Forecasting of Airborne Conidia Quantities and Potential Insect Associations of Cryphonectria parasitica, the Causal Agent of Chestnut Blight, in England.

Sweet chestnut, an Asiatic tree introduced in many parts of Europe including the United Kingdom, is planted for nut production, timber, and amenity. Its major threat is the disease called blight, caused by the fungus Cryphonectria parasitica, which infects through wounds by airborne spores. Field trapping using sticky rods rotating traps was performed in an infected area in Devon (between May 2021 and April 2023). An improved dual hydrolysis Taqman probes real-time PCR was used. The number of spores was calculated by comparing the cycle threshold to the Ct of standards with known amounts of conidia or known target fragment copies cloned into a plasmid. Weekly spore counts were in the range of around 60 to approximately 8.5 × 103, with fluctuations of peaks (mainly in late summer-autumn 2021) and troughs. The effects of weather parameters were modelled, finding correlations between spore numbers and temperature, humidity, dewpoint, rainfall, wind speed, and wind duration. Additionally, an insect trapping was performed to confirm the presence/absence and quantity of C. parasitica conidia potentially phoretic on some insects by using the same molecular approach. None of the ten collected insect species harboured spores of this fungus.

Is digit ratio (2D:4D) a biomarker for lactate? Evidence from a cardiopulmonary test on professional male footballers.

BACKGROUND: Lactate accumulation is associated with vigorous exercise, cardiovascular disease and a number of cancers. Digit ratio (2D:4D) has also been linked to oxygen metabolism, myocardial infarction and various cancers. Such similarities suggest the possibility that 2D:4D is a biomarker of lactate. Here, we consider the relationship between 2D:4D and lactate during an incremental cardiopulmonary exercise test. METHOD: The participants were male professional football players. The treadmill test began at a speed of 8 km/h when the first lactate measurement was taken. The speed was increased by 2 km/h every 3.15 min, with measurements at 10, 12, 14 and 16 km/h. RESULTS: There were 72 Caucasian and 7 Black participants, results are reported for the most numerous group. Lactate levels increased with running speed and were not correlated with age, body size or body composition. Median splits of digit ratios (right, left and right-left 2D:4D [Dr-l]) were calculated. In comparison to the Low ratio group, the High ratio group showed higher lactate levels across speeds. Effect sizes varied from very large to huge (right 2D:4D), large (left 2D:4D) and medium (Dr-l). At the individual level, positive correlations between digit ratios and lactate at the five different speeds varied from large (right 2D:4D), medium (left 2D:4D) and small (Dr-l). CONCLUSION: There were large positive associations between right 2D:4D and lactate at all running speeds. We discuss our findings in relation to oxygen metabolism and suggest that 2D:4D may be a biomarker for lactate in the wider context of the latter's importance in health and disease.

The associations between digit ratio (2D:4D and right - left 2D:4D), maximal oxygen consumption and ventilatory thresholds in professional male football players.

INTRODUCTION: Digit ratio (2D:4D: the relative length of the 2nd and 4th digit) is thought to be a negative correlate of prenatal testosterone. The 2D:4D is related to oxygen metabolism, but the precise nature of this relationship is unclear. The purpose of the present study was to consider associations between digit ratios (right 2D:4D, left 2D:4D, right-left 2D:4D [Dr-l]) and VO2max and ventilatory thresholds (VT1 and VT2). METHODS: One hundred and thirty-three Caucasian (n = 133) professional football players competing in Cyprus participated in the study. Players underwent anthropometric measurements, and digit lengths were measured from hand scans. They also completed an incremental cardiopulmonary test to exhaustion on a treadmill. RESULTS: There were negative correlations between digit ratios and VO2max (right 2D:4D, r = -.65; left 2D:4D r = -.37, both p < .0001; Dr-l r = -.30, p = .0005). There were no relationships between digit ratios and VT1. For VT2, there were negative relationships with digit ratios (right 2D:4D, r = -.43, p < .0001; left 2D:4D, r = -.21 and Dr-l, r = -.21, both p = .02). Digit ratios are negatively related to VO2max with large (right 2D:4D) and medium (left 2D:4D, Dr-l) effect sizes. For VT2, there were also negative correlations, which were medium (right 2D:4D) and small (left 2D:4D, Dr-l). CONCLUSION: Our findings may help clarify the relationships between digit ratios and high-intensity actions for extended periods, which are dependent on efficient oxygen metabolism.

Development of reverse genetics system for Guanarito virus: substitution of E1497K in the L protein of Guanarito virus S-26764 strain changes plaque phenotype and growth kinetics.

Guanarito virus (GTOV) is the causative agent of Venezuelan hemorrhagic fever. GTOV belongs to the genus Mammarenavirus, family Arenaviridae and has been classified as a Category A bioterrorism agent by the United States Centers for Disease Control and Prevention. Despite being a high-priority agent, vaccines and drugs against Venezuelan hemorrhagic fever are not available. GTOV S-26764, isolated from a non-fatal human case, produces an unclear cytopathic effect (CPE) in Vero cells, posing a significant obstacle to research and countermeasure development efforts. Vero cell-adapted GTOV S-26764 generated in this study produced clear CPE and demonstrated rapid growth and high yield in Vero cells compared to the original GTOV S-26764. We developed a reverse genetics system for GTOV to study amino acid changes acquired through Vero cell adaptation and leading to virus phenotype changes. The results demonstrated that E1497K in the L protein was responsible for the production of clear plaques as well as enhanced viral RNA replication and transcription efficiency. Vero cell-adapted GTOV S-26764, capable of generating CPE, will allow researchers to easily perform neutralization assays and anti-drug screening against GTOV. Moreover, the developed reverse genetics system will accelerate vaccine and antiviral drug development.IMPORTANCEGuanarito virus (GTOV) is a rodent-borne virus. GTOV causes fever, prostration, headache, arthralgia, cough, sore throat, nausea, vomiting, diarrhea, epistaxis, bleeding gums, menorrhagia, and melena in humans. The lethality rate is 23.1% or higher. Vero cell-adapted GTOV S-26764 shows a clear cytopathic effect (CPE), whereas the parental virus shows unclear CPE in Vero cells. We generated a reverse genetics system to rescue recombinant GTOVs and found that E1497K in the L protein was responsible for the formation of clear plaques as well as enhanced viral RNA replication and transcription efficiency. This reverse genetic system will accelerate vaccine and antiviral drug developments, and the findings of this study contribute to the understanding of the function of GTOV L as an RNA polymerase.

Digit Ratio (2D:4D; Right-Left 2D:4D) and Multiple Phenotypes for Same-Sex Attraction: The BBC Internet Study Revisited.

Same-sex attraction may be linked to low prenatal androgen (in men) and high prenatal androgen (in women). Digit ratio (2D:4D) is thought to be a negative correlate of prenatal androgen and right-left 2D:4D (Dr-l) to reflect lateralized differences in sensitivity to prenatal androgen. Lower 2D:4D has been reported for lesbians compared to heterosexuals, but links to high 2D:4D in gay men are less clear. The largest study thus far (the BBC Internet study) found no significant difference between the 2D:4D of lesbians and heterosexual women but a higher 2D:4D in gay men compared to heterosexual men. Here we consider the possibility that low and high prenatal androgen is associated with same-sex attraction in men (n = 108,779) and women (n = 87,742), resulting in more than two phenotypes. We examined the associations between 2D:4D, Dr-l, and same-sex attraction scores in the BBC Internet study. In contrast to the earlier report, which considered sexual orientation in categories, there were positive linear associations in men (right and left 2D:4D, but not Dr-l) and negative linear associations in women (right 2D:4D and Dr-l, but not left 2D:4D). There were no curvilinear relationships for right and left 2D:4D. However, Dr-l showed a U-shaped association with same-sex attraction in men. Thus, (1) high prenatal androgen may be implicated in female homosexuality, while both low and high prenatal androgen may be implicated in male homosexuality, and (2) large side differences in sensitivity to androgen may be associated with elevated same-sex attraction in men.

The roles of XJ13 and XJ44-specific mutations within the Candid #1 GPC in Junin virus attenuation.

Junin virus (JUNV) is a member of the Arenaviridae family of viruses and is the pathogen responsible for causing Argentine hemorrhagic fever, a potentially lethal disease endemic to Argentina. A live attenuated vaccine for human use, called Candid#1, is approved only in Argentina. Candid#1 vaccine strain of Junin virus was obtained through serial passage in mouse brain tissues followed by passage in Fetal Rhesus macaque lung fibroblast (FRhL) cells. Previously, the mutations responsible for attenuation of this virus in Guinea pigs were mapped in the gene encoding for glycoprotein precursor (GPC) protein. The resulting Candid#1 glycoprotein complex has been shown to cause endoplasmic reticulum (ER) stress in vitro resulting in the degradation of the GPC. To evaluate the attenuating properties of specific mutations within GPC, we created recombinant viruses expressing GPC mutations specific to key Candid#1 passages and evaluated their pathogenicity in our outbred Hartley guinea pig model of Argentine hemorrhagic fever. Here, we provide evidence that early mutations in GPC obtained through serial passaging attenuate the visceral disease and increase immunogenicity in guinea pigs. Specific mutations acquired prior to the 13th mouse brain passage (XJ13) are responsible for attenuation of the visceral disease while having no impact on the neurovirulence of Junin virus. Additionally, our findings demonstrate that the mutation within an N-linked glycosylation motif, acquired prior to the 44th mouse brain passage (XJ44), is unstable but necessary for complete attenuation and enhanced immunogenicity of Candid#1 vaccine strain. The highly conserved N-linked glycosylation profiles of arenavirus glycoproteins could therefore be viable targets for designing attenuating viruses for vaccine development against other arenavirus-associated illnesses.

Digit ratio (2D:4D), laryngeal cancer and vocal fold leukoplakia.

BACKGROUND: To date, there are no studies that have analyzed the possible influence of exposure to prenatal sex hormones on the risk of laryngeal cancer (LC) and premalignant laryngeal lesion-vocal fold leukoplakia (VFL). Digit ratio (2D:4D) is suggested to be a proxy of prenatal sex hormone exposure. OBJECTIVE: To examine 2D:4D in patients with LC and clarify if it could add to the verified risk factors in estimating the overall risk of LC. METHODS: 511 subjects participated in the study. The study group included 269 patients: with LC (N = 114, 64 men) and VFL (N = 155, 116 men). Controls included 242 healthy individuals (66.40 ± 4.50 years (106 men)). RESULTS: Predictive models estimating the risk of VFL and LC in women, based solely on predictors like smoking and alcohol consumption had a lower area under the ROC curve (AUC) than the model with left 2D:4D. AUC for the model estimating the likelihood of VFL increased from 0.83 to 0.85, and for LC from 0.76 to 0.79. CONCLUSIONS: Low left 2D:4D may be associated with an increased risk of developing leukoplakia and laryngeal cancer in women. In the case of laryngeal cancer, left 2D:4D may serve as additional variable (to other known risk factors, such as smoking and/or alcohol consumption), which can improve cancer risk prediction.

Off-Season Arthroscopic Partial Meniscectomy in National Collegiate Athletic Association Division I Football Players Has a Longer Return to Sport Time than In-Season Surgery.

Purpose: To report the outcomes of routine arthroscopic meniscectomy in National Collegiate Athletic Association (NCAA) Division I Football players. Methods: NCAA athletes who underwent arthroscopic meniscectomy over 5 years were included. Players who had incomplete data, previous knee surgery, ligamentous injury, and/or microfractures were excluded. Data collected were player position, timing of surgery, procedures performed, return to play (RTP) rate and time, and postoperative performance. Continuous variables were analyzed with Student t-tests or a one-way analysis of variance. Results: Thirty-six athletes (38 knees) who underwent arthroscopic partial meniscectomy (31 lateral, 7 medial) were included. The mean RTP time was 71 ± 39 days. The mean RTP time in athletes who underwent in-season surgery) was significantly shorter than the RTP in athletes who had off-season surgery (58 ± 41 days vs 85 ± 33 days, P < .05). The mean RTP in 29 athletes (31 knees) with lateral meniscectomy was similar to the 7 athletes (7 knees) who had medial meniscectomy (70 ± 36 vs 77 ± 56, P = .6803). The mean RTP time was similar between football players who underwent isolated lateral meniscectomy and those who had lateral meniscectomy with chondroplasty (61 ± 36 days vs 75±41 days, P = .32). Athletes played an average of 7.7 ± 4.9 games the season they returned; position category and anatomical compartment of the knee lesion had no bearing on number of games played (P = .1864 and P = .425). Conclusions: NCAA Division 1 football players who underwent arthroscopic partial meniscectomy RTP at approximately 2.5 months' postoperatively. Athletes who underwent off-season surgery had longer RTP time compared with those who underwent in-season surgery. RTP time and performance after surgery did not differ based on player position, anatomical location of the lesions, or chondroplasty at the time of meniscectomy. Level of Evidence: Level IV, therapeutic case series.

Superior Capsule Reconstruction With Fascia Lata Allograft Has Initial Stiffness and Ultimate Load Comparable to the Native Shoulder Superior Capsule: A Cadaveric Biomechanical Study.

PURPOSE: The purpose of this study was to compare the biomechanical characteristics of a fascia lata superior capsule reconstruction (FL-SCR) to the native superior capsule. METHODS: The native superior capsule of 8 cadaveric shoulders was tested with cyclic loading from 10 to 50 N for 30 cycles in 20° of glenohumeral abduction followed by load to failure at 60 mm/min. Following native superior capsule testing, FL-SCR was performed, which was tested as described for the native capsule. Paired t test was used for statistical analyses with P < .05 for significance. RESULTS: The stiffness for cycle 1 to 50 N was significantly higher for the native superior capsule compared to the FL-SCR (P = .001). By cycle 30, the stiffness between the two was not statistically different (P = .734). During load to failure, the initial stiffness to 2 mm for the FL-SCR and the native superior capsule was not statistically different (P = .262). The linear stiffness and yield load of the native superior capsule were significantly greater than that of the FL-SCR (94.5 vs 28.0 N/mm, P = .013; 386.9 vs 123.8 N, P = .029). There was no significant difference in ultimate load between the native superior capsule and the FL-SCR (444.9 vs 369.0 N, P = .413). CONCLUSIONS: FL-SCR has initial stiffness and ultimate load similar to the native superior capsule. CLINICAL RELEVANCE: The biomechanical properties of FL allograft make it an appealing option as a graft choice for superior capsule reconstruction.

Parental Income and the Sexual Behavior of Their Adult Children: A Trivers-Willard Perspective.

Parental income is negatively and linearly related to the digit ratio (2D:4D; a proxy for prenatal sex steroids) of their children. Children of parents with high income are thought to be exposed to higher prenatal testosterone and develop lower 2D:4D. It is further hypothesized that 2D:4D relates to sexual orientation, although it is unclear whether the association is linear or curvilinear. Here, we consider patterns of parental income and its association with the sexual behavior of their adult children in a large online study (the BBC internet study). There were curvilinear relationships with parental income in male and female children. The highest frequencies of homosexuality and bisexuality were found in the lowest income group (bottom 25% of the population), the lowest frequencies in the income group representing the upper 50% of the population, and intermediate values in the other groups (low 50% and top 25% of the population). Parental income showed a U-shaped association with scores for same-sex attraction and an inverted U-shaped association with opposite-sex attraction. Thus, for the first time, we show that same-sex attraction is related to parental income. The curvilinear relationship between parental income and sexual behavior in their adult children may result from an association between very high fetal estrogen or testosterone and attraction to partners of the same sex. Among non-heterosexuals, and in both sexes, very high fetal estrogen may be associated with femme or submissive sexual roles, and very high fetal testosterone with butch and assertive sexual roles.

Right-left digit ratios, a novel form of asymmetry: Patterns of instability in children and relationships to platelet counts and hospitalization in adults with COVID-19.

High right minus left (R-L) asymmetry of digit ratios has been reported to be linked to hospitalization for COVID-19. Here we examined the developmental patterns of this novel form of asymmetry in children and further explored their relationships to platelet counts and hospitalization for COVID-19 in adult patients. We considered ratios calculated from four digits (2D, 3D, 4D, 5D) in: (i) a sample of healthy participants aged 2 years to 18 years (n = 680, 340 males) and (ii) 96 adult patients (42 males) hospitalized for COVID-19 and 100 controls (53 males). The protocol for (ii) included a questionnaire and laboratory test results. In sample (i) of the six unsigned digit ratio asymmetries, those which included 5D had the highest mean asymmetry with the greatest between-individual variation and they were unstable over the age range of 2 years to 18 years. In sample (ii) patients showed higher asymmetries than controls in four ratios (2D:4D, 2D:5D, 3D:5D, 4D:5D) and a sum of asymmetries of the two independent ratios (2D:4D+3D:5D) correlated positively with platelet counts and hospitalization. Conclusion: Means and SDs of digit ratio asymmetry that include the 5th digit are high and age-unstable. Digit ratio asymmetry, particularly 5th digit ratio asymmetry and a composite measure of 2D:4D + 3D:5D asymmetry, may be positively linked to high platelet counts in COVID-19 patients and to an elevated risk of hospitalization.

Depletion of CD4 and CD8 T Cells Reduces Acute Disease and Is Not Associated with Hearing Loss in ML29-Infected STAT1-/- Mice.

Lassa virus (LASV) is a zoonotic virus endemic to western Africa that can cause a potentially lethal and hemorrhagic disease, Lassa fever (LF). Survivors suffer a myriad of sequelae, most notably sudden onset sensorineural hearing loss (SNHL), the mechanism of which remains unclear. Unfortunately, studies aiming to identify the mechanism of these sequelae are limited due to the biosafety level 4 (BSL4) requirements of LASV itself. ML29, a reassortant virus proposed as an experimental vaccine candidate against LASV, is potentially an ideal surrogate model of LF in STAT1-/- mice due to similar phenotype in these animals. We intended to better characterize ML29 pathogenesis and potential sequelae in this animal model. Our results indicate that while both CD4 and CD8 T cells are responsible for acute disease in ML29 infection, ML29 induces significant hearing loss in a mechanism independent of either CD4 or CD8 T cells. We believe that this model could provide valuable information for viral-associated hearing loss in general.

Unbiased approach to identify and assess efficacy of human SARS-CoV-2 neutralizing antibodies.

Coronavirus disease 2019 (COVID-19) continues to significantly impact the global population, thus countermeasure platforms that enable rapid development of therapeutics against variants of SARS-CoV-2 are essential. We report use of a phage display human antibody library approach to rapidly identify neutralizing antibodies (nAbs) against SARS-CoV-2. We demonstrate the binding and neutralization capability of two nAbs, STI-2020 and STI-5041, against the SARS-CoV-2 WA-1 strain as well as the Alpha and Beta variants. STI-2020 and STI-5041 were protective when administered intravenously or intranasally in the golden (Syrian) hamster model of COVID-19 challenged with the WA-1 strain or Beta variant. The ability to administer nAbs intravenously and intranasally may have important therapeutic implications and Phase 1 healthy subjects clinical trials are ongoing.

The Antiviral Effects of 2-Deoxy-D-glucose (2-DG), a Dual D-Glucose and D-Mannose Mimetic, against SARS-CoV-2 and Other Highly Pathogenic Viruses.

Viral infection almost invariably causes metabolic changes in the infected cell and several types of host cells that respond to the infection. Among metabolic changes, the most prominent is the upregulated glycolysis process as the main pathway of glucose utilization. Glycolysis activation is a common mechanism of cell adaptation to several viral infections, including noroviruses, rhinoviruses, influenza virus, Zika virus, cytomegalovirus, coronaviruses and others. Such metabolic changes provide potential targets for therapeutic approaches that could reduce the impact of infection. Glycolysis inhibitors, especially 2-deoxy-D-glucose (2-DG), have been intensively studied as antiviral agents. However, 2-DG's poor pharmacokinetic properties limit its wide clinical application. Herein, we discuss the potential of 2-DG and its novel analogs as potent promising antiviral drugs with special emphasis on targeted intracellular processes.

Intimate Partner Violence, Sexual Assault, and Child Abuse Resource Utilization During COVID-19.

INTRODUCTION: Key measures in preventing spread of the virus that causes coronavirus disease 2019 (COVID-19) are social distancing and stay-at-home mandates. These measures along with other stressors have the potential to increase incidences of intimate partner violence (IPV), sexual assault, and child maltreatment. METHODS: We performed a retrospective review of county police dispatches, emergency department (ED) visits, Sexual Assault Nurse Examiner (SANE) consults, Domestic Violence Healthcare Project (DVHP) team consults, and Child Protection Team consults at a large, tertiary, Level I trauma center. We queried International Classification of Diseases Revision 10 codes most specific to IPV, sexual assault, and child maltreatment from March-October 2020 compared to 2019. Similarly, the number of consults performed by SANE, DVHP, and our Child Protection Team were collected. We compared all ED visits and consultations to total ED visits for the reviewed time period. Finally, the total number of calls and referrals to a child advocacy center and resource call line for victims were recorded during this timeframe. RESULTS: Police dispatches for IPV-related assaults increased by 266 reports from 2019 to 2020 (P = 0.015). Emergency department visits related to IPV increased from 0.11% of visits in 2019 to 0.15% in 2020 (P = 0.032), and DVHP consults increased from 0.31% in 2019 to 0.48% in 2020 of ED visits in the first three months (P < 0.001). Child maltreatment visits increased from 0.47% of visits in 2019 to 0.81% of visits in 2020 (P = 0.028), and a higher percentage of patients required Child Protection team consults from 1% in 2019 to 1.6% in 2020 (P = 0.004). Sexual assault-related visits and SANE consults both showed a small increase that was not statistically significant. Fewer calls and referrals were made to our child advocacy center and resource call line, decreasing by 99 referrals and 252 calls, respectively. CONCLUSION: Despite decreased ED volumes throughout the pandemic, we observed an increase in police dispatches, ED visits, and utilization of hospital consult services related to IPV and child maltreatment following the initiation of stay-at-home orders. However, use of community resources, such as the local child advocacy center, declined.

Can Digit Ratio (2D:4D) Be Indicative of Predispositions to Autoimmune Thyroid Diseases in Women - Hashimoto Thyroiditis and Graves' Disease?

Hashimoto thyroiditis and Graves' disease are autoimmune thyroid diseases which occur much more frequently in women than in men. Estrogen receptors are found in the thyroid gland and can modulate the gland's function. Digit ratio (2D:4D) is thought to be a negative correlate of prenatal testosterone and a positive correlate of prenatal estrogen. This study aimed to examine a relationship between right and left 2D:4D in women with Hashimoto thyroiditis and Graves' disease. The cross-sectional study included 106 women with autoimmune thyroid disease: 73 women diagnosed with Hashimoto thyroiditis and 33 women with Graves' disease, together with 70 healthy women as controls. Second and fourth digit length, weight, height were measured directly, and 2D:4D and BMI were calculated. Compared to controls, right and left 2D:4D were significantly higher in women with Hashimoto thyroiditis and lower in women with Graves' disease, the effects were higher for right 2D:4D. The mean length of right 4D was significantly lower in the examined women with Hashimoto thyroiditis than in Graves' disease. Higher right and left 2D:4D in women with Hashimoto thyroiditis suggests that prenatal exposure to high levels of estrogens relative to testosterone may play a role in the development of this disease. Lower right and left 2D:4D in women with Graves' disease suggest a role of high prenatal androgens relative to estrogens in Graves' disease pathogenesis.

Nodular Lymphocyte-predominant Hodgkin Lymphoma With Nodular Sclerosis: An Underrecognized Feature Associated With Pattern D.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) with unusual features, including some that can overlap morphologically with classic Hodgkin lymphoma (CHL), have been described. Herein, we describe 12 cases of NLPHL with fibrous bands and capsular fibrosis resembling, in part, nodular sclerosis (NS) CHL. Seven of 12 cases harbored Reed-Sternberg-like cells, further suggestive of CHL, but all cases lacked associated eosinophils and/or plasma cells in the background. In this cohort, all cases had areas of so-called pattern D (nodular T-cell rich) as a sole component in 7 (58%) cases or as a hybrid pattern along with pattern E (diffuse T-cell/histiocyte-rich) in 5 (42%) cases. The immunophenotype of the large neoplastic cells in these cases supported their being lymphocyte predominant cells of NLPHL, positive for CD20, CD79a, and OCT2, and negative for CD15 and CD30. However, PAX5 was weak in 9 of 11 cases similar to Hodgkin/Reed-Sternberg cells in CHL. We conclude that some cases of NLPHL are associated with fibrous bands and capsular fibrosis and resemble, in part, NS CHL. In our experience, NLPHL with NS-like features occurs in 10% to 15% of cases of NLPHL and is associated with a variant pattern (D and/or E). In addition, all patients in this cohort were not treated before biopsy, suggesting that the prominent sclerosis in these cases is inherent to disease biology. Recognition of NLPHL with NS-like features further expands the morphologic spectrum of NLPHL and helps avoid potential misdiagnosis as CHL.

CD2-negative lymphoma-associated T-cells: a potential mechanism of immune-evasion in diffuse large B-cell lymphoma.

CD2 is a costimulatory protein expressed in all mature T/NK-cells, in particular memory T-cells. CD58 (or LFA-3) is the receptor for CD2 and is ubiquitously expressed. CD2-CD58 interaction has key functions in T-cell activation and organization of the immunological synapse between T- and antigen-presenting cells. Cancer cells have developed multiple mechanisms to evade immune surveillance. Loss of CD58 expression is one frequently reported in diffuse large B-cell lymphomas (DLBCL). On the other hand, in non-hematological neoplasms, tumor infiltrating lymphocytes (TILs) with reduced expression of CD2 have been associated with defective cytotoxicity and T-cell exhaustion. Here, we reported a case of DLBCL involving the jejunal mucosa associated with a rim of cytotoxic reactive T-cells with features of immune evasion (CD2- and TCR-) and T-cell exhaustion (PD1 + high). This case likely exemplifies a previously unrecognized immune evasion mechanism in lymphoma involving a decreased CD2 expression in the lymphoma-associated T-cells.

CD4 T-cell depletion prevents Lassa fever associated hearing loss in the mouse model.

Lassa virus (LASV) is the causative agent of Lassa fever (LF), which presents as a lethal hemorrhagic disease in severe cases. LASV-induced hearing loss in survivors is a huge socioeconomic burden, however, the mechanism(s) leading to hearing loss is unknown. In this study, we evaluate in a mouse LF model the auditory function using auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE) to determine the mechanisms underlying LASV-induced hearing loss. In the process, we pioneered measures of ABR and DPOAE tests in rodents in biosafety level 4 (BSL-4) facilities. Our T cell depletion studies demonstrated that CD4 T-cells play an important role in LASV-induced hearing loss, while CD8 T-cells are critical for the pathogenicity in the acute phase of LASV infection. Results presented in this study may help to develop future countermeasures against acute disease and LASV-induced hearing loss.

Machupo Virus with Mutations in the Transmembrane Domain and Glycosylation Sites of the Glycoprotein Is Attenuated and Immunogenic in Animal Models of Bolivian Hemorrhagic Fever.

Several highly pathogenic mammarenaviruses cause severe hemorrhagic and neurologic disease in humans for which vaccines and antivirals are limited or unavailable. New World (NW) mammarenavirus Machupo virus (MACV) infection causes Bolivian hemorrhagic fever in humans. We previously reported that the disruption of specific N-linked glycan sites on the glycoprotein (GPC) partially attenuates MACV in an interferon alpha/beta and gamma (IFN-α/ß and -γ) receptor knockout (R-/-) mouse model. However, some capability to induce neurological pathology still remained. The highly pathogenic Junin virus (JUNV) is another NW arenavirus closely related to MACV. An F427I substitution in the GPC transmembrane domain (TMD) rendered JUNV attenuated in a lethal mouse model after intracranial inoculation. In this study, we rationally designed and rescued a MACV containing mutations at two glycosylation sites and the corresponding F438I substitution in the GPC TMD. The MACV mutant is fully attenuated in IFN-α/ß and -γ R-/- mice and outbred guinea pigs. Furthermore, inoculation with this mutant MACV completely protected guinea pigs from wild-type MACV lethal challenge. Last, we found the GPC TMD F438I substitution greatly impaired MACV growth in neuronal cell lines of mouse and human origins. Our results highlight the critical roles of the glycans and the TMD on the GPC in arenavirus virulence, which provide insight into the rational design of potential vaccine candidates for highly pathogenic arenaviruses. IMPORTANCE For arenaviruses, the only vaccine available is the live attenuated Candid#1 vaccine, a JUNV vaccine approved in Argentina. We and others have found that the glycans on GPC and the F427 residue in the GPC TMD are important for virulence of JUNV. Nevertheless, mutating either of them is not sufficient for full and stable attenuation of JUNV. Using reverse genetics, we disrupted specific glycosylation sites on MACV GPC and also introduced the corresponding F438I substitution in the GPC TMD. This MACV mutant is fully attenuated in two animal models and protects animals from lethal infection. Thus, our studies highlight the feasibility of rational attenuation of highly pathogenic arenaviruses for vaccine development. Another important finding from this study is that the F438I substitution in GPC TMD could substantially affect MACV replication in neurons. Future studies are warranted to elucidate the underlying mechanism and the implication of this mutation in arenavirus neural tropism.