in diversified farming systems compared to one of two reference systems. It contains evidence from 48 countries of effects on species from 33 taxonomic orders (spanning insects, plants, birds, mammals, eukaryotes, annelids, fungi, and bacteria) of diversified farming systems producing annual or perennial crops across 12 commodity groups. The dataset presented provides a resource for researchers and practitioners to easily access information on where diversified farming systems effectively contribute to biodiversity and food production outcomes.


Assuntos
Agricultura , Biodiversidade , Produção Agrícola , Animais
20.
BMC Immunol ; 22(1): 59, 2021 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-34445953

RESUMO

BACKGROUND: Innate lymphoid cells (ILC) are lymphoid lineage innate immune cells that do not mount antigen-specific responses due to their lack of B and T-cell receptors. ILCs are predominantly found at mucosal surfaces, as gatekeepers against invading infectious agents through rapid secretion of immune regulatory cytokines. HIV associated destruction of mucosal lymphoid tissue depletes ILCs, among other immune dysfunctions. Studies have described limited restoration of ILCs during the first three years of combined antiretroviral therapy (cART). Little is known about restoration of ILCs during long-term cART, particularly in sub-Saharan Africa which hosts increasing numbers of adults with at least a decade of cART. RESULTS: We examined phenotypes and function of ILCs from peripheral blood mononuclear cells after 12 years of suppressive cART. We report that ILC1 frequencies (T-BET + CD127 + and CD161 +) were higher in cART-treated HIV-infected relative to age-matched health HIV-negative adults; P = 0.04 whereas ILC precursors (ILCP) were comparable in the two groups (P = 0.56). Interferon gamma (IFN-γ) secretion by ILC1 was higher among cART-treated HIV-infected relative to HIV-negative adults (P = 0.03). CONCLUSION: HIV associated alteration of ILC persisted during cART and may likely affect the quality of host innate and adaptive immune responses during long-term cART.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...