Efficient therapeutic options are needed to control the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that has caused more than 922,000 fatalities as of 13 September 2020. We ...report the isolation and characterization of two ultrapotent SARS-CoV-2 human neutralizing antibodies (S2E12 and S2M11) that protect hamsters against SARS-CoV-2 challenge. Cryo-electron microscopy structures show that S2E12 and S2M11 competitively block angiotensin-converting enzyme 2 (ACE2) attachment and that S2M11 also locks the spike in a closed conformation by recognition of a quaternary epitope spanning two adjacent receptor-binding domains. Antibody cocktails that include S2M11, S2E12, or the previously identified S309 antibody broadly neutralize a panel of circulating SARS-CoV-2 isolates and activate effector functions. Our results pave the way to implement antibody cocktails for prophylaxis or therapy, circumventing or limiting the emergence of viral escape mutants.
Our objective was to investigate the effects of prepartum metabolizable protein (MP) supply and management strategy on milk production and blood biomarkers in early lactation dairy cows. Ninety-six ...multigravida Holstein cows were used in a randomized complete block design study, blocked by calving date, and then assigned randomly to 1 of 3 treatments within block. Cows on the first treatment were fed a far-off lower MP diet MP = 83 g/kg of dry matter (DM) between −55 and −22 d before expected calving and then a close-up lower MP diet (MP = 83 g/kg of DM) until parturition (LPLP). Cows on the second treatment were fed the far-off lower MP diet between −55 to −22 d before expected parturition and then a prepartum higher MP diet (MP = 107 g/kg of DM) until calving (LPHP). Cows on the third treatment had a shortened 43-d dry period and were fed the prepartum higher MP diet from dry-off to parturition (SDHP). After calving, cows received the same fresh diet from d 0 to 14 and the same high diet from d 15 to 84. Data were analyzed separately for wk −6 to −1 and wk 1 to 12, relative to parturition. Dry matter intake from wk −6 to −1 was not different between LPHP and LPLP and increased for SDHP compared with LPLP. In contrast, dry matter intake for wk 1 to 12 postpartum did not change for LPHP versus LPLP or for SDHP versus LPLP. Compared with LPLP cows, LPHP cows had lower energy-corrected milk yield and tended to have decreased milk fat yield during wk 1 to 12 of lactation. Conversely, yields of energy-corrected milk and milk fat and protein were similar for SDHP compared with LPLP. Plasma urea N during wk −3 to −1 increased for LPHP versus LPLP and for SDHP versus LPLP; however, no differences in plasma urea N were observed postpartum. Elevated prepartum MP supply did not modify circulating total fatty acids, β-hydroxybutyrate, total protein, albumin, or aspartate aminotransferase during the prepartum and postpartum periods. Increased MP supply prepartum combined with a shorter dry period (SDHP vs. LPLP) tended to increase whole-blood β-hydroxybutyrate postpartum; however, other blood metabolites were not affected. Taken together, under the conditions of this study, elevated MP supply in close-up diets reduced milk production without affecting blood metabolites in multiparous dairy cows during early lactation. A combination of a shorter dry period and increased prepartum MP supply (i.e., SDHP vs. LPLP) improved prepartum dry matter intake without modifying energy-corrected milk yield and blood biomarkers in early lactation cows.
Abstract
The objective was to evaluate the effects of peripartum supplementation of a methionine hydroxy analogue (MHA) to primiparous, spring-calving beef females on dam and progeny performance. ...Angus heifers (n = 60) were blocked by expected parturition date, stratified by body weight (BW) and body condition score (BCS), and randomized to 1 of 15 pens. Pens were randomly assigned to 1 of 3 dietary treatments: a basal diet supplemented with 0 (M0), 15 (M15), or 30 (M30) g/animal/d of MHA (provided as MFP feed supplement, Novus International Inc., St. Charles, MO). Diets were fed from 45 ± 13 (SD) d pre-calving through 81 ± 13 d postpartum (DPP), after which all cow–calf pairs were managed as a single group on pasture until weaning (199 ± 13 DPP). Dam BW, BCS, and blood samples were taken at 6 predetermined timepoints. Progeny data were collected at birth, 2 intermediate timepoints, and at weaning. Milk samples were collected for composition analysis at 7 ± 2 DPP and at 55 ± 5 DPP. Serial progesterone samples were analyzed to establish resumption of cyclicity, and ultrasonography was performed at 55 ± 5 DPP to evaluate ovarian function. Cows were bred via artificial insemination at 82 ± 13 DPP and subsequently exposed to bulls for a 55-d breeding season. Pen was the experimental unit, and preplanned orthogonal contrasts were tested (linear effect and M0 vs. M15 + M30). Dam BW and BCS were not affected by treatment (P ≥ 0.29) throughout the study. Week 1 milk fat concentration increased linearly (P = 0.05) and total solids tended to increase linearly (P = 0.07) as MHA increased; however, no other milk components were affected (P ≥ 0.16). Treatment did not affect (P ≥ 0.16) dam reproductive parameters or progeny growth from birth until weaning. Post-calving, circulating methionine equivalents tended to linearly increase (P = 0.10) with increasing MHA supplementation. At breeding, plasma urea N linearly decreased (P = 0.03) with increased supplementation of MHA, and plasma non-esterified fatty acids were less (P = 0.04) in MHA-supplemented dams compared with dams receiving no MHA. Maternal circulating glucose, glutathione peroxidase, and thiobarbituric acid-reactive substances were not affected (P ≥ 0.15) by treatment at any point. These data indicate that peripartum supplementation of MHA may increase milk fat composition shortly after calving, but MHA supplementation did not improve progeny growth or dam reproductive performance in the current study.
Abstract
To determine effects of Cu, Zn, and Mn source and inclusion during late gestation, multiparous beef cows n = 48; 649 ± 80 kg body weight (BW); 5.3 ± 0.5 body condition score (BCS) were ...individually-fed hay and supplement to meet or exceed all nutrient recommendations except Cu, Zn, and Mn. From 91.2 ± 6.2 d pre-calving to 11.0 ± 3.2 d post-calving, cows received: no additional Cu, Zn, or Mn (control, CON), sulfate-based Cu, Zn, and Mn (inorganic, ITM) or metal methionine hydroxy analogue chelates (MMHAC) of Cu, Zn, and Mn at 133% recommendations, or a combination of inorganic and chelated Cu, Zn, and Mn (reduce and replace, RR) to meet 100% of recommendations. Data were analyzed with treatment and breeding group (and calf sex if P < 0.25 for offspring measures) as fixed effects, animal as experimental unit, and sampling time as a repeated effect for serum, plasma, and milk measures over time. Post-calving cow liver Cu was greater (P ≤ 0.07) in MMHAC compared with all other treatments. Calves born to RR had greater (P ≤ 0.05) liver Cu than ITM and CON, and MMHAC had greater (P = 0.06) liver Cu than CON. Liver Mn was less (P ≤ 0.08) for RR calves than all other treatments. Calf plasma Zn was maintained (P ≥ 0.15) from 0 to 48 h of age in ITM and MMHAC but decreased (P ≤ 0.03) in CON and RR. Gestational cow BW, BCS, and metabolites were not affected (P ≥ 0.13) by treatment, but gestational serum thiobarbituric acid reactive substances (TBARS) were greater (P = 0.01) for CON than MMHAC. Treatment did not affect (P ≥ 0.13) calf birth size, vigor, placental size and minerals, or transfer of passive immunity. Neonatal calf serum Ca was greater (P ≤ 0.05) for MMHAC than all other treatments; other calf serum chemistry and plasma cortisol were not affected (P ≥ 0.12). Pre-suckling colostrum yield, and lactose concentration and content, were greater (P ≤ 0.06) for MMHAC compared with ITM and RR. Colostral triglyceride and protein concentrations were greater (P ≤ 0.08) for RR than MMHAC and CON. Cow lactational BW and BCS, milk yield and composition, and pre-weaning calf BW and metabolism were not affected (P ≥ 0.13) by treatment. Lactational serum TBARS were greater (P = 0.04) for RR than CON at day 35 and greater (P ≤ 0.09) for MMHAC at day 60 than all other treatments. Source and inclusion of Cu, Zn, and Mn altered maternal and neonatal calf mineral status, but calf size and vigor at birth, passive transfer, and pre-weaning growth were not affected in this study.
This study investigated the effects of expressing through writing either positive feelings, negative feelings, or both about an upsetting event in order to assess which mode of expression facilitated ...greater emotional and cognitive processing. Undergraduate student participants with self-reported unresolved upsetting experiences were randomly assigned to one of three writing groups. After completing three writing sessions, they were evaluated at baseline, postexperimentally, and at 1-month follow-up. All groups experienced positive benefits; however, participants in the positive writing group showed greater adaptive cognitive changes than the other groups. Thus it appears that the written expression of positive feelings is as therapeutic as the written expression of negative emotions, which may prompt increased cognitive reorganization or benefit finding among a nonclinical sample.
An ideal therapeutic anti-SARS-CoV-2 antibody would resist viral escape
, have activity against diverse sarbecoviruses
, and be highly protective through viral neutralization
and effector functions
. ...Understanding how these properties relate to each other and vary across epitopes would aid the development of therapeutic antibodies and guide vaccine design. Here we comprehensively characterize escape, breadth and potency across a panel of SARS-CoV-2 antibodies targeting the receptor-binding domain (RBD). Despite a trade-off between in vitro neutralization potency and breadth of sarbecovirus binding, we identify neutralizing antibodies with exceptional sarbecovirus breadth and a corresponding resistance to SARS-CoV-2 escape. One of these antibodies, S2H97, binds with high affinity across all sarbecovirus clades to a cryptic epitope and prophylactically protects hamsters from viral challenge. Antibodies that target the angiotensin-converting enzyme 2 (ACE2) receptor-binding motif (RBM) typically have poor breadth and are readily escaped by mutations despite high neutralization potency. Nevertheless, we also characterize a potent RBM antibody (S2E12
) with breadth across sarbecoviruses related to SARS-CoV-2 and a high barrier to viral escape. These data highlight principles underlying variation in escape, breadth and potency among antibodies that target the RBD, and identify epitopes and features to prioritize for therapeutic development against the current and potential future pandemics.
Abstract
An adequate supply of Zn should effectively reach tissues to support fundamental physiological functions. This study compared tissue enrichment using stable Zn isotopes when fed as ...methionine hydroxy analog chelate (Zn-MHAC Novus International Inc., St. Charles, MO) or an amino acid complex (Zn-AAC) in growing pigs. Twenty gilts (31.5 ± 2.8 kg BW) were individually housed and fed a common diet (corn-soy-based with phytase) with 26 mg/kg of Zn from ingredients and 15 mg/kg supplemented as Zn sulfate. At d 28, pigs were surgically catheterized in the jugular vein and moved to metabolism crates. After 2 d of recovery, 16 pigs were randomly selected to receive an oral bolus containing 1 of 2 doses (8 or 12 mg) of Zn67 in the form of Zn-AAC (8 or 12 mg) and Zn70 in the form of Zn-MHAC. The remaining 4 pigs received a placebo bolus and served as controls. Blood samples were collected periodically between -15 and 1,440 min relative to bolus. Total urine and fecal output were collected at 0, 6, 12, and 24 h relative to bolus. All pigs were euthanized 24 h after bolus to harvest tissues. Zinc isotope enrichment was calculated from analyzed samples as the difference of Zn67 and Zn70 portions between control and isotope-bolused pigs. Data were analyzed as a 2×2 factorial (mineral source×dose) using PROC MIXED procedure of SAS. No interactions between trace mineral source and isotope dose for any tested variables were observed. Gastrointestinal and central metabolism tissues, including stomach, duodenum, jejunum, ileum, pancreas, liver, and kidney, demonstrated greater enrichment from Zn-MHAC than Zn-AAC (P ≤ 0.001). In reproductive tissues, ovary showed similar Zn enrichment between Zn-MHAC and Zn-ACC (P = 0.841). However, there was greater enrichment from Zn-MHAC than Zn-AAC in the uterus (P = 0.002). For musculoskeletal tissues, despite a numerical increase for Zn-MHAC compared with Zn-AAC, there was no significant difference of Zn source on enrichment of metacarpal bones (P = 0.190). The hoof matrix tended to have greater enrichment from Zn-MHAC than Zn-AAC (P = 0.097). There were no differences between trace mineral sources on enrichment of Zn in the muscle (P = 0.839). Immune tissues, including thymus (P < 0.001) and spleen (P = 0.017), demonstrated greater enrichment from Zn-MHAC than Zn-AAC. Despite a numerical increase with Zn-MHAC, plasma area under the curve (AUC) was not significantly different between Zn-MHAC and Zn-AAC (P = 0.467). Similarly, despite a numerical increase, the higher dose of Zn isotope did not significantly increase (P > 0.050) enrichment in gastrointestinal, central metabolic, reproductive, musculoskeletal (except for muscle: P = 0.042), immune tissues, or plasma AUC. There were no differences in Zn AUC (0-24h; P > 0.100) enrichment between trace mineral source and dose in feces and urine. In conclusion, Zn-MHAC delivered more Zn to physiologically important tissues that support productivity and health of pigs than Zn-AAC.
•Cinnamaldehyde supplementation increased nitrogen use-efficiency to sustain synthesis of ECM.•Dietary supplementation of cinnamaldehyde may be used to improve nitrogen metabolism and increase feed ...use-efficiency in lactating dairy cows.
Dietary supplementation of essential oils (EO) may increase milk yield and feed use-efficiency in Holstein cattle. A study was conducted to determine the effect of EO feed additives in dairy cattle productivity. The hypothesis was that compared with cinnamaldehyde feed additive supplementation, the supplementation with an additive containing a blend of cinnamaldehyde and garlic oil would improve feed use-efficiency in lactating dairy cattle. Forty-eight lactating Holstein cows (34 multiparous, days in milk (DIM) 118 ± 31.1, and 14 primiparous, DIM 134 ± 38.8) were enroled and randomly assigned to one of three treatments for 8 weeks: 1) control diet (CTRL; no EO supplementation; n = 16), 2) supplementation with cinnamaldehyde (CIN; 600 mg of a prototype to provide 125 mg of cinnamaldehyde; Novus International Inc., St. Charles, MO; n = 16), or 3) supplementation with essential oil blend (EOB; Next Enhance® CGO feed additive, Novus International Inc., St. Charles, MO; to provide 125 mg of cinnamaldehyde and 10 mg of garlic oil; n = 16). Cows were housed in a free-stall barn and the diet was offered as total mixed ration (TMR) formulated with 36% forage and 64% concentrate. The TMR was fed individually and EO additives were top-dressed. Production data were collected and analyzed using the Mixed procedure of SAS (version 9.4) where the fixed effects of treatment, time (i.e., week or day, as repeated measurements), and all possible interactions were included in the model. Compared with CTRL, CIN and EOB decreased (P < 0.05) dry matter intake (DMI, 30.1, 28.2, and 29.6 kg/day respectively). Yields of milk, fat, protein and lactose, and percentage of fat, protein and lactose were not affected by treatments. Compared with CTRL, CIN and EOB decreased (P < 0.05) milk urea nitrogen (MUN) concentrations (11.8, 10.9 and 11.4 mg/dL, respectively). Compared with CTRL, EOB reduced (P < 0.05) somatic cell count (126 and 84 × 103 cells/mL, respectively). Body weight, body condition score, and plasma free fatty acid concentrations were not affected by treatments. Compared with CTRL and EOB, CIN increased (P < 0.05) energy-corrected milk yield (ECM) to DMI ratio (1.63, 1.64 and 1.68, respectively). Moreover, there was a tendency (P < 0.10) for EOB and CIN treatments to increase milk yield to DMI ratio. Compared with CTRL, CIN elicited an increase (P < 0.05) in the conversion efficiency of dietary nitrogen into milk protein (28.1 and 28.7%, respectively). In our study, CIN supplementation increased nitrogen use-efficiency to sustain synthesis of ECM. Therefore, dietary supplementation of cinnamaldehyde may be used to improve nitrogen metabolism and increase feed use-efficiency in lactating dairy cows.
PDF
